Ranjana Advani

All Publications

• Integrating Novel Agents Into the Clinical Management of Classic Hodgkin Lymphoma. JCO oncology practice Schroers-Martin, J. G., Advani, R. 2024: OP2400277

  Abstract

  Classic Hodgkin lymphoma (cHL) is highly curable at all stages. Research efforts over the past few decades have largely focused on interim PET-adapted strategies for therapy de-escalation or intensification. The overarching goals have been to increase cure rates, minimize potential therapy-related effects, and optimize survivorship. Better understanding of the biology of cHL has led to the development and approval of effective novel agents including the antibody-drug conjugate brentuximab vedotin and the checkpoint inhibitor immunotherapies. In this review, we discuss recent trial results and how these agents are integrated into clinical practice with the goal of further optimizing outcomes.

  View details for DOI 10.1200/OP.24.00277

  View details for PubMedID 39265129

• Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. The New England journal of medicine Ansell, S. M., Radford, J., Connors, J. M., Dlugosz-Danecka, M., Kim, W., Gallamini, A., Ramchandren, R., Friedberg, J. W., Advani, R., Hutchings, M., Evens, A. M., Smolewski, P., Savage, K. J., Bartlett, N. L., Eom, H., Abramson, J. S., Dong, C., Campana, F., Fenton, K., Puhlmann, M., Straus, D. J., ECHELON-1 Study Group 2022

  Abstract

  BACKGROUND: Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.METHODS: We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.RESULTS: A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P=0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.CONCLUSIONS: Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).

  View details for DOI 10.1056/NEJMoa2206125

  View details for PubMedID 35830649

• Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial LANCET Horwitz, S., O'Connor, O. A., Pro, B., Illidge, T., Fanale, M., Advani, R., Bartlett, N. L., Christensen, J., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W., Feldman, T., Lennard, A., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Shustov, A., Huttmann, A., Savage, K. J., Yuen, S., Iyer, S., Zinzani, P., Hua, Z., Little, M., Rao, S., Woolery, J., Manley, T., Trumper, L., Aboulafia, D., Alpdogan, O., Ando, K., Arcaini, L., Baldini, L., Bellam, N., Bartlett, N., Ben Yehuda, D., Benedetti, F., Borchman, P., Bordessoule, D., Brice, P., Briones, J., Caballero, D., Carella, A., Chang, H., Cheong, J., Cho, S., Choi, I., Choquet, S., Colita, A., Congui, A., D'amore, F., Dang, N., Davison, K., De Guibert, S., Brown, P., Delwail, V., Demeter, J., di Raimondo, F., Do, Y., Domingo, E., Douvas, M., Dreyling, M., Ernst, T., Fay, K., Ferrero, S., Flinn, I., Forero-Torres, A., Fox, C., Friedberg, J., Fukuhara, N., Garcia-Marco, J., Cruz, J., Codina, J., Gressin, R., Grigg, A., Gurion, R., Haioun, C., Hajek, R., Hanel, M., Hatake, K., Hensen, R., Horowitz, N., Huttmann, A., Ishizawa, K., Islas-Ohlmayer, M., Jacobsen, E., Janakiram, M., Jurczak, W., Kaminski, M., Kato, K., Kirgner, I., Kuo, C., Lazaroiu, M., Le Du, K., Lee, J., Legouill, S., Larosee, P., Levi, I., Link, B., Maisonneuve, H., Maruyama, D., Mayer, J., McCarty, J., McKay, P., Minami, Y., Mocikova, H., Morra, E., Munoz, J., Nagai, H., O'Connor, O., Opat, S., Pettengell, R., Pezzutto, A., Pfreundschuh, M., Pluta, A., Porcu, P., Quach, H., Rambaldi, A., Renwick, W., Reyes, R., Izquierdo, A., Ruan, J., Rusconi, C., Salles, G., Santoro, A., Sarriera, J., Savage, K., Shibayama, H., Suh, C., Sureda, A., Tanimoto, M., Taniwaki, M., Tilly, H., Trneny, M., Trumper, L., Tsukamoto, N., Vitolo, U., Walewski, J., Weidmann, E., Wilhelm, M., Witzens-Harig, M., Yacoub, A., Yamamoto, K., Yoon, S., Yun, H., Zain, J., Zinzan, P., ECHELON 2 Study Grp 2019; 393 (10168): 229–40

  View details for DOI 10.1016/S0140-6736(18)32984-2

  View details for Web of Science ID 000456000000026

• Modern principles in the management of nodular lymphocyte-predominant Hodgkin lymphoma BRITISH JOURNAL OF HAEMATOLOGY Spinner, M. A., Varma, G., Advani, R. H. 2019; 184 (1): 17–29

  View details for DOI 10.1111/bjh.15616

  View details for Web of Science ID 000454410300005

• Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet (London, England) Horwitz, S., O'Connor, O. A., Pro, B., Illidge, T., Fanale, M., Advani, R., Bartlett, N. L., Christensen, J. H., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W. S., Feldman, T., Lennard, A., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Shustov, A., Huttmann, A., Savage, K. J., Yuen, S., Iyer, S., Zinzani, P. L., Hua, Z., Little, M., Rao, S., Woolery, J., Manley, T., Trumper, L., ECHELON-2 Study Group, Aboulafia, D., Advani, R., Alpdogan, O., Ando, K., Arcaini, L., Baldini, L., Bellam, N., Bartlett, N., Belada, D., Yehuda, D. B., Benedetti, F., Borchman, P., Bordessoule, D., Brice, P., Briones, J., Caballero, D., Carella, A. M., Chang, H., Cheong, J. W., Cho, S., Choi, I., Choquet, S., Colita, A., Congui, A. G., D'amore, F., Dang, N., Davison, K., de Guibert, S., Brown, P. d., Delwail, V., Demeter, J., di Raimondo, F., Do, Y. R., Domingo, E., Douvas, M., Dreyling, M., Ernst, T., Fanale, M., Fay, K., Feldman, T., Ferrero, S. F., Flinn, I. W., Forero-Torres, A., Fox, C., Friedberg, J., Fukuhara, N., Garcia-Marco, J., Cruz, J. G., Codina, J. G., Gressin, R., Grigg, A., Gurion, R., Christensen, J. H., Haioun, C., Hajek, R., Hanel, M., Hatake, K., Hensen, R., Horowitz, N., Horwitz, S., Huttmann, A., Illes, A., Illidge, T., Ishizawa, K., Islas-Ohlmayer, M., Jacobsen, E., Janakiram, M., Jurczak, W., Kaminski, M., Kato, K., Kim, W. S., Kirgner, I., Iyer, S., Kuo, C., Lazaroiu, M. C., Du, K. L., Lee, J., LeGouill, S., Lennard, A., LaRosee, P., Levi, I., Link, B., Maisonneuve, H., Maruyama, D., Mayer, J., McCarty, J., McKay, P., Minami, Y., Mocikova, H., Morra, E., Morschhauser, F., Munoz, J., Nagai, H., O'Connor, O., Opat, S., Pettengell, R., Pezzutto, A., Pfreundschuh, M., Pluta, A., Porcu, P., Pro, B., Quach, H., Rambaldi, A., Renwick, W., Reyes, R., Izquierdo, A. R., Rossi, G., Ruan, J., Rusconi, C., Salles, G., Santoro, A., Sarriera, J., Savage, K., Shibayama, H., Shustov, A., Suh, C., Sureda, A., Tanimoto, M., Taniwaki, M., Tilly, H., Tobinai, K., Trneny, M., Trumper, L., Tsukamoto, N., Tsukasaki, K., Vitolo, U., Walewski, J., Weidmann, E., Wilhelm, M., Witzens-Harig, M., Yacoub, A., Yamamoto, K., Yeh, S., Yoon, S., Yuen, S., Yun, H. J., Zain, J., Zinzani, P. L. 2018

  Abstract

  BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

  View details for PubMedID 30522922

• CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma NEW ENGLAND JOURNAL OF MEDICINE Advani, R., Flinn, I., Popplewell, L., Forero, A., Bartlett, N. L., Ghosh, N., Kline, J., Roschewski, M., LaCasce, A., Collins, G. P., Thu Tran, Lynn, J., Chen, J. Y., Volkmer, J., Agoram, B., Huang, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Chao, M. P., Smith, S. M. 2018; 379 (18): 1711–21

  View details for DOI 10.1056/NEJMoa1807315

  View details for Web of Science ID 000448891600006

• Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma JOURNAL OF CLINICAL ONCOLOGY Evens, A. M., Advani, R. H., Helenowski, I. B., Fanale, M., Smith, S. M., Jovanovic, B. D., Bociek, G. R., Klein, A. K., Winter, J. N., Gordon, L. I., Hamlin, P. A. 2018; 36 (30): 3015-+

  View details for DOI 10.1200/JCO.2018.79.0139

  View details for Web of Science ID 000447725000007

• Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Evens, A. M., Advani, R. H., Helenowski, I. B., Fanale, M., Smith, S. M., Jovanovic, B. D., Bociek, G. R., Klein, A. K., Winter, J. N., Gordon, L. I., Hamlin, P. A. 2018: JCO2018790139

  Abstract

  Purpose To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. Patients and Methods We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. Results Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively ( P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% ( P < .001), respectively, the latter persisting on multivariable analyses. Conclusion Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.

  View details for PubMedID 30179569

• End-of-treatment and serial PET imaging in primary mediastinal B-cell lymphoma following dose-adjusted EPOCH-R: a paradigm shift in clinical decision making HAEMATOLOGICA Melani, C., Advani, R., Roschewski, M., Walters, K. M., Chen, C. C., Baratto, L., Ahlman, M. A., Miljkovic, M. D., Steinberg, S. M., Lam, J., Shovlin, M., Dunleavy, K., Pittaluga, S., Jaffe, E. S., Wilson, W. H. 2018; 103 (8): 1337–44

  Abstract

  Dose-adjusted-EPOCH-R obviates the need for radiotherapy in most patients with primary mediastinal B-cell lymphoma. End-of-treatment PET, however, does not accurately identify patients at risk of treatment failure, thereby confounding clinical decision making. To define the role of PET in primary mediastinal B-cell lymphoma following dose-adjusted-EPOCH-R, we extended enrollment and follow up on our published phase II trial and independent series. Ninety-three patients received dose-adjusted-EPOCH-R without radiotherapy. End-of-treatment PET was performed in 80 patients, of whom 57 received 144 serial scans. One nuclear medicine physician from each institution blindly reviewed all scans from their respective institution. End-of-treatment PET was negative (Deauville 1-3) in 55 (69%) patients with one treatment failure (8-year event-free and overall survival of 96.0% and 97.7%). Among 25 (31%) patients with a positive (Deauville 4-5) end-of-treatment PET, there were 5 (20%) treatment failures (8-year event-free and overall survival of 71.1% and 84.3%). Linear regression analysis of serial scans showed a significant decrease in SUVmax in positive end-of-treatment PET non-progressors compared to an increase in treatment failures. Among 6 treatment failures, the median end-of-treatment SUVmax was 15.4 (range, 1.9-21.3), and 4 achieved long-term remission with salvage therapy. Virtually all patients with a negative end-of-treatment PET following dose-adjusted-EPOCH-R achieved durable remissions and should not receive radiotherapy. Among patients with a positive end-of-treatment PET, only 5/25 (20%) had treatment-failure. Serial PET imaging distinguished end-of-treatment PET positive patients without treatment failure, thereby reducing unnecessary radiotherapy by 80%, and should be considered in all patients with an initial positive PET following dose-adjusted-EPOCH-R (clinicaltrials.gov identifier 00001337).

  View details for PubMedID 29748435

• Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma BLOOD LaCasce, A. S., Bociek, R., Sawas, A., Caimi, P., Agura, E., Matous, J., Ansell, S. M., Crosswell, H. E., Islas-Ohlmayer, M., Behler, C., Cheung, E., Forero-Torres, A., Vose, J., O'Connor, O. A., Josephson, N., Wang, Y., Advani, R. 2018; 132 (1): 40–48

  Abstract

  Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.

  View details for DOI 10.1182/blood-2017-11-815183

  View details for Web of Science ID 000439126500010

  View details for PubMedID 29703778

• The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project HAEMATOLOGICA Bellei, M., Foss, F. M., Shustov, A. R., Horwitz, S. M., Marcheselli, L., Kim, W., Cabrera, M. E., Dlouhy, I., Nagler, A., Advani, R. H., Pesce, E. A., Ko, Y., Martinez, V., Montoto, S., Chiattone, C., Moskowitz, A., Spina, M., Biasoli, I., Manni, M., Federico, M., Int T-cell Project Network 2018; 103 (7): 1191–97

  Abstract

  This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P<0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively (P<0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, P=0.001), whereas late relapse (>12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation.

  View details for PubMedID 29599200

• Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network BRITISH JOURNAL OF HAEMATOLOGY Federico, M., Bellei, M., Marcheselli, L., Schwartz, M., Manni, M., Tarantino, V., Pileri, S., Ko, Y., Cabrera, M. E., Horwitz, S., Kim, W. S., Shustov, A., Foss, F. M., Nagler, A., Carson, K., Pinter-Brown, L. C., Montoto, S., Spina, M., Feldman, T. A., Lechowicz, M. J., Smith, S. M., Lansigan, F., Gabus, R., Vose, J. M., Advani, R. H., T Cell Project Network 2018; 181 (6): 760–69

  Abstract

  Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.

  View details for PubMedID 29672827

• Activity and tolerabilty of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: Initial phase 1b/2 results. Advani, R. H., Flinn, I., Popplewell, L., Forero-Torres, A., Bartlett, N. L., Ghosh, N., Kline, J., Tran, T., Lynn, J., Chen, J. Y., Agoram, B., Huang, J., Takimoto, C. M., Chao, M., Smith, S. M. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.7504

  View details for Web of Science ID 000442916002575

• Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma BLOOD Herrera, A. F., Moskowitz, A. J., Bartlett, N. L., Vose, J. M., Ramchandren, R., Feldman, T. A., LaCasce, A. S., Ansell, S. M., Moskowitz, C. H., Fenton, K., Ogden, C., Taft, D., Zhang, Q., Kato, K., Campbell, M., Advani, R. H. 2018; 131 (11): 1183–94

  Abstract

  In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

  View details for PubMedID 29229594

• Allogeneic transplantation using TLI-ATG conditioning for Hodgkin lymphoma after failure of autologous transplantation. Blood advances Spinner, M. A., Advani, R. H., Hoppe, R. T., Lowsky, R. n., Muffly, L. S. 2018; 2 (13): 1547–50

  View details for PubMedID 29970391

• CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma. The New England journal of medicine Advani, R., Flinn, I., Popplewell, L., Forero, A., Bartlett, N. L., Ghosh, N., Kline, J., Roschewski, M., LaCasce, A., Collins, G. P., Tran, T., Lynn, J., Chen, J. Y., Volkmer, J., Agoram, B., Huang, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Chao, M. P., Smith, S. M. 2018; 379 (18): 1711–21

  Abstract

  BACKGROUND: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.METHODS: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose.RESULTS: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.CONCLUSIONS: The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .).

  View details for PubMedID 30380386

• PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. Journal of clinical oncology Roemer, M. G., Advani, R. H., Ligon, A. H., Natkunam, Y., Redd, R. A., Homer, H., Connelly, C. F., Sun, H. H., Daadi, S. E., Freeman, G. J., Armand, P., Chapuy, B., De Jong, D., Hoppe, R. T., Neuberg, D. S., Rodig, S. J., Shipp, M. A. 2016; 34 (23): 2690-2697

  Abstract

  Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS).Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

  View details for DOI 10.1200/JCO.2016.66.4482

  View details for PubMedID 27069084

• A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis LANCET ONCOLOGY Kim, S. J., Yoon, D. H., Jaccard, A., Chng, W. J., Lim, S. T., Hong, H., Park, Y., Chang, K. M., Maeda, Y., Ishida, F., Shin, D., Kim, J. S., Jeong, S. H., Yang, D., Jo, J., Lee, G., Choi, C. W., Lee, W., Chen, T., Kim, K., Jung, S., Murayama, T., Oki, Y., Advani, R., d'Amore, F., Schmitz, N., Suh, C., Suzuki, R., Kwong, Y. L., Lin, T., Kim, W. S. 2016; 17 (3): 389-400

  Abstract

  The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted.We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort.We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group.PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy.Samsung Biomedical Research Institute.

  View details for DOI 10.1016/S1470-2045(15)00533-1

  View details for PubMedID 26873565

• A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. British journal of haematology Advani, R. H., Ansell, S. M., Lechowicz, M. J., Beaven, A. W., Loberiza, F., Carson, K. R., Evens, A. M., Foss, F., Horwitz, S., Pro, B., Pinter-Brown, L. C., Smith, S. M., Shustov, A. R., Savage, K. J., M Vose, J. 2016; 172 (4): 535-544

  Abstract

  Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survial, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

  View details for DOI 10.1111/bjh.13855

  View details for PubMedID 26627450

• Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era BRITISH JOURNAL OF HAEMATOLOGY Diefenbach, C. S., Li, H., Hong, F., Gordon, L. I., Fisher, R. I., Bartlett, N. L., Crump, M., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J., Advani, R. H. 2015; 171 (4): 530-538

  Abstract

  The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

  View details for DOI 10.1111/bjh.13634

  View details for PubMedID 26343802

• Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease—the Role of Functional Imaging. Current treatment options in oncology Iberri, D. J., Hoppe, R. T., Advani, R. H. 2015; 16 (9): 45-?

  Abstract

  Early-stage classical Hodgkin lymphoma (CHL) is a highly curable malignancy. Historically, extended-field radiotherapy (EFRT) alone showed excellent cure rates, but the risk of radiotherapy (RT)-associated toxicities led to combined modality therapy (CMT) replacing RT alone. RT has subsequently evolved further with significant reductions of dose and field size, and is currently restricted to involved sites only (ISRT). Contemporary CMT yields cure rates in excess of 85 %, and most studies do not have adequate follow-up required to evaluate the risk reduction in late effects. In an effort to avoid RT altogether, response-adapted treatment approaches utilizing results of interim [(18)F]fluorodeoxyglucose (FDG) positron emission tomography with fused computed tomography (PET/CT) imaging have been studied. Results from two studies in favorable-risk (UK RAPID and EORTC H10F) and one in unfavorable-risk patients (EORTC H10U) suggest that omission of RT in patients with a negative interim PET/CT response (Deauville score ≤2) yields slightly inferior progression-free survival (PFS) compared to conventional CMT, but with no difference in overall survival (OS) albeit with short-term follow-up. In order to extrapolate results to daily practice, it is critical to understand the selection of patients entered on trials since definitions of favorable and unfavorable disease vary between study groups. Currently, CMT continues to be the standard of care for the vast majority of patients with early-stage CHL and RT is an integral part of therapy in patients with bulky disease. However, for selected patients with favorable characteristics, emerging data suggest that a chemotherapy-alone approach is reasonable.

  View details for DOI 10.1007/s11864-015-0360-6

  View details for PubMedID 26187795

• Response-adapted therapy for aggressive non-Hodgkin's lymphomas based on early [18F] FDG-PET scanning: ECOG-ACRIN Cancer Research Group study (E3404) BRITISH JOURNAL OF HAEMATOLOGY Swinnen, L. J., Li, H., Quon, A., Gascoyne, R., Hong, F., Ranheim, E. A., Habermann, T. M., Kahl, B. S., Horning, S. J., Advani, R. H. 2015; 170 (1): 56-65

  Abstract

  A persistently positive positron emission tomography (PET) scan during therapy for diffuse large B-cell lymphoma (DLBCL) is predictive of treatment failure. A response-adapted strategy consisting of an early treatment change to four cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET-positive patients received four cycles of R-ICE, PET-negative patients received two more cycles of R-CHOP. A ≥45% 2-year progression-free survival (PFS) for mid-treatment PET-positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two-year PFS was 70%; 42% [90% confidence interval (CI), 19-63%] for PET-positives and 76% (90% CI 65-84%) for PET-negatives. Three-year overall survival (OS) was 69% (90% CI 43-85%) and 93% (90% CI 86-97%) for PET-positive and -negative cases, respectively. The 2-year PFS for mid-treatment PET-positive patients intensified to R-ICE was 42%, with a wide confidence interval due to the low proportion of positive mid-treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

  View details for DOI 10.1111/bjh.13389

  View details for PubMedID 25823885

• Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial. Journal of clinical oncology Advani, R. H., Hong, F., Fisher, R. I., Bartlett, N. L., Robinson, K. S., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Gordon, L. I., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J. 2015; 33 (17): 1936-1942

  Abstract

  The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

  View details for DOI 10.1200/JCO.2014.57.8138

  View details for PubMedID 25897153

• Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial JOURNAL OF CLINICAL ONCOLOGY Advani, R. H., Hong, F., Fisher, R. I., Bartlett, N. L., Robinson, K. S., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Gordon, L. I., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J. 2015; 33 (17): 1936-U111

  Abstract

  The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

  View details for DOI 10.1200/JCO.2014.57.8138

  View details for Web of Science ID 000355999800014

  View details for PubMedID 25897153

  View details for PubMedCentralID PMC4451176

• Ibrutinib in Previously Treated Waldenstrom's Macroglobulinemia NEW ENGLAND JOURNAL OF MEDICINE Treon, S. P., Tripsas, C. K., Meid, K., Warren, D., Varma, G., Green, R., Argyropoulos, K. V., Yang, G., Cao, Y., Xu, L., Patterson, C. J., Rodig, S., Zehnder, J. L., Aster, J. C., Harris, N. L., Kanan, S., Ghobrial, I., Castillo, J. J., Laubach, J. P., Hunter, Z. R., Salman, Z., Li, J., Cheng, M., Clow, F., Graef, T., Palomba, M. L., Advani, R. H. 2015; 372 (15): 1430-1440

  Abstract

  MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects.After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

  View details for DOI 10.1056/NEJMoa1501548

  View details for PubMedID 25853747

• Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404). Leukemia & lymphoma Ganjoo, K., Hong, F., Horning, S. J., Gascoyne, R. D., Natkunam, Y., Swinnen, L. J., Habermann, T. M., Kahl, B. S., Advani, R. H. 2014; 55 (4): 768-772

  Abstract

  Peripheral T-cell lymphoma (PTCL) and natural killer (NK) cell lymphoma have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab (A), was studied in combination with standard cyclosphosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients. Patients were treated with 6-8 cycles of ACHOP followed by eight doses of maintenance A (15 mg/kg every 21 days). Forty-six patients were enrolled on this phase 2 study from July 2006 through March 2009. Forty-four patients were evaluable for toxicity and 39 were evaluable for response, progression and survival. A total of 324 cycles (range: 2-16, median 7) were administered to 39 evaluable patients and only nine completed all planned treatment. The overall response rate was 90% with 19 (49%) complete response/complete response unconfirmed (CR/CRu) and 16 (41%) a partial response (PR). The 1-year progression-free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, two while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n = 8), anemia (n = 3), thrombocytopenia (n = 5), congestive heart failure (n = 4), venous thrombosis (n = 3), gastrointestinal hemorrhage/perforation (n = 2), infection (n = 8) and fatigue (n = 6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.

  View details for DOI 10.3109/10428194.2013.816700

  View details for PubMedID 23786456

• Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. Journal of clinical oncology Advani, R. H., Horning, S. J., Hoppe, R. T., Daadi, S., Allen, J., Natkunam, Y., Bartlett, N. L. 2014; 32 (9): 912-918

  Abstract

  Universal expression of CD20 by malignant cells in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) led us to evaluate rituximab (R) as a therapeutic option.Patients with previously treated or newly diagnosed NLPHL were treated with R (375 mg/m(2) once per week for 4 weeks) or, after a protocol amendment, with R plus R maintenance (MR; administered once every 6 months for 2 years). Primary and secondary outcome measures were progression-free survival (PFS) and overall response rate (ORR), respectively.A total of 39 patients were enrolled (R, n = 23; R + MR, n = 16). After four once-per-week treatments, ORR was 100% (complete response, 67%; partial response, 33%). At median follow-ups of 9.8 years for R and 5 years for R + MR, median PFS were 3 and 5.6 years (P = .26), respectively; median overall survival (OS) was not reached. Estimated 5-year PFS and OS for patients treated with R versus R + MR were 39.1% (95% CI, 23.5 to 65.1) and 95.7% (95% CI, 87.7 to 100) versus 58.9% (95% CI, 38.0 to 91.2) and 85.7% (95% CI, 69.2 to 100), respectively. Nine of 23 patients experiencing relapse had evidence of transformation to aggressive B-cell lymphoma; six of these patients had infradiaphragmatic involvement at study entry.R is an active agent in NLPHL. Although responses are not durable in most patients, a significant minority experience remissions lasting > 5 years. R + MR results in a nonsignificant increase in PFS compared with R. R may be considered in the relapsed setting for NLPHL. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of rebiopsy and long-term follow-up.

  View details for DOI 10.1200/JCO.2013.53.2069

  View details for PubMedID 24516013

• Mature Results of a Phase II Study of Rituximab Therapy for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Journal of clinical oncology Advani, R. H., Horning, S. J., Hoppe, R. T., Daadi, S., Allen, J., Natkunam, Y., Bartlett, N. L. 2014; 32 (9): 912-918

  View details for DOI 10.1200/JCO.2013.53.2069

  View details for PubMedID 24516013

• Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood Chang, J. E., Li, H., Smith, M. R., Gascoyne, R. D., Paietta, E. M., Yang, D. T., Advani, R. H., Horning, S. J., Kahl, B. S. 2014; 123 (11): 1665-1673

  Abstract

  Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n = 44) vs ASCT (n = 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomib's contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537.

  View details for DOI 10.1182/blood-2013-08-523845

  View details for PubMedID 24458437

  View details for PubMedCentralID PMC3954048

• How I treat nodular lymphocyte predominant Hodgkin lymphoma BLOOD Advani, R. H., Hoppe, R. T. 2013; 122 (26): 4182-4188

  Abstract

  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon entity that, in contrast to classical Hodgkin lymphoma (cHL), universally expresses CD20, a hallmark of the disease. The majority of the patients present with early-stage disease, and treatment with local radiation provides excellent disease control and overall survival (OS). For locally extensive or advanced stages, paradigms used for cHL have been employed, with similar outcomes. Unlike cHL, late relapses may occur, as well as a propensity to transform to an aggressive B-cell non-Hodgkin lymphoma that underscores the importance of long-term follow-up and rebiopsy at the time of relapse. Deaths caused by NLPHL are uncommon, and in older series, secondary malignancies and other treatment-related toxicities contributed appreciably to overall mortality. Expression of CD20 in NLPHL has led to the evaluation of rituximab as a therapeutic option. Although results with single-agent rituximab in the front-line setting are inferior to conventional therapy, rituximab is a reasonable choice for relapsed disease because of the high overall response rate and excellent tolerability. Most patients have a long OS; therefore, overall goals of therapy should be to minimize the risk for relapse and long-term toxicity.

  View details for DOI 10.1182/blood-2013-07-453241

  View details for Web of Science ID 000329741000012

  View details for PubMedID 24215035

• Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood Tan, D., Horning, S. J., Hoppe, R. T., Levy, R., Rosenberg, S. A., Sigal, B. M., Warnke, R. A., Natkunam, Y., Han, S. S., Yuen, A., Plevritis, S. K., Advani, R. H. 2013; 122 (6): 981-987

  Abstract

  Recent studies report an improvement in overall survival (OS) of patients with follicular lymphoma (FL). Previously untreated patients with grade 1-2 FL referred from 1960-2003 and treated at Stanford were identified. Four eras were considered: era 1, pre-anthracycline (1960-1975, n=180); era 2, anthracycline (1976-1986, n=426), era 3, aggressive chemotherapy/purine analogs (1987-1996, n=471) and era 4, rituximab (1997-2003, n=257). Clinical characteristics, patterns of care and survival outcomes were assessed. Observed OS was compared with the expected OS calculated from Berkeley Mortality Database life tables derived from population matched by gender and age at time of diagnosis. The median OS was 13.6 years. Age, gender and stage did not differ across the eras. Although primary treatment varied, event free survival after the first treatment did not differ between eras (p=0.17). Median OS improved from approximately 11 years in eras 1 and 2 to 18.4 years in era 3 and has not yet been reached for era 4 (p<0.001) with no suggestion of a plateau in any era. These improvements in OS exceeded improvements in survival in the general population during the same time period. Several factors, including better supportive care and effective therapies for relapsed disease, are likely responsible for this improvement.

  View details for DOI 10.1182/blood-2013-03-491514

  View details for PubMedID 23777769

• Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma NEW ENGLAND JOURNAL OF MEDICINE Wang, M. L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreyling, M., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Li, L., Zhang, L., Newberry, K., Ou, Z., Cheng, N., Fang, B., McGreivy, J., Clow, F., Buggy, J. J., Chang, B. Y., Beaupre, D. M., Kunkel, L. A., Blum, K. A. 2013; 369 (6): 507-516

  Abstract

  Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

  View details for DOI 10.1056/NEJMoa1306220

  View details for Web of Science ID 000322842000007

  View details for PubMedID 23782157

• Targeted Therapy in Relapsed Classical Hodgkin Lymphoma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Dinner, S., Advani, R. 2013; 11 (8): 968-976

  Abstract

  Although frontline treatment of advanced Hodgkin lymphoma (HL) produces high cure rates, disease either will not respond to or will relapse after initial therapy in approximately a quarter of patients. Many patients with disease relapse can be successfully salvaged with second-line chemotherapy followed by autologous stem cell transplantation (ASCT). Patients whose disease relapses after ASCT are rarely cured. A unique pathophysiologic feature of HL is that the malignant Reed-Sternberg (HRS) cell is rare and resides within a microenvironment of inflammatory and immune-related cells. The recent FDA approval of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) for patients with either primary refractory HL or those whose disease relapses after ASCT represents a major advance in therapy. This article focuses on BV and other novel agents that target the HRS cell surface, intracellular signaling pathways, and tumor microenvironment.

  View details for PubMedID 23946175

• Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood Kanakry, J. A., Li, H., Gellert, L. L., Lemas, M. V., Hsieh, W., Hong, F., Tan, K. L., Gascoyne, R. D., Gordon, L. I., Fisher, R. I., Bartlett, N. L., Stiff, P., Cheson, B. D., Advani, R., Miller, T. P., Kahl, B. S., Horning, S. J., Ambinder, R. F. 2013; 121 (18): 3547-3553

  Abstract

  Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. We sought to determine whether plasma EBV-DNA could serve as a surrogate for EBER-ISH and to explore its prognostic utility in HL. Specimens from the Cancer Cooperative Intergroup Trial E2496 were used to compare pretreatment plasma EBV-DNA quantification with EBV tumor status by EBER-ISH. A cutoff of >60 viral copies/100 µL plasma yielded 96% concordance with EBER-ISH. Pretreatment and month 6 plasma specimens were designated EBV(-) or EBV(+) by this cutoff. Patients with pretreatment EBV(+) plasma (n = 54) had inferior failure-free survival (FFS) compared with those with pretreatment EBV(-) plasma (n = 274), log-rank P = .009. By contrast, no difference in FFS was observed when patients were stratified by EBER-ISH. Pretreatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBV(+) patients (n = 7) had inferior FFS compared with plasma EBV(-) patients (n = 125), log-rank P = .007. These results confirm that plasma EBV-DNA is highly concordant with EBER-ISH in HL and suggest that it may have prognostic utility both at baseline and after therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003389.

  View details for DOI 10.1182/blood-2012-09-454694

  View details for PubMedID 23386127

  View details for PubMedCentralID PMC3643756

• Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma NEW ENGLAND JOURNAL OF MEDICINE Dunleavy, K., Pittaluga, S., Maeda, L. S., Advani, R., Chen, C. C., Hessler, J., Steinberg, S. M., Grant, C., Wright, G., Varma, G., Staudt, L. M., Jaffe, E. S., Wilson, W. H. 2013; 368 (15): 1408-1416

  Abstract

  Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

  View details for DOI 10.1056/NEJMoa1214561

  View details for Web of Science ID 000317333600008

  View details for PubMedID 23574119

• Efficacy of abbreviated Stanford V chemotherapy and involved-field radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial ANNALS OF ONCOLOGY Advani, R. H., Hoppe, R. T., Baer, D., Mason, J., Warnke, R., Allen, J., Daadi, S., Rosenberg, S. A., Horning, S. J. 2013; 24 (4): 1044-1048

  Abstract

  To assess the efficacy of an abbreviated Stanford V regimen in patients with early-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS PATIENTS: with untreated nonbulky stage I-IIA supradiaphragmatic HL were eligible for the G4 study. Stanford V chemotherapy was administered for 8 weeks followed by radiation therapy (RT) 30 Gy to involved fields (IF). Freedom from progression (FFP), disease-specific survival (DSS) and overall survival (OS) were estimated.All 87 enrolled patients completed the abbreviated regimen. At a median follow-up of 10 years, FFP, DSS and OS are 94%, 99% and 94%, respectively. Therapy was well tolerated with no treatment-related deaths.Mature results of the abbreviated Stanford V regimen in nonbulky early-stage HL are excellent and comparable to the results from other contemporary therapies.

  View details for DOI 10.1093/annonc/mds542

  View details for PubMedID 23136225

• The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496 BRITISH JOURNAL OF HAEMATOLOGY Evens, A. M., Hong, F., Gordon, L. I., Fisher, R. I., Bartlett, N. L., Connors, J. M., Gascoyne, R. D., Wagner, H., Gospodarowicz, M., Cheson, B. D., Stiff, P. J., Advani, R., Miller, T. P., Hoppe, R. T., Kahl, B. S., Horning, S. J. 2013; 161 (1): 76-86

  Abstract

  There is a lack of contemporary prospective data examining the adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) and Stanford V (SV; doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone) regimens in older Hodgkin lymphoma (HL) patients. Forty-four advanced-stage, older HL patients (aged ≥60 years) were treated on the randomized study, E2496. Toxicities were mostly similar between chemotherapy regimens, although 24% of older patients developed bleomycin lung toxicity (BLT), which occurred mainly with ABVD (91%). Further, the BLT-related mortality rate was 18%. The overall treatment-related mortality for older HL patients was 9% vs. 0·3% for patients aged <60 years (P < 0·001). Among older patients, there were no survival differences between ABVD and SV. According to age, outcomes were significantly inferior for older versus younger patients (5-year failure-free survival: 48% vs. 74%, respectively, P = 0·002; 5-year overall survival: 58% and 90%, respectively, P < 0·0001), although time-to-progression (TTP) was not significantly different (5-year TTP: 68% vs. 78%, respectively, P = 0·37). Furthermore, considering progression and death without progression as competing risks, the risk of progression was not different between older and younger HL patients (5 years: 30% and 23%, respectively, P = 0·30); however, the incidence of death without progression was significantly increased for older HL patients (22% vs. 9%, respectively, P < 0·0001). Altogether, the marked HL age-dependent survival differences appeared attributable primarily to non-HL events.

  View details for DOI 10.1111/bjh.12222

  View details for Web of Science ID 000316333300009

  View details for PubMedID 23356491

• Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496) JOURNAL OF CLINICAL ONCOLOGY Gordon, L. I., Hong, F., Fisher, R. I., Bartlett, N. L., Connors, J. M., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Gospodarowicz, M., Advani, R., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J. 2013; 31 (6): 684-691

  Abstract

  Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.

  View details for DOI 10.1200/JCO.2012.43.4803

  View details for Web of Science ID 000315086400016

  View details for PubMedID 23182987

  View details for PubMedCentralID PMC3574266

• Risk of Therapy-Related Secondary Leukemia in Hodgkin Lymphoma: The Stanford University Experience Over Three Generations of Clinical Trials JOURNAL OF CLINICAL ONCOLOGY Koontz, M. Z., Horning, S. J., Balise, R., Greenberg, P. L., Rosenberg, S. A., Hoppe, R. T., Advani, R. H. 2013; 31 (5): 592-598

  Abstract

  To assess therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) risk in patients treated for Hodgkin lymphoma (HL) on successive generations of Stanford clinical trials.Patients with HL treated at Stanford with at least 5 years of follow-up after completing therapy were identified from our database. Records were reviewed for outcome and development of t-AML/MDS.Seven hundred fifty-four patients treated from 1974 to 2003 were identified. Therapy varied across studies. Radiotherapy evolved from extended fields (S and C studies) to involved fields (G studies). Primary chemotherapy was mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or procarbazine, mechlorethamine, and vinblastine (PAVe) in S studies; MOPP, PAVe, vinblastine, bleomycin, and methotrexate (VBM), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in C studies; and VbM (reduced dose of bleomycin compared with VBM) or mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) in G studies. Cumulative exposure to alkylating agent (AA) was notably lower in the G studies compared with the S and C studies, with a 75% to 83% lower dose of nitrogen mustard in addition to omission of procarbazine and melphalan. Twenty-four (3.2%) of 754 patients developed t-AML/MDS, 15 after primary chemotherapy and nine after salvage chemotherapy for relapsed HL. The incidence of t-AML/MDS was significantly lower in the G studies (0.3%) compared with the S (5.7%) or C (5.2%) studies (P < .001). Additionally, in the G studies, no t-AML/MDS was noted after primary therapy, and the only patient who developed t-AML/MDS did so after second-line therapy.Our data demonstrate the relationship between the cumulative AA dose and t-AML/MDS. Limiting the dose of AA and decreased need for secondary treatments have significantly reduced the incidence of t-AML/MDS, which was extremely rare in the G studies (Stanford V era).

  View details for DOI 10.1200/JCO.2012.44.5791

  View details for PubMedID 23295809

• Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma BLOOD Rubenstein, J. L., Li, J., Chen, L., Advani, R., Drappatz, J., Gerstner, E., Batchelor, T., Krouwer, H., Hwang, J., Auerback, G., Kadoch, C., Lowell, C., Munster, P., Cha, S., Shuman, M. A., Damon, L. E. 2013; 121 (5): 745-751

  Abstract

  Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab.Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

  View details for DOI 10.1182/blood-2012-07-440974

  View details for Web of Science ID 000314867200007

  View details for PubMedID 23197589

  View details for PubMedCentralID PMC3563362

• Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies JOURNAL OF CLINICAL ONCOLOGY Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., Sukbuntherng, J., Izumi, R., Hamdy, A., Hedrick, E., Fowler, N. H. 2013; 31 (1): 88-94

  Abstract

  Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies.Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles.Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months.Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

  View details for DOI 10.1200/JCO.2012.42.7906

  View details for PubMedID 23045577

• Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial BLOOD Tan, K. L., Scott, D. W., Hong, F., Kahl, B. S., Fisher, R. I., Bartlett, N. L., Advani, R. H., Buckstein, R., Rimsza, L. M., Connors, J. M., Steidl, C., Gordon, L. I., Horning, S. J., Gascoyne, R. D. 2012; 120 (16): 3280-3287

  Abstract

  Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial.

  View details for DOI 10.1182/blood-2012-04-421057

  View details for Web of Science ID 000311619200019

  View details for PubMedID 22948049

  View details for PubMedCentralID PMC3476539

• Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90-Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499 JOURNAL OF CLINICAL ONCOLOGY Smith, M. R., Li, H., Gordon, L., Gascoyne, R. D., Paietta, E., Forero-Torres, A., Kahl, B. S., Advani, R., Hong, F., Horning, S. J. 2012; 30 (25): 3119-3126

  Abstract

  To test the hypothesis that consolidation therapy with yttrium-90 ((90)Y) -ibritumomab tiuxetan after brief initial therapy with four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle-cell lymphoma would be a well-tolerated regimen that would improve outcomes compared with historical R-CHOP data.Patients ≥ 18 years old with histologically confirmed mantle-cell lymphoma expressing CD20 and cyclin D1 who had not received any previous therapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were eligible. The study enrolled and treated 57 patients, of whom 56 patients were eligible. Fifty-two patients (50 eligible patients) received (90)Y-ibritumomab tiuxetan. The study design required 52 eligible patients to detect a 50% improvement in the median time to treatment failure (TTF) compared with that reported for six cycles of R-CHOP.With 56 analyzed patients (median age, 60 years; men, 73%), the overall response rate was 82% (55% complete response/complete response-unconfirmed). With a median follow-up of 72 months, the median TTF was 34.2 months. The median overall survival (OS) has not been reached, with an estimated 5-year OS of 73% (79% for patients ≤ age 65 years v 62% for patients > age 65 years; P = .08 [log-rank test]). There were no unexpected toxicities.R-CHOP given for four cycles followed by (90)Y-ibritumomab tiuxetan compared favorably with historical results with six cycles of R-CHOP in patients with previously untreated mantle-cell lymphoma. This regimen was well tolerated and should be applicable to most patients with this disease.

  View details for DOI 10.1200/JCO.2012.42.2444

  View details for Web of Science ID 000308558800018

  View details for PubMedID 22851557

• Brentuximab Vedotin in Transplant-Naive Patients with Relapsed or Refractory Hodgkin Lymphoma: Analysis of Two Phase I Studies ONCOLOGIST Forero-Torres, A., Fanale, M., Advani, R., Bartlett, N. L., Rosenblatt, J. D., Kennedy, D. A., Younes, A. 2012; 17 (8): 1073-1080

  Abstract

  Brentuximab vedotin is an antibody-drug conjugate designed to selectively deliver monomethyl auristatin E, a microtubule-disrupting agent, to CD30-expressing cells. Brentuximab vedotin induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). The objective of this post-hoc analysis was to characterize the safety and efficacy of brentuximab vedotin for patients with relapsed or refractory HL who refused or were ineligible for ASCT.This case series included 20 transplant-naïve patients who were enrolled in two phase I multicenter studies. Patients received brentuximab vedotin intravenously every 3 weeks or every week for 3 out of 4 weeks.The majority of patients were transplant-naïve because of chemorefractory disease. Median age was 31.5 years (range, 12-87 years). Treatment-emergent adverse events in >20% of patients were peripheral neuropathy, fatigue, nausea, pyrexia, diarrhea, weight decreased, anemia, back pain, decreased appetite, night sweats, and vomiting; most events were grade 1 or 2. Six patients obtained objective responses: two complete remissions and four partial remissions. Median duration of response was not met; censored durations ranged from >6.8 to >13.8 months. Three of six responders subsequently received ASCT.Brentuximab vedotin was associated with manageable adverse events in transplant-naïve patients with relapsed or refractory HL. The objective responses observed demonstrate that antitumor activity is not limited to patients who received brentuximab vedotin after ASCT. The promising activity observed in this population warrants further study.

  View details for DOI 10.1634/theoncologist.2012-0133

  View details for Web of Science ID 000308126100010

  View details for PubMedID 22855426

  View details for PubMedCentralID PMC3425525

• Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study JOURNAL OF CLINICAL ONCOLOGY Pro, B., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M., Connors, J. M., Yang, Y., Sievers, E. L., Kennedy, D. A., Shustov, A. 2012; 30 (18): 2190-2196

  Abstract

  Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL.Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review.Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events in ≥ 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%).Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL. Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy.

  View details for DOI 10.1200/JCO.2011.38.0402

  View details for Web of Science ID 000305413200010

  View details for PubMedID 22614995

• Cardiac toxicity associated with bevacizumab (Avastin) in combination with CHOP chemotherapy for peripheral T cell lymphoma in ECOG 2404 trial LEUKEMIA & LYMPHOMA Advani, R. H., Hong, F., Horning, S. J., Kahl, B. S., Manola, J., Swinnen, L. J., Habermann, T. M., Ganjoo, K. 2012; 53 (4): 718-720

  View details for DOI 10.3109/10428194.2011.623256

  View details for Web of Science ID 000302067100030

  View details for PubMedID 21916830

• STAGE I-IIIA NON-BULKY HODGKIN'S LYMPHOMA. IS FURTHER DISTINCTION BASED ON PROGNOSTIC FACTORS USEFUL? THE STANFORD EXPERIENCE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Advani, R. H., Hoppe, R. T., Maeda, L. S., Baer, D. M., Mason, J., Rosenberg, S. A., Horning, S. J. 2011; 81 (5): 1374-1379

  Abstract

  In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center.This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors.At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged.The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

  View details for DOI 10.1016/j.ijrobp.2010.07.041

  View details for PubMedID 20934280

• MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP CLINICAL CANCER RESEARCH Alencar, A. J., Malumbres, R., Kozloski, G. A., Advani, R., Talreja, N., Chinichian, S., Briones, J., Natkunam, Y., Sehn, L. H., Gascoyne, R. D., Tibshirani, R., Lossos, I. S. 2011; 17 (12): 4125-4135

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) heterogeneity has prompted investigations for new biomarkers that can accurately predict survival. A previously reported 6-gene model combined with the International Prognostic Index (IPI) could predict patients' outcome. However, even these predictors are not capable of unambiguously identifying outcome, suggesting that additional biomarkers might improve their predictive power.We studied expression of 11 microRNAs (miRNA) that had previously been reported to have variable expression in DLBCL tumors. We measured the expression of each miRNA by quantitative real-time PCR analyses in 176 samples from uniformly treated DLBCL patients and correlated the results to survival.In a univariate analysis, the expression of miR-18a correlated with overall survival (OS), whereas the expression of miR-181a and miR-222 correlated with progression-free survival (PFS). A multivariate Cox regression analysis including the IPI, the 6-gene model-derived mortality predictor score and expression of the miR-18a, miR-181a, and miR-222, revealed that all variables were independent predictors of survival except the expression of miR-222 for OS and the expression of miR-18a for PFS.The expression of specific miRNAs may be useful for DLBCL survival prediction and their role in the pathogenesis of this disease should be examined further.

  View details for DOI 10.1158/1078-0432.CCR-11-0224

  View details for Web of Science ID 000291644700029

  View details for PubMedID 21525173

  View details for PubMedCentralID PMC3117929

• Current concepts and controversies in the management of early stage Hodgkin lymphoma LEUKEMIA & LYMPHOMA Maeda, L. S., Lee, M., Advani, R. H. 2011; 52 (6): 962-971

  Abstract

  Over the past three decades, due to the recognition of late effects related to high-dose extended field radiotherapy and heavy alkylator chemotherapy, combined modality therapy with abbreviated chemotherapy and limited field radiotherapy has emerged as the standard of care for early stage Hodgkin lymphoma, with cure rates in excess of 80%. Currently, however, controversy remains over identifying the most appropriate criteria to risk-stratify patients with early stage disease, so that those with a favorable prognosis receive limited treatment without compromising cure rates and those with unfavorable risk receive more intensified therapy. The optimal risk stratification system remains unclear, with variable definitions of favorable and unfavorable disease used by research groups in North America and Europe. Thus, comparison of clinical trial results has been challenging, and additional controversies persist regarding optimal chemotherapy regimens, duration of therapy, and the role of radiotherapy. Investigations are ongoing to assess the potential of functional imaging and biomarkers as tools for risk stratification. The collective goal is to further refine current stratification strategies to allow for an individualized, risk-adapted treatment approach that minimizes long-term late effects without compromising high cure rates.

  View details for DOI 10.3109/10428194.2011.557455

  View details for PubMedID 21463118

• Optimal therapy of advanced Hodgkin lymphoma. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program Advani, R. 2011; 2011: 310-316

  Abstract

  Advanced-stage Hodgkin lymphoma (HL) has become a curable disease in the majority of patients. Research during the last decade has challenged chemotherapy with Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) as the standard of care and debates continue regarding the role of radiation therapy (RT) in this patient population. The incorporation of interim positron emission tomography (PET) imaging and, recently, further characterization of HL on cellular and molecular levels are emerging as tools for treatment stratification and predictors of disease status. Newer targeted therapies have emerged that are very effective in the relapsed setting and are actively being explored as frontline therapy. Lastly, the expanding population of survivors cured of HL outnumbers patients with the disease and needs to be monitored for therapy-related late effects.

  View details for DOI 10.1182/asheducation-2011.1.310

  View details for PubMedID 22160051

• Comparison of conventional prognostic indices in patients older than 60 years with diffuse large B-cell lymphoma treated with R-CHOP in the US Intergroup Study (ECOG 4494, CALGB 9793): consideration of age greater than 70 years in an elderly prognostic index (E-IPI) 48th Annual Meeting of the American-Society-of-Hematology Advani, R. H., Chen, H., Habermann, T. M., Morrison, V. A., Weller, E. A., Fisher, R. I., Peterson, B. A., Gascoyne, R. D., Horning, S. J. WILEY-BLACKWELL PUBLISHING, INC. 2010: 143–51

  Abstract

  To assess if immunochemotherapy influenced the prognostic value of IPI in elderly diffuse large B-cell lymphoma (DLBCL) patients, we evaluated the performance of the standard International Prognostic Index (IPI) and following modifications: age adjusted (AA)-IPI, revised (R)-IPI, and an elderly IPI with age cut-off 70 years (E-IPI) in patients > 60 years treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). In 267 patients, by IPI/AA-IPI 60% were high-intermediate, 53% high and 12% low risk. With R-IPI, 60% were poor risk and none very good risk. Using E-IPI, 45% were high-intermediate/high risk and 27% low risk. No differences in outcome were seen in the low/low-intermediate groups with IPI/AA-IPI. For E-IPI, failure-free survival (FFS) and overall survival (OS) were significantly different for low/low-intermediate groups. No differences were detected in the four indices with model fit/discrimination measures; however, E-IPI ranked highest. For elderly R-CHOP treated patients, distribution of IPI/AA-IPI skewed toward high/high-intermediate risk with no differences in FFS/OS between low/low-intermediate risk. In contrast, with E-IPI, more are classified as low risk with significant differences in FFS/OS for low-intermediate compared to low risk. The R-IPI does not identify a very good risk group, thus minimizing its utility in this population. The prognostic discrimination provided by the E-IPI for low and low-intermediate elderly DLBCL patients needs validation by other datasets.

  View details for DOI 10.1111/j.1365-2141.2010.08331.x

  View details for PubMedID 20735398

• Risk stratification in extranodal natural killer/T-cell lymphoma EXPERT REVIEW OF ANTICANCER THERAPY Kohrt, H., Lee, M., Advani, R. 2010; 10 (9): 1395-1405

  Abstract

  Extranodal natural killer/T-cell lymphoma (ENKL), a subtype of natural killer/T-cell malignancies, is a rare subset of lymphomas with significant biological and clinical heterogeneity. The prognosis of ENKL is variable and therapeutic approaches are not well established. The optimal dose, combination, and sequence of radiotherapy and chemotherapy are evolving, as is the role of stem cell transplantation. Radiotherapy is an essential component of therapy for early-stage disease. The clinical course of advanced disease is highly aggressive, with frequent chemotherapy resistance and a poor prognosis. For relapsed disease, asparaginase-based regimens have provided encouraging results and are currently under investigation in the frontline setting. Our article discusses the key aspects of biology, pathogenesis and clinical presentation that contribute to the heterogeneity, and proposes a stratified approach to the treatment of ENKL based on clinical, pathologic and biologic risk factors. Although considerable advances have been made in our understanding of the biology and prognosis of this lymphoma, it remains critical that all patients with a diagnosis of ENKL are enrolled and treated in clinical trials so that optimal therapies can be identified.

  View details for DOI 10.1586/ERA.10.130

  View details for Web of Science ID 000282259800012

  View details for PubMedID 20836675

• Prediction of Survival in Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes: Integration of Tumor and Microenvironment Contributions 51st Annual Meeting and Exposition of the American-Society-of-Hematology Alizadeh, A. A., Gentles, A. J., Alencar, A. J., Kohrt, H. E., Houot, R., Talreja, N., Shyam, R., Natkunam, Y., Gascoyne, R. D., Briones, J., Advani, R., Lossos, I. S., Levy, R. AMER SOC HEMATOLOGY. 2009: 258–58

  View details for Web of Science ID 000272725800623

• Efficacy of Abbreviated Stanford V Chemotherapy and Involved Field Radiotherapy in Early Stage Hodgkin's Disease: Mature Results of the G4 Trial. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Advani, R. H., Hoppe, R. T., Baer, D. M., Mason, J., Rosenberg, S. A., Horning, S. J. AMER SOC HEMATOLOGY. 2009: 666–67

  View details for Web of Science ID 000272725802038

• Management of T-cell and natural-killer-cell neoplasms in Asia: consensus statement from the Asian Oncology Summit 2009 LANCET ONCOLOGY Kwong, Y., Anderson, B. O., Advani, R., Kim, W., Levine, A. M., Lim, S. 2009; 10 (11): 1093-1101

  Abstract

  T-cell and natural-killer (NK)-cell lymphomas are neoplasms with geographical variations in frequencies. T-cell lymphomas are more prevalent in Asia than in Europe and North America, and NK-cell lymphomas occur almost exclusively in Asia and South America. These low frequencies mean that the diagnosis and optimum treatment of patients with T-cell and NK-cell lymphomas have not been studied prospectively in randomised controlled trials. Because T-cell and NK-cell lymphomas are more prevalent in Asia, the establishment of management recommendations by Asian oncologists in collaboration with international experts is pertinent. This review outlines guidelines commensurate with different levels of health-care resources and expertise. Consensus statements were formulated for diagnosis, staging, follow-up, and treatment approaches in patients with T-cell and NK-cell lymphomas--aimed at unifying the design of studies and interpretation of results. For patients not in clinical trials, consensus opinions offer useful guidelines on optimum management.

  View details for Web of Science ID 000271852800019

  View details for PubMedID 19880063

• Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma 10th International Conference on Malignant Lymphoma Advani, R., Forero-Torres, A., Furman, R. R., Rosenblatt, J. D., Younes, A., Ren, H., Harrop, K., Whiting, N., Drachman, J. G. AMER SOC CLINICAL ONCOLOGY. 2009: 4371–77

  Abstract

  To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.

  View details for DOI 10.1200/JCO.2008.21.3017

  View details for PubMedID 19636010

• Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease 9th International Conference on Malignant Lymphoma Advani, R., Maeda, L., Lavori, P., Quon, A., Hoppe, R., Breslin, S., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2007: 3902–7

  Abstract

  To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

  View details for DOI 10.1200/JCO.2007.11.9867

  View details for PubMedID 17664458

• Angioimmunoblastic T cell lymphoma: Treatment experience with cyclosporine LEUKEMIA & LYMPHOMA Advani, R., Horwitz, S., Zelenetz, A., Horning, S. J. 2007; 48 (3): 521-525

  Abstract

  Angioimmunoblastic T cell lymphoma is a distinct entity for which there is no standard therapy. On the basis of the rationale that CsA may represent a novel drug for AITL, a disease with considerable immune dysregulation, and encouraging case reports, the authors have treated 12 patients with this agent. Ten had failed prior steroids and/or chemotherapy and two had no prior therapy. CsA was administered at a dose of 3 - 5 mg/kg PO bid for 6 - 8 weeks and gradually tapered by 50 mg every 1 - 3 weeks. Responding patients received a maintenance dose of 50 - 100 mg, with a gradual taper after a maximal response was achieved as tolerated. Doses were titrated for renal dysfunction or hypertension. CsA levels were not monitored. Eight of 12 patients responded (three complete and five partial remissions). Dose reductions were required in six patients; renal insufficiency (n = 3), fatigue (n = 2), and hypertension (n = 1). Two patients developed acute infections and one patient died shortly after active treatment. These results suggest that CsA deserves further testing as a novel therapy for AITL. By interrupting T-cell activation, CsA may alter the immune dysregulation that characterizes AILT. The efficacy of CsA is being explored in patients with recurrent AILT in a prospective trial (ECOG 2402).

  View details for DOI 10.1080/10428190601137658

  View details for PubMedID 17454592

• Stage I and II follicular non-Hodgkin's lymphoma: Long-term follow-up of no initial therapy 8th International Conference on Malignant Lymphoma Advani, R., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2004: 1454–59

  Abstract

  To analyze the outcome of no initial therapy in stage I and II follicular small-cleaved (FSC) and follicular mixed (FM) non-Hodgkin's lymphoma (NHL) on overall survival, time to treatment, incidence and course of transformation, and cause of death.This was a retrospective analysis. Criteria for selection were patients with stage I and IIA FSC and FM (grades 1 and 2) NHL with therapy deferred for at least 3 months after diagnosis and a minimum follow-up of 1 year.Forty-three patients were identified (11 stage I, 32 stage II), with a median age of 58 years. Reasons for no initial therapy included: physician choice (n = 20), large abdominal radiation field required (n = 10), advanced age (n = 7), concern for xerostomia (n = 4), or patient refusal (n = 2). At a median follow-up of 86 months, 27 patients (63%) had not been treated. The median time to treatment in the remaining 16 patients was 22 months. Four of 16 patients transformed to a higher-grade lymphoma. Nine patients died-six due to progressive lymphoma. Estimated survivals at 5, 10, and 20 years were 97%, 85%, and 22%, respectively.In selected stage I and II follicular NHL patients, deferred therapy is an acceptable approach, as more than half of our patients remained untreated at a median of 6 or more years, and survival was comparable to that seen in reports with immediate treatment.

  View details for DOI 10.1200/JCO.2004.10.086

  View details for PubMedID 15024027

• Loncastuximab in high-risk and heavily pretreated relapsed / refractory diffuse large B-cell lymphoma: a real-world analysis from 21 US centers. Haematologica Zelikson, V., Gurumurthi, A., Sawalha, Y., Annunzio, K., Saha, A., Dong, N., Qualls, D., Amoozgar, B., Kahl, B., Baird, J., Challa, P., Huntington, S. F., Santos, J., Bair, S., Narkhede, M., Li, S., Frosch, Z., Ho, C., Smith, S. D., Winter, A., Landsburg, D., Furqan, F., Hamadani, M., Baird, K., Romancik, J., Alharthy, H., Law, J., Bojanini, L., Advani, R., Hu, B., Johnson, P. C., Grover, N. S., Merril, M., Crombie, J. L., Shafagati, N., Sterling, C., Nastoupil, L. J., Epperla, N., Ayers, E. C. 2024: 0

  Abstract

  Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab-teserine (Lonca) is an antibody drug conjugate (ADC) which was FDA approved for R/R DLBCL patients who have received at least 2 prior lines of therapy based on the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting (RWS). This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis includes 187 patients with notably higher risk baseline features compared to LOTIS-2 including a higher proportion of patients with bulky disease (17% vs 0%), high-grade B-cell histology (HGBL) (22% vs 8%), and increased number of prior lines of therapy (median 4 vs 3). The complete response (CR) rate was 14% and overall response rate (ORR) was 32%. Median event free (EFS) and overall survival (OS) were 2.1 and 4.6 months, respectively. Those with bulky disease and HGBL had significantly worse outcomes, and those with non-germinal center cell of origin and CR to most recent line of therapy demonstrated superior outcomes. In summary, in this largest retrospective cohort study of Lonca in the RWS, the response rates, EFS, and OS were lower than those reported in LOTIS-2, which is likely reflective of its use in higher risk and more heavily pre-treated patients within the real world compared to those enrolled on clinical study.

  View details for DOI 10.3324/haematol.2024.285977

  View details for PubMedID 39540227

• Magrolimab Plus Rituximab with/without Chemotherapy in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Blood advances Maakaron, J., Asch, A. S., Popplewell, L., Collins, G. P., Flinn, I. W., Ghosh, N., Keane, C., Ku, M., Mehta, A., Roschewski, M., Hacohen-Kleiman, G., Huo, Y., Zhang, Y., Renard, C., Smith, S. M., Advani, R. H. 2024

  Abstract

  Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for available salvage therapies have limited options for long-term disease control, necessitating novel treatments. Previously, magrolimab (anti-cluster-of-differentiation-47 antibody) plus rituximab (M+R) demonstrated ability to induce complete responses (CR) in R/R DLBCL. Here we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R, and initial safety and efficacy of M+R plus gemcitabine-oxaliplatin (M+R-GemOx), in R/R DLBCL. After magrolimab priming, 4 M+R patient groups received 10-45 mg/kg magrolimab with 375 mg/m2 rituximab; M+R-GemOx patients received 30 or 45 mg/kg magrolimab with 375 mg/m2 rituximab, 1000 mg/m2 gemcitabine, and 100 mg/m2 oxaliplatin. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of 132 patients treated, 99 received M+R and 33 received M+R-GemOx. Most common any-grade TEAEs were fatigue (M+R, 40%; M+R-GemOx, 70%), infusion-related reactions (M+R, 39%), or anemia (M+R-GemOx, 70%). Treatment-related TEAEs led to magrolimab discontinuation in 7% (M+R) and 6% (M+R-GemOx). One death was considered treatment related (M+R-GemOx, colitis). M+R ORR was 24% (CR, 12%), and median DOR was 9.3 months. Median PFS and OS were 1.8 and 9.2 months, respectively. M+R-GemOx ORR was 52% (CR, 39%); 12-month DOR rate was 66.6% (95% CI, 33.1-86.1%). Median PFS and OS were 3.9 months and not reached, respectively. These results demonstrate that M+R with/without GemOx is well tolerated, and M+R-GemOx has clinical activity in patients with R/R DLBCL.

  View details for DOI 10.1182/bloodadvances.2024013338

  View details for PubMedID 39293083

• Magrolimab Plus Rituximab in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Phase 1/2 Trial 3-Year Follow-up. Blood advances Mehta, A., Popplewell, L., Collins, G. P., Smith, S. M., Flinn, I. W., Bartlett, N. L., Ghosh, N., Hacohen-Kleiman, G., Huo, Y., Su-Feher, L., Renard, C., Advani, R. H., Roschewski, M. 2024

  Abstract

  Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining the anti-cluster-of-differentiation (CD) 47 activity of magrolimab with the anti-CD20 activity of rituximab (M+R) has antitumor activity against R/R iNHL. Here, we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 groups of phase 1b M+R patients received 10-45 mg/kg magrolimab maintenance doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included assessment of circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 (95% CI, 5.6-not estimable) months. The median time-to-response was 1.8 (range, 1.6-5.5) months; median PFS and OS were 7.4 (95% CI, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M+R in patients with iNHL and support further exploration of CD47-based treatment combinations.

  View details for DOI 10.1182/bloodadvances.2024013277

  View details for PubMedID 39213421

• Phase 2 Trial of the Farnesyltransferase Inhibitor Tipifarnib for Relapsed/Refractory Peripheral T Cell Lymphoma. Blood advances Witzig, T. E., Sokol, L., Kim, W. S., de la Cruz, F., Martin Garcia-Sancho, A. M., Advani, R. H., Roncero Vidal, J. M., De Oña, R., Marin-Niebla, A., Izquierdo, A. R., Terol, M. J., Domingo-Domenech, E., Saunders, A., Bendris, N., Mackey, J., Leoni, M., Foss, F. M. 2024

  Abstract

  A phase 2, international, open-label, non-randomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR); secondary endpoints included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n=38 angioimmunoblastic T-cell lymphoma (AITL), n=25 PTCL not otherwise specified (PTCL-NOS), and n=2 other T-cell lymphomas. The ORR was 39.7% (95% CI, 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in AITL patients (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included: neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the non-responder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pre-treated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. ClinicalTrials.gov NCT02464228.

  View details for DOI 10.1182/bloodadvances.2024012806

  View details for PubMedID 38991123

• Clinical Practice Recommendations for Hematopoietic Cell Transplantation and Cellular Therapies in Follicular Lymphoma: A Collaborative Effort on behalf of The American Society of Transplantation and Cellular Therapy and the European Society of Blood and Marrow Transplantation. Transplantation and cellular therapy Iqbal, M., Kumar, A., Dreger, P., Chavez, J., Sauter, C. S., Sureda, A. M., Bachanova, V., Maziarz, R. T., Dreyling, M., Smith, S. M., Jacobson, C., Glass, B., Casulo, C., Oluwole, O. O., Montoto, S., Advani, R., Cohen, J., Salles, G., Hamad, N., Kuruvilla, J., Kahl, B. S., Shadman, M., Kanate, A. S., Budde, L. E., Kamdar, M., Flowers, C., Hamadani, M., Kharfan-Dabaja, M. A. 2024

  Abstract

  Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project. Key statements/recommendations are as follows: 1) Autologous HCT is recommended as an option for consolidation therapy in patients with progression of untransformed disease within 24 months of front line chemoimmunotherapy and upon achieving a complete (CR) or partial response (PR) to salvage second line therapies; 2) CAR-T is considered as a treatment option for patients who did not achieve CR or PR after second or subsequent lines of therapies; 3) Allogeneic HCT is considered as consolidative treatment in relapsed FL patients with chemosensitive disease who have received 3 or more lines of systemic therapy and are the following clinical scenarios: post CAR-T failure; lack of access to CAR-T or have therapy related myeloid neoplasm. These clinical practice recommendations will help guide clinicians managing patients with FL.

  View details for DOI 10.1016/j.jtct.2024.06.025

  View details for PubMedID 38972511

• The role of response adapted therapy in the era of novel agents. Seminars in hematology Schroers-Martin, J. G., Advani, R. H. 2024

  Abstract

  The optimal treatment of classic Hodgkin Lymphoma (cHL) requires an individualized approach, with therapy guided by pretreatment clinical risk stratification and interim response assessment with positron emission tomography (PET). The overall goal is to achieve high cure rates while minimizing acute toxicity and late therapy-related effects. Interim PET-adapted strategies (iPET) were initially developed with traditional chemotherapy, reducing intensity after interim complete response and escalating treatment for patients with iPET+ disease. Recently, novel agents including brentuximab vedotin and the checkpoint inhibitor immunotherapies (CPIs) pembrolizumab and nivolumab have been adopted into the front-line treatment of cHL, and PET-adapted approaches may be relevant for these drugs as well. In this review we discuss response-adapted strategies utilizing novel agents, consider challenges including indeterminate radiographic findings with CPIs, and address emerging techniques for response assessment including new PET-based imaging metrics and the role of circulating tumor DNA.

  View details for DOI 10.1053/j.seminhematol.2024.06.002

  View details for PubMedID 39004520

• Seven-year overall survival analysis from ECHELON-1 study of A plus AVD versus ABVD in patients with previously untreated stage III/IV classical Hodgkin lymphoma Ansell, S. M., Straus, D. J., Connors, J. M., Jurczak, W., Kim, W., Gallamini, A., Ramchandren, R., Friedberg, J. W., Advani, R. H., Hutchings, M., Evens, A. M., Savage, K. J., Eom, H., Feldman, T. A., Abramson, J. S., Dong, C., Savani, B. N., Zomas, A., Fenton, K., Radford, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557401701

• Emerging immunotherapies in the Hodgkin Lymphoma Armamentarium. Expert opinion on emerging drugs Spinner, M. A., Advani, R. H. 2024

  Abstract

  Brentuximab vedotin and the PD-1 inhibitors have improved outcomes for classic Hodgkin lymphoma (cHL), but better therapies are needed for patients who relapse after these agents. Based on improved understanding of cHL biology, there is a robust pipeline of novel therapies in development. In this review, we highlight emerging immunotherapeutic agents and combinations for cHL.We review clinical trials of novel PD-1/PD-L1 inhibitors beyond FDA-approved agents, checkpoint inhibitors targeting CTLA-4, LAG-3, TIM-3, TIGIT, and CD47/SIRP⍺, PD-1 inhibitor combinations with immunomodulatory agents and epigenetic modifying therapies, antibody-drug conjugates, bispecific antibodies, and cellular therapies including anti-CD30 CAR-T and allogeneic NK cell therapy. We review the key safety and efficacy data from published phase 1-2 studies and highlight trials in progress including the first phase 3 trial for PD-1 inhibitor-refractory cHL.Many novel immunotherapies hold great promise in cHL. Rational combinations with existing agents and next generation antibody and CAR-T constructs may improve response rates and durability. Identifying biomarkers of response to these immunotherapies and using more sensitive tools to assess response, such as circulating tumor DNA, may further inform treatment decisions and enable a precision medicine approach in the future.

  View details for DOI 10.1080/14728214.2024.2349083

  View details for PubMedID 38676917

• Long-term outcome of peripheral T-cell lymphomas: Ten-year follow-up of the International Prospective T-cell Project. British journal of haematology Civallero, M., Schroers-Martin, J. G., Horwitz, S., Manni, M., Stepanishyna, Y., Cabrera, M. E., Vose, J., Spina, M., Hitz, F., Nagler, A., Montoto, S., Chiattone, C., Skrypets, T., Perez Saenz, M. A., Priolo, G., Luminari, S., Lymboussaki, A., Pavlovsky, A., Marino, D., Liberati, M., Trotman, J., Mannina, D., Federico, M., Advani, R. 2024

  Abstract

  Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of haematological cancers with generally poor clinical outcomes. However, a subset of patients experience durable disease control, and little is known regarding long-term outcomes. The International T-cell Lymphoma Project (ITCLP) is the largest prospectively collected cohort of patients with PTCLs, providing insight into clinical outcomes at academic medical centres globally. We performed a long-term outcome analysis on patients from the ITCLP with available 10-year follow-up data (n = 735). The overall response rate to first-line therapy was 68%, while 5- and 10-year overall survival estimates were 49% and 40% respectively. Most deaths occurred prior to 5 years, and for patients alive at 5 years, the chance of surviving to 10 years was 84%. However, lymphoma remained the leading cause of death in the 5- to 10-year period (67%). Low-risk International Prognostic Index and Prognostic Index for T-cell lymphoma scores both identified patients with improved survival, while in multivariate analysis, age >60 years and Eastern Cooperative Oncology Group performance status 2-4 were associated with inferior outcomes. The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front-line therapeutic approaches in PTCLs.

  View details for DOI 10.1111/bjh.19433

  View details for PubMedID 38532575

• International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Binkley, M. S., Flerlage, J. E., Savage, K. J., Akhtar, S., Steiner, R., Zhang, X. Y., Dickinson, M., Prica, A., Major, A., Hendrickson, P. G., Hopkins, D., Ng, A., Casulo, C., Baron, J., Roberts, K. B., Al Kendi, J., Balogh, A., Ricardi, U., Torka, P., Specht, L., De Silva, R., Pickard, K., Blazin, L. J., Henry, M., Smith, C. M., Halperin, D., Brady, J., Brennan, B., Senchenko, M. A., Reeves, M., Hoppe, B. S., Terezakis, S., Talaulikar, D., Picardi, M., Kirova, Y., Fergusson, P., Hawkes, E. A., Lee, D., Doo, N. W., Barraclough, A., Cheah, C. Y., Ku, M., Hamad, N., Mutsando, H., Gilbertson, M., Marconi, T., Viiala, N., Maurer, M. J., Eichenauer, D. A., Hoppe, R. T. 2024: JCO2301655

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL.Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation.We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41).In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

  View details for DOI 10.1200/JCO.23.01655

  View details for PubMedID 38531001

• Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Journal for immunotherapy of cancer Brouwer-Visser, J., Fiaschi, N., Deering, R. P., Cygan, K. J., Scott, D., Jeong, S., Boucher, L., Gupta, N. T., Gupta, S., Adler, C., Topp, M. S., Bannerji, R., Duell, J., Advani, R. H., Flink, D. M., Chaudhry, A., Thurston, G., Ambati, S. R., Jankovic, V. 2024; 12 (3)

  Abstract

  Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab.Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing.Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here.This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.

  View details for DOI 10.1136/jitc-2023-008338

  View details for PubMedID 38519055

• Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: a report from The North American Mantle Cell Lymphoma Consortium. Journal of hematology & oncology Vose, J. M., Fu, K., Wang, L., Mansoor, A., Stewart, D., Cheng, H., Smith, L., Yuan, J., Qureishi, H. N., Link, B. K., Cessna, M. H., Barr, P. M., Kahl, B. S., Mckinney, M. S., Khan, N., Advani, R. H., Martin, P., Goy, A. H., Phillips, T. J., Mehta, A., Kamdar, M., Crump, M., Pro, B., Flowers, C. R., Jacobson, C. A., Smith, S. M., Stephens, D. M., Bachanova, V., Jin, Z., Wu, S., Hernandez-Ilizaliturri, F., Torka, P., Anampa-Guzman, A., Kashef, F., Li, X., Sharma, S., Greiner, T. C., Armitage, J. O., Lunning, M., Weisenburger, D. D., Bociek, R. G., Iqbal, J., Yu, G., Bi, C., North American Mantle Cell Lymphoma Consortium 2023; 16 (1): 122

  Abstract

  BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases.RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p<0.0001) and progression-free survival (PFS, p<0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p<0.0001 for OS and p=0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort.CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.

  View details for DOI 10.1186/s13045-023-01520-7

  View details for PubMedID 38104096

• Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling. Nature Alig, S. K., Esfahani, M. S., Garofalo, A., Li, M. Y., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M. C., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J. G., Sworder, B. J., Rai, S., King, D. A., Schultz, A., Bögeholz, J., Su, S., Kathuria, K. R., Liu, C. L., Kang, X., Strohband, M. J., Langfitt, D., Pobre-Piza, K. F., Surman, S., Tian, F., Spina, V., Tousseyn, T., Buedts, L., Hoppe, R., Natkunam, Y., Fornecker, L. M., Castellino, S. M., Advani, R., Rossi, D., Lynch, R., Ghesquières, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., André, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. 2023

  Abstract

  The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels1-4. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq5 we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.

  View details for DOI 10.1038/s41586-023-06903-x

  View details for PubMedID 38081297

• A clinical trial of therapeutic vaccination in lymphoma with serial tumor sampling and single cell analysis. Blood advances Shree, T., Haebe, S. E., Czerwinski, D. K., Eckhert, E., Day, G., Sathe, A., Grimes, S. M., Frank, M. J., Maeda, L., Alizadeh, A. A., Advani, R. H., Hoppe, R. T., Long, S. R., Martin, B. A., Ozawa, M. G., Khodadoust, M. S., Ji, H. P., Levy, R. 2023

  Abstract

  In situ vaccination (ISV) triggers an immune response to tumor-associated antigens at one tumor site that can then tackle disease throughout the body. Here we report clinical and biological results of a phase I/II ISV trial in patients with low-grade lymphoma (NCT02927964) combining an intratumoral TLR9 agonist with local low-dose radiation, and ibrutinib (an inhibitor of B and T cell kinases). Adverse events were predominately low grade. The overall response rate was 50%, including one complete response. All patients experienced tumor reduction at distant sites. Single cell analyses of serial fine needle aspirates from injected and uninjected tumors revealed correlates of clinical response, such as lower CD47 and higher MHCII expression on tumor cells, enhanced T and NK cell effector function, and reduced immune suppression from TGFß and inhibitory T regulatory 1 cells. While changes at the local injected site were more pronounced, changes at distant uninjected sites more often associated with clinical responses. Functional immune response assays and tracking of T cell receptor sequences provided evidence of treatment-induced tumor-specific T cell responses. Induction of immune effectors and reversal of negative regulators were both important in producing clinically meaningful tumor responses. NCT02927964.

  View details for DOI 10.1182/bloodadvances.2023011589

  View details for PubMedID 37939259

• Genomic, Transcriptional, and Immunological Validation of Distinct Molecular Subtypes of Classic Hodgkin Lymphoma through Tissue-Based and Noninvasive Methods Alig, S. K., Esfahani, M., Garofalo, A., Li, M., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J., Sworder, B. J., Rai, S., King, D., Schultz, A., Bogeholz, J., Su, S., Kathuria, K. R., Liu, C., Kang, X., Langfitt, D. M., Pobre-Piza, K., Tian, F., Strohband, M. J., Spina, V., Tousseyn, T., Buedts, L., Fornecker, L., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Ghesquieres, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186810

  View details for Web of Science ID 001159306700178

• PET4 Response As an Independent Predictor of Long-Term Outcomes in ECHELON2 (A+CHP Vs. CHOP) in CD30+PTCL Iyer, S. P., Mehta-Shah, N., Advani, R. H., Bartlett, N. L., Christensen, J., Morschhauser, F., Domenech, E., Pagani, C., Kim, W., Alpdogan, O., Suh, C., Feldman, T., Tilly, H., Zinzani, P., Rambaldi, A., Belada, D., Mayer, J., Choi, I., Cheong, J., Jain, S., Keenan, F., Fanale, M. A., Savage, K. J., Horwitz, S. M. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-184933

  View details for Web of Science ID 001159740302183

• Efficacy and Safety of Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study Advani, R. H., Avigdor, A., Balari, A., Lavie, D., Hohaus, S., Zaucha, J. M., Hua, V., Zilioli, V., Gazitua, R., Ozcan, M., Odeleye-Ajakaye, A., Reddy, N., Marinello, P., Winter, J. N. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-181171

  View details for Web of Science ID 001159740302177

• Investigating the Cell States and Prognostic Impact of Tumor Microenvironment Ecosystems in Classic Hodgkin Lymphoma Su, S., Subramanian, A., Flerlage, T., Flerlage, J. E., Alig, S. K., Moding, E. J., Hoppe, R. T., Advani, R. H., Natkunam, Y., Alizadeh, A. A., Binkley, M. S. AMER SOC HEMATOLOGY. 2023

  View details for Web of Science ID 001159740302125

• Development and Validation of the Early-Stage Hodgkin Lymphoma (HL) International Prognostication Index (E-HIPI): A Report from the Hodgkin Lymphoma International Study for Individual Care (HoLISTIC) Consortium Evens, A. M., Rodday, A., Maurer, M. J., Advani, R. H., Andre, M., Gallamini, A., Hay, A. E., Hodgson, D., Hoppe, R. T., Hutchings, M., Johnson, P., Link, B. K., Opat, S., Raemaekers, J. M., Upshaw, J., Xiang, Q., Counsell, N., Parsons, S. K., Radford, J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-173320

  View details for Web of Science ID 001159740302167

• Results from an Intergroup Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Classic Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Research Group (E4412) Diefenbach, C. S., Jegede, O., Ansell, S. M., Steidl, C., Natkunam, Y., Scott, D. W., Mehta-Shah, N., Amengual, J. E., Forlenza, C. J., Cole, P. D., Bartlett, N. L., David, K. A., Advani, R. H., Ambinder, R. F., Thomas, S., Ibrahimi, S., Kahl, B. S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-184531

  View details for Web of Science ID 001159306702120

• Loncastuximab in High-Risk and Heavily-Pretreated Relapsed/Refractory Diffuse Large BCell Lymphoma: A Real World Analysis from 21 US Centers Ayers, E., Zelikson, V., Gurumurthi, A., Sawalha, Y., Annunzio, K., Saha, A., Dong, N., Qualls, D., Amoozgar, B., Kahl, B. S., Baird, J. H., Challa, P., Huntington, S. F., Santos, J., Bair, S. M., Narkhede, M. S., Li, S., Frosch, Z. K., Ho, C. I., Smith, S. D., Winter, A., Landsburg, D. J., Furqan, F., Hamadani, M., Baird, K., Romancik, J. T., Alharthy, H., Law, J., Bojanini, L., Advani, R. H., Hu, B., Johnson, P., Grover, N. S., Kundu, D., Merrill, M., Crombie, J. L., Shafagati, N., Sterling, C., Nastoupil, L. J., Epperla, N. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-174257

  View details for Web of Science ID 001159306701069

• NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023. Journal of the National Comprehensive Cancer Network : JNCCN Zelenetz, A. D., Gordon, L. I., Abramson, J. S., Advani, R. H., Andreadis, B., Bartlett, N. L., Budde, L. E., Caimi, P. F., Chang, J. E., Christian, B., DeVos, S., Dholaria, B., Fayad, L. E., Habermann, T. M., Hamid, M. S., Hernandez-Ilizaliturri, F., Hu, B., Kaminski, M. S., Karimi, Y., Kelsey, C. R., King, R., Krivacic, S., LaCasce, A. S., Lim, M., Messmer, M., Narkhede, M., Rabinovitch, R., Ramakrishnan, P., Reid, E., Roberts, K. B., Saeed, H., Smith, S. D., Svoboda, J., Swinnen, L. J., Tuscano, J., Vose, J. M., Dwyer, M. A., Sundar, H. 2023; 21 (11): 1118-1131

  Abstract

  Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

  View details for DOI 10.6004/jnccn.2023.0057

  View details for PubMedID 37935098

• Investigating PET Responses to Treatment in Nodular Lymphocyte-Predominant Hodgkin Lymphoma. International journal of radiation oncology, biology, physics Park, N. J., Hiniker, S. M., Guo, H. H., Advani, R. H., Hoppe, R. T., Binkley, M. S. 2023; 117 (2S): e480

  Abstract

  PURPOSE/OBJECTIVE(S): There is no standard treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Although response by positron emission tomography (PET) for classic Hodgkin lymphoma (cHL) has allowed for response-adapted treatment, similar approaches for NLPHL have not been developed. This is in part due to the lack of data for PET response to treatment. Therefore, we sought to investigate PET responses to management for NLPHL.MATERIALS/METHODS: We retrospectively identified 47 patients who were diagnosed with or treated for NLPHL between 2001-2018 at a single institution and underwent a staging PET. We recorded clinical data and PET metrics for patients who received various forms of management, including chemotherapy (CT), radiation therapy (RT), combined modality therapy (CMT = CT+RT, with rituximab in a subset), rituximab monotherapy, and observation after excision. Metabolic response was scored according to the Deauville 5-point scale criteria, with complete metabolic response defined as a score 1-3.RESULTS: We identified 47 patients with median age of 26 (IQR = 17-50). They predominantly were male (74.5%) and had early stage (23.4% I, 36.2% II) versus advanced stage (29.8% III, 10.5% IV) NLPHL. The majority of patients had their immunoarchitectural pattern scored (n = 36, 76.6%), with typical pattern (A/B) being the most frequent type (58.3%). The median follow-up was 5.7 years (IQR = 2.3-9.3). Overall survival was 100% at 5 years and 92.3% at 10 years. Primary management included CMT (n = 10, 21.3%; with rituximab in a subset n = 1, 10.0%), CT alone (n = 22, 46.8%; with rituximab in a subset n = 5, 22.7%), RT alone (n = 8, 17.0%), rituximab alone (n = 3, 6.4%), and observation after excision (n = 4, 8.5%). On baseline PET, median SUVmax was 10.7 (range = 1.7-35.4). Of the 10 patients who received CMT, the complete metabolic response rates were 42.9% at interim-chemotherapy PET and 75% at post-chemotherapy PET, which improved to 100% after consolidative radiotherapy. There was no difference in complete metabolic response rate to chemotherapy for typical versus variant pattern (P = 0.60). Of the 22 patients who received CT alone, 66.7% had a complete metabolic response at the interim PET and 72.7% at the end of chemotherapy. For RT, rituximab alone, and observation, the complete metabolic response rates at median 3 months (range 1-5 months) after treatment were 87.5%, 66.7%, 75.0%, respectively.CONCLUSION: Based on our cohort, we found that patients with NLPHL had a lower complete metabolic response to CT (75%) compared to cHL (85-90%) and PET-response was improved following RT for those receiving CMT. There was no significant difference in PET-response for those with variant versus typical immunoarchitectural patterns. Our findings will allow for the development of PET response-adapted therapy for NLPHL.

  View details for DOI 10.1016/j.ijrobp.2023.06.1699

  View details for PubMedID 37785523

• Overall survival of cHL patients who progress after autologous stem cell transplant: results in novel agent era. Blood advances Desai, S. H., Spinner, M. A., Evens, A. M., Sýkorová, A., Bachanova, V., Goyal, G., Kahl, B. S., Dorritie, K. A., Azzi, J., Kenkre, V. P., Chang, C., Michalka, J., Ansell, S. M., Fusco, B., Sumransub, N., Hatic, H., Saba, R., Ibrahim, U., Harris, E. I., Shah, H. R., Wagner-Johnston, N. D., Arai, S., Nowakowski, G. S., Mocikova, H., Jagadeesh, D., Blum, K., Diefenbach, C., Iyengar, S., Rappazzo, K. C., Baidoun, F., Choi, Y., Prochazka, V., Advani, R. H., Micallef, I. N. 2023

  Abstract

  In pre-novel agent era, median post progression overall survival (PPS) of classic Hodgkin lymphoma (cHL) patients (pts) who progress after ASCT have been 2-3 years. Recently, Checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved depth and durability of response in this population. Here we report estimate of PPS in pts with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult pts with relapsed cHL after ASCT were included. Study objective was post progression overall survival (PPS), defined at time from post-transplant progression to death or last follow up. Of 1158 pts who underwent ASCT, 367 had progressive disease. Median age was 34 years (range: 27-46), 192 were male. Median PPS was 114.57 (CI95: 91-NA) months, 9.5 years. In multivariable analysis, increasing age, progression within 6 months and pre-ASCT positive PET were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS compared to no CPI/no BV group (HR: 3.5, CI95: 1.6-7.8, p=0.001). Receipt of alloSCT did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably to prior reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to AlloSCT was not associated with PPS in this population.

  View details for DOI 10.1182/bloodadvances.2023011205

  View details for PubMedID 37729621

• Novel agents in relapsed/refractory diffuse large B-cell lymphoma. Hematological oncology Varma, G., Goldstein, J., Advani, R. H. 2023; 41 Suppl 1: 92-106

  Abstract

  Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), ineligible for or relapsing after autologous stem-cell transplant or chimeric antigen-receptor T-cell therapies have poor outcomes. Several novel agents, polatuzumab vedotin, tafasitamab, loncastuximab tesirine, and selinexor, have been approved and offer new opportunities for this difficult to treat population. Studies are evaluating combination of these agents with chemotherapy and other emerging therapies. Additionally, advances in our understanding of DLBCL biology, genetics, and immune microenvironment have allowed for the identification of new therapeutic targets like Ikaros and Aiolos, IRAK4, MALT1, and CD47 with several agents in ongoing clinical trials. In this chapter we review updated data supporting the use of the approved agents and discuss other emerging novel therapies for patients with R/R DLBCL.

  View details for DOI 10.1002/hon.3143

  View details for PubMedID 37294966

• 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023. Hematological oncology Binkley, M. S., Flerlage, J. E., Borchmann, P., Fuchs, M., Hartmann, S., Eich, H. T., Savage, K. J., Lo, A., Skinnider, B., Akhtar, S., Rauf, M. S., Maghfoor, I., Pinnix, C. C., Steiner, R., Milgrom, S. A., Vega, F., Alomari, M., Zhang, X., Collins, G., Advani, R. H., Metzger, M., Dickinson, M., Wirth, A., Tsang, R., Prica, A., Major, A., Smith, S., Hendrickson, P. G., Kelsey, C. R., Hopkins, D., McKay, P., Ng, A., Koenig, J., Constine, L. S., Casulo, C., Sakthivel, G., Baron, J., Plastaras, J. P., Roberts, K. B., Gao, S., Al Kendi, J., Al Rahbi, N., Balogh, A., Levis, M., Ricardi, U., Sridhar, A., Torka, P., Specht, L., De Silva, R., Shah, N., Pickard, K., Osborne, W., Blazin, L. J., Henry, M., Chang, I., Smith, C. M., Halperin, D., Miall, F., Brady, J., Mikhaeel, G., Brennan, B., Penn, A., Senchenko, M. A., Volchkov, E. V., Reeves, M., Hoppe, B., Terezakis, S., Talaulikar, D., Della Pepa, R., Picardi, M., Kirova, Y., Fergusson, P., Northend, M., Shankar, A., Maurer, M. J., Natkunam, Y., Kelly, K. M., Eichenauer, D. A., Hoppe, R. T. 2023; 41 Suppl 2: 100-101

  View details for DOI 10.1002/hon.3163_62

  View details for PubMedID 39112383

• 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023. Hematological oncology Alig, S. K., Esfahani, M. S., Garofalo, A., Li, M. Y., Rossi, C., Adams, R., Binkley, M. S., Jin, M. C., Olsen, M., Telenius, A., Mutter, J., Sworder, B. J., Schroers-Martin, J., King, D. A., Schultz, A., Bögeholz, J., Su, S., Kathuria, K. R., Kang, X., Liu, C. L., Spina, V., Tousseyn, T., Buedts, L., Flerlage, T., Flerlage, J. E., Castellino, S. M., Advani, R., Rossi, D., Lynch, R., Ghesquières, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., André, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. 2023; 41 Suppl 2: 96-98

  View details for DOI 10.1002/hon.3163_60

  View details for PubMedID 39112400

• 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023. Hematological oncology Manni, M., Chiattone, C. S., Prince, M. H., Pavlovsky, A., Tomuleasa, C., Miranda, E., Kriachok, I., Hawkes, E. A., Fiad, L., Hitz, F., Alpdogan, O., Nair, R., Advani, R., Minoia, C., Horwitz, S., Cabrera, M. E., Vose, J. M., Lymboussakis, A., Civallero, M., Skrypets, T., Stepanishyna, Y., Federico, M., Luminari, S. 2023; 41 Suppl 2: 311-312

  View details for DOI 10.1002/hon.3164_218

  View details for PubMedID 39112146

• 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023. Hematological oncology Civallero, M., Advani, R., Horwitz, S., Manni, M., Cabrera, M. E., Vose, J., Spina, M., Hits, F., Nagler, A., Montoto, S., Miranda, E., Skrypets, T., Saenz, M. P., Priolo, G., Luminari, S., Lymboussakis, A., Pavlovsky, A., Marino, D., Liberati, M., Trotman, J., Mannina, D., Federico, M. 2023; 41 Suppl 2: 491-492

  View details for DOI 10.1002/hon.3164_360

  View details for PubMedID 39112225

• Final results of a phase II study of CHOEP plus lenalidomide as initial therapy for patients with stage II-IV peripheral T-cell lymphoma. British journal of haematology Stuver, R., Horwitz, S. M., Advani, R. H., Vose, J. M., Lee, H. J., Mehta-Shah, N., Zain, J. M., Haverkos, B., Lechowicz, M. J., Moskowitz, A. J., Pham, L. Q., Leyden, E., Ansell, S. M., Lunning, M. A. 2023

  Abstract

  There remains no one standard induction for nodal-based peripheral T-cell lymphoma (PTCL). We conducted a phase II study of lenalidomide plus CHOEP as a novel induction strategy. Patients received CHOEP at standard doses in combination with 10 mg of lenalidomide on days 1-10 of a 21-day cycle for six cycles of therapy followed by observation, high-dose therapy with autologous stem cell rescue, or maintenance lenalidomide per provider preference. Among 39 patients evaluable for efficacy, the objective response rate after six cycles was 69%, with complete response in 49%, partial response in 21%, stable disease in 0% and progressive disease in 13%. Thirty-two patients (82%) completed full induction, and seven patients (18%) discontinued for toxicity, primarily hematologic. Any grade hematologic toxicity occurred in over 50% of patients, with grade 3 or 4 febrile neutropenia occurring in 35% of patients despite mandated growth factors. With a median followup of surviving patients of 21.3 months, the estimated 2-year progression-free and overall survival were 55% (95% CI 37%-70%) and 78% (95% CI 59%-89%), respectively. In sum, six cycles of lenalidomide plus CHOEP resulted in a modest response rate primarily due to hematologic toxicity, which prevented all patients from completing planned induction.

  View details for DOI 10.1111/bjh.18885

  View details for PubMedID 37217196

• The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network. Blood advances Hapgood, G., Civallero, M., Stepanishyna, Y., Vose, J. M., Cabrera, M. E., Advani, R. H., Pileri, S. A., Manni, M., Horwitz, S. M., Foss, F. M., Hitz, F., Radford, J., Dlouhy, I., Chiattone, C. S., Kim, W., Skrypets, T., Nagler, A., Trotman, J., Luminari, S., Federico, M. 2023

  Abstract

  The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP)(NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. 127 patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60y, elevated LDH and low serum albumin were independent prognostic factors. The model identified three groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-yr OS of 78% [95% CI 29-127], 46% [95% CI 24-68], and 25% [95% CI 20-30], respectively (P<0·001) and 5-yr PFS of 66% [95% CI 33-99], 37% [95% CI 9-65], and 17% [95% CI 9-25], respectively (P<0·001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the three groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

  View details for DOI 10.1182/bloodadvances.2023010037

  View details for PubMedID 37163360

• Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment. HemaSphere Stevens, W. B., Los-de Vries, G. T., Langois-Jacques, C., Clear, A. J., Stathi, P., Sander, B., Rosenwald, A., Calaminici, M., Hoster, E., Hiddemann, W., Gaulard, P., Salles, G., Klapper, W., Xerri, L., Burton, C., Tooze, R. M., Smith, A. G., Buske, C., Scott, D. W., Natkunam, Y., Advani, R., Sehn, L. H., Raemaekers, J., Gribben, J., Lockmer, S., Kimby, E., Kersten, M. J., Maucort-Boulch, D., Ylstra, B., van Dijk, E., de Jong, D. 2023; 7 (4): e863

  View details for DOI 10.1097/HS9.0000000000000863

  View details for PubMedID 37038467

• Improved overall survival in stage III/ IV classical Hodgkin lymphoma: An updated analysis of ECHELON-1 Collins, G. P., Ansell, S. M., Straus, D. J., Connors, J. M., Dlugosz-Danecka, M., Kim, W., Gallamini, A., Ramchandren, R., Friedberg, J. W., Advani, R., Hutchings, M., Evens, A. M., Smolewski, P., Savage, K. J., Bartlett, N. L., Eom, H., Abramson, J. S., Feldman, T., Dong, C., Campana, F., Fenton, K., Puhlmann, M., Radford, J., ECHELON 1 Study Grp WILEY. 2023: 105

  View details for Web of Science ID 001049283000173

• Treatment Approaches for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Clinical lymphoma, myeloma & leukemia Binkley, M. S., Advani, R. H. 2023

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare variant of Hodgkin lymphoma characterized by a persistent risk of relapse but an excellent overall survival. Historically, it was treated similarly to classic Hodgkin lymphoma, but efforts have been made to deintensify treatment due to risk of late toxicity associated with intensive therapy. For patients with completely resected stage IA NLPHL, no further treatment may be considered, particularly for pediatric patients. For those with stage I-II NLPHL without risk factors such as B symptoms, sites>2, or variant pattern histology, lower intensity treatment with radiotherapy or chemotherapy alone may be sufficient. However, combined modality therapy is a standard treatment for favorable and unfavorable risk stage I-II NLPHL associated with excellent progression-free and overall survival rates. For patients with advanced stage NLPHL, the optimal chemotherapy is not defined, but R-CHOP appears to be an effective treatment. Efforts to study NLPHL through multicenter collaborative efforts are crucial to develop evidence based and individualized treatments for patients with NLPHL.

  View details for DOI 10.1016/j.clml.2023.03.014

  View details for PubMedID 37076366

• Report of consensus panel 1 from the 11th International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naive patients. Seminars in hematology Buske, C., Castillo, J. J., Abeykoon, J. P., Advani, R., Arulogun, S. O., Branagan, A. R., Cao, X., D'Sa, S., Hou, J., Kapoor, P., Kastritis, E., Kersten, M. J., LeBlond, V., Leiba, M., Matous, J. V., Paludo, J., Qiu, L., Tam, C. S., Tedeschi, A., Thomas, S. K., Tohidi-Esfahani, I., Varettoni, M., Vos, J. M., Garcia-Sanz, R., San-Miguel, J., Dimopoulos, M. A., Treon, S. P., Trotman, J. 2023

  Abstract

  Consensus Panel 1 (CP1) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with updating guidelines for the management of symptomatic, treatment-naive patients with WM. The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function. For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable. Covalent BTK inhibitors (cBTKi) offer a continuous, generally well-tolerated alternative for the primary treatment of WM patients, particularly those unsuitable for CIT. In a Phase III randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM. While the overall findings of a prospective, randomized trial updated at IWWM-11 did not show superiority of fixed duration rituximab maintenance over observation following attainment of a major response to Benda-R induction, a subset analysis showed benefit in patients >65 years and those with a high IPPSWM score. Whenever possible, the mutational status of MYD88 and CXCR4 should be determined before treatment initiation, as alterations in these 2 genes predict sensitivity towards cBTKi activity. Treatment approaches for WM-associated cryoglobulins, cold agglutinins, AL amyloidosis, Bing-Neel syndrome (BNS), peripheral neuropathy, and hyperviscosity syndrome follow the common principle of reducing tumor and abnormal protein burden rapidly and deeply to improve symptoms. In BNS, ibrutinib can be highly active and produce durable responses. In contrast, cBTKi are not recommended for treating AL amyloidosis. The panel emphasized that continuous improvement of treatment options for symptomatic, treatment-naive WM patients critically depends on the participation of patients in clinical trials, whenever possible.

  View details for DOI 10.1053/j.seminhematol.2023.03.005

  View details for PubMedID 37099027

• Report of consensus panel 2 from the 11th international workshop on Waldenstrom's macroglobulinemia on the management of relapsed or refractory WM patients. Seminars in hematology D'Sa, S., Matous, J. V., Advani, R., Buske, C., Castillo, J. J., Gatt, M., Kapoor, P., Kersten, M. J., Leblond, V., Leiba, M., Palomba, M. L., Paludo, J., Qiu, L., Sarosiek, S., Shadman, M., Talaulikar, D., Tam, C. S., Tedeschi, A., Thomas, S. K., Tohidi-Esfahani, I., Trotman, J., Varettoni, M., Vos, J., Garcia-Sanz, R., San-Miguel, J., Dimopoulos, M. A., Treon, S. P., Kastritis, E. 2023

  Abstract

  The consensus panel 2 (CP2) of the 11th International Workshop on Waldenstrom's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

  View details for DOI 10.1053/j.seminhematol.2023.03.003

  View details for PubMedID 37147252

• Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents. Blood Spinner, M. A., Sica, R. A., Tamaresis, J. S., Lu, Y., Chang, C., Lowsky, R., Frank, M. J., Johnston, L. J., Miklos, D. B., Muffly, L., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Weng, W. K., Binkley, M. S., Hoppe, R. T., Advani, R. H., Arai, S. 2023

  Abstract

  The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade following the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for R/R cHL patients who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011-2020 (N=183) compared to 2001-2010 (N=159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era (4-year estimates 89.1% vs 79.0%, HR 0.53, 95% CI 0.33-0.85, p=0.011) with a trend towards lower non-relapse mortality beyond 2 years post-transplant. Among patients who progressed after AHCT, 4-year post-progression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients transplanted in the modern era, age ³45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, while receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS (HR 0.21, 95% CI 0.05-0.80, p=0.030). Extranodal disease at relapse was associated with inferior OS (HR 3.12, 95% CI 1.25-7.77, p=0.014). Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

  View details for DOI 10.1182/blood.2022018827

  View details for PubMedID 36857637

• Lack of Reproducibility of Histopathological Features in MYC-rearranged Large B-cell Lymphoma Using Digital Whole Slide Images: A Study from the Lunenburg Lymphoma Biomarker Consortium. Histopathology Natkunam, Y., de Jong, D., Farinha, P., Gaulard, P., Klapper, W., Rosenwald, A., Sander, B., Tooze, R., Advani, R., Burton, C., Gribben, J. G., Kersten, M. J., Kimby, E., Lenz, G., Molina, T., Morschhauser, F., Scott, D., Sehn, L., Stevens, W., Clear, A., Baia, M., Habi, A., Elsensohn, M. H., Langlois-Jacques, C., Maucort-Boulch, D., Calaminici, M. 2023

  Abstract

  Subclassification of large B-cell lymphoma (LBCL) is challenging due to the overlap in histopathologic, immunophenotypic, and genetic data. In particular, the criteria to separate diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescent in situ hybridization (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study of how various histopathological features are used by a panel of eight expert hematopathologists.Digital whole slide images of hematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardized consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytologic characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or IG-partner FISH-based designations or clinical outcome measures.Our findings indicate that there are no specific conventional morphological parameters that help subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication.

  View details for DOI 10.1111/his.14896

  View details for PubMedID 36849712

• Investigating and modeling positron emission tomography factors associated with large cell transformation from low-grade lymphomas. EJHaem Obeid, J. P., Hiniker, S. M., Schroers-Martin, J., Guo, H. H., No, H. J., Moding, E. J., Advani, R. H., Alizadeh, A. A., Hoppe, R. T., Binkley, M. S. 2023; 4 (1): 90-99

  Abstract

  Low-grade lymphomas have a 1%-3% annual risk of transformation to a high-grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case-control series of patients matched by histology and follow-up time. We measured PET parameters including maximum standard uptake value (SUV-max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)-based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow-up time was similar. We observed a significant incremental increase in SUV-max and TLG between control, pretransformation and post-transformation groups (P < 0.05). By multivariable analysis, we identified a significant interaction between SUV-max and TLG such that SUV-max had highest significance for low volume cases (P = 0.04). We developed a scoring model incorporating SUV-max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low-grade lymphoma.

  View details for DOI 10.1002/jha2.615

  View details for PubMedID 36819184

  View details for PubMedCentralID PMC9928791

• Checkpoint inhibitor-based salvage regimens prior to autologous stem cell transplant improve event-free survival in relapsed/refractory classic Hodgkin lymphoma. American journal of hematology Desai, S. H., Spinner, M. A., David, K., Bachanova, V., Goyal, G., Kahl, B., Dorritie, K., Azzi, J., Kenkre, V. P., Arai, S., Chang, C., Fusco, B., Sumransub, N., Hatic, H., Saba, R., Ibrahim, U., Harris, E. I., Shah, H., Murphy, J., Ansell, S., Jagadish, D., Orellana-Noia, V., Diefenbach, C., Iyenger, S., Rappazzo, K. C., Mishra, R., Choi, Y., Nowakowski, G. S., Advani, R. H., Micallef, I. N. 2023

  Abstract

  Clinical trials of novel salvage therapies have encouraging outcomes for relapsed/refractory transplant-eligible classic Hodgkin lymphoma (R/R cHL) but comparison with conventional chemotherapy is lacking. Herein, we report the final analysis of a multicenter retrospective cohort of R/R cHL assessing outcomes by type of salvage therapy before autologous stem cell transplant (ASCT). R/R cHL patients who underwent ASCT at 14 institutions across the United States were included. Outcomes were compared among patients receiving conventional chemotherapy, brentuximab vedotin (BV)+chemotherapy, BV alone, and a checkpoint inhibitor (CPI)-based regimens before ASCT. Study endpoints included event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All endpoints are defined from relapse. Of 936 patients, 728 received conventional chemotherapy, 73 received BV+chemotherapy, 70 received BV alone, and 65 received CPI-based regimens prior to ASCT. When adjusted for time to relapse, pre-ASCT response and use of BV maintenance, patients receiving CPI-based regimens had superior 2-year EFS compared to conventional chemotherapy, BV+chemotherapy, and BV alone (79.7, 49.6, 62.3, and 36.9%, respectively, p<.0001). Among 649 patients transplanted after 1 line of salvage therapy, CPI-based regimens were associated with superior 2-year PFS compared to conventional chemotherapy (98% vs. 68.8%, hazard ratio: 0.1, 95% confidence interval: 0.03-0.5, p<.0001). OS did not differ by pre-ASCT salvage regimen. In this large multicenter retrospective study, CPI-based regimens improved EFS and PFS compared to other salvage regimens independent of pre-ASCT response. These data support earlier sequencing of CPI-based regimens in R/R cHL in the pre-ASCT setting.

  View details for DOI 10.1002/ajh.26827

  View details for PubMedID 36629030

• Anti-CD30 antibody-drug conjugate therapy in lymphoma: current knowledge, remaining controversies, and future perspectives. Annals of hematology Prince, H. M., Hutchings, M., Domingo-Domenech, E., Eichenauer, D. A., Advani, R. 2022

  Abstract

  CD30 is overexpressed in several lymphoma types, including classic Hodgkin lymphoma (cHL), some peripheral T-cell lymphomas (PTCL), and some cutaneous T-cell lymphomas. The antibody-drug conjugate brentuximab vedotin targets CD30-positive cells and has been evaluated for the treatment of various lymphoma entities. This narrative review summarizes 10years of experience with brentuximab vedotin for the treatment of CD30-positive lymphomas, discusses novel therapies targeting CD30 in development, and highlights remaining controversies relating to CD30-targeted therapy across lymphoma types. The collective body of evidence for brentuximab vedotin demonstrates that exploitation of CD30 can provide sustained benefits across a range of different CD30-positive lymphomas, in both clinical trials and real-world settings. Preliminary experience with brentuximab vedotin in combination with immune checkpoint inhibitors for relapsed/refractory cHL is encouraging, but further exploration is required. The optimal use of brentuximab vedotin for first-line therapy of PTCL remains to be determined. Further research is required on brentuximab vedotin treatment in high-risk patient populations, and in rare lymphoma subtypes, for which no standard of care exists. Novel therapies targeting CD30 include chimeric antigen receptor therapies and bispecific antibody T-cell engagers, which may be expected to further improve outcomes for patients with CD30-positive lymphomas in the coming years.

  View details for DOI 10.1007/s00277-022-05054-9

  View details for PubMedID 36512081

• Brentuximab Vedotin Combined with Chemotherapy in Newly Diagnosed, Early-Stage, Unfavorable-Risk Hodgkin Lymphoma: Extended Follow-up with Evaluation of Baseline Metabolic Tumor Volume and PET2 Stuver, R., Michaud, L., Casulo, C., Advani, R. H., Budde, E. L., Barr, P. M., Batlevi, C., Caron, P. C., Constine, L. S., Dandapani, S., Drullinsky, P., Friedberg, J. W., Grieve, C., Hamilton, A., Hamlin, P. A., Hoppe, R., Horwitz, S. M., Khan, N., Matasar, M. J., Noy, A., Palomba, M., Schoder, H., Straus, D. J., Vemuri, S., Yahalom, J., Yang, J. C., Younes, A., Zelenetz, A. D., Moskowitz, C. H., Kumar, A., Moskowitz, A. J. AMER SOC HEMATOLOGY. 2022: 1756-1758

  View details for DOI 10.1182/blood-2022-156382

  View details for Web of Science ID 000893223201316

• Trial in Progress: First Report of the Phase 1/2 Study of the Safety and Efficacy of CPO107, a Bispecific Agent Targeting CD20/CD47 in CD20 Expressing Non-Hodgkin Lymphoma (NHL) Skarbnik, A. P., Chen, F. L., Mountjoy, L., Myint, Z., Young, P. A., Whiteley, A. R., Novick, S., Su, J., Wang, Q., Romanko, K., Wang, X., Li, Y., Zhong, S., Song, L., Advani, R. H. AMER SOC HEMATOLOGY. 2022: 12059-12060

  View details for DOI 10.1182/blood-2022-164746

  View details for Web of Science ID 000893230305040

• Age, Albumin, and LDH Predict Outcome of Patients with Limited Stage Peripheral T Cell Lymphoma: A Prognostic Model Developed on 244 Cases Enrolled in the T Cell Project 1 By the International T Cell Project Network Hapgood, G., Civallero, M., Stepanishyna, Y., Vose, J. M., Elena Cabrera, M., Advani, R. H., Pileri, S. A., Manni, M., Horwitz, S. M., Foss, F. M., Hitz, F., Radford, J., Dlouhy, I., Chiattone, C. S., Kim, W., Skrypets, T., Nagler, A., Trotman, J., Luminari, S., Federico, M. AMER SOC HEMATOLOGY. 2022: 1476-1478

  View details for DOI 10.1182/blood-2022-158883

  View details for Web of Science ID 000893223201199

• Magrolimab in Combination with Rituximab plus Chemotherapy in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Maakaron, J., Asch, A. S., Popplewell, L. L., Collins, G. P., Flinn, I. W., Ghosh, N., Keane, C., Ku, M., Mehta, A., Roschewski, M., O'Hear, C., Ren, X., Villa, B., Lal, I., Smith, S. M., Advani, R. H. AMER SOC HEMATOLOGY. 2022: 3728-3730

  View details for DOI 10.1182/blood-2022-167772

  View details for Web of Science ID 000893223203336

• Distinct Molecular Subtypes of Classic Hodgkin Lymphoma Identified By Comprehensive Noninvasive Profiling Alig, S. K., Esfahani, M., Li, M. Y., Adams, R., Garofalo, A., Jin, M. C., Olsen, M., Telenius, A., Sworder, B., Schroers-Martin, J., King, D. A., Rossi, C., Schultz, A., Kathuria, K. R., Liu, C., Spina, V., Buedts, L., Flerlage, J. E., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1295-1296

  View details for DOI 10.1182/blood-2022-164744

  View details for Web of Science ID 000893223201127

• Exploratory Analysis of Factors Influencing Efficacy and Safety of Camidanlumab Tesirine: Data from the Open-Label, Multicenter, Phase 2 Study of Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL) Herrera, A. F., Ansell, S. M., Zinzani, P., Radford, J., Maddocks, K. J., Pinto, A., Collins, G. P., Bachanova, V., Bartlett, N. L., Bence-Bruckler, I., Hamadani, M., Kline, J., Mayer, J., Savage, K. J., Advani, R. H., Caimi, P. F., Casasnovas, R., Feldman, T. A., Hess, B. T., Bastos-Oreiro, M., Iyengar, S., Szomor, A., Townsend, W., Andre, M., Dyczkowski, J., Eisen, S., Urban, A., Pantano, S., Cruz, H. G., Wang, L., Negievich, Y., Wuerthner, J., Carlo-Stella, C. AMER SOC HEMATOLOGY. 2022: 3673-3677

  View details for DOI 10.1182/blood-2022-157583

  View details for Web of Science ID 000893223203312

• Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Stage Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study Advani, R. H., Avigdor, A., Sureda, A., Lavie, D., Hohaus, S., Zaucha, J. M., Vu Minh Hua, Zilioli, V., Gazitua, R., Ozcan, M., Odeleye-Ajakaye, A., Ogbu, U. C., Nahar, A., Winter, J. N. AMER SOC HEMATOLOGY. 2022: 1759-1760

  View details for DOI 10.1182/blood-2022-163787

  View details for Web of Science ID 000893223201317

• Viral cfDNA Profiling Reveals Distinct EBV Subtypes and Stratifies Risk in Hodgkin Lymphomas Garofalo, A., Alig, S. K., Schroers-Martin, J., Shyam, R., Olsen, M., Kurtz, D. M., Rossi, C., Schultz, A., Kathuria, K. R., Liu, C., Spina, V., Flerlage, J. E., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Casasnovas, O., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1318-1319

  View details for DOI 10.1182/blood-2022-159230

  View details for Web of Science ID 000893223201135

• Polatuzumab Vedotin Combined with R-ICE (PolaR-ICE) As Second-Line Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Herrera, A. F., Chen, L., Crombie, J. L., Cohen, J. B., Advani, R. H., LaCasce, A. S., Popplewell, L. L., Puverel, S., Peters, L., Daniels, S., Godfrey, J., Shouse, G., Mei, M., Kambhampati, S., Budde, L., Nikolaenko, L., Rosen, S. T., Kwak, L. W., Forman, S. J., Matasar, M. J. AMER SOC HEMATOLOGY. 2022: 1065-1067

  View details for DOI 10.1182/blood-2022-165699

  View details for Web of Science ID 000893223201028

• Activating Immune Effectors and Dampening Immune Suppressors Generates Successful Therapeutic Cancer Vaccination in Patients with Lymphoma Shree, T., Haebe, S., Czerwinski, D. K., Eckhert, E., Day, G., Sathe, A., Grimes, S. M., Frank, M. J., Maeda, L. S., Alizadeh, A. A., Advani, R. H., Hoppe, R., Long, S. R., Martin, B., Ozawa, M. G., Khodadoust, M. S., Ji, H. P., Levy, R. AMER SOC HEMATOLOGY. 2022: 6450-6451

  View details for DOI 10.1182/blood-2022-167469

  View details for Web of Science ID 000893223206208

• HL-507 First-Line Brentuximab Vedotin Plus Chemotherapy Improves Overall Survival in Patients With Stage III/IV Classical Hodgkin Lymphoma: An Updated Analysis of ECHELON-1. Clinical lymphoma, myeloma & leukemia Straus, D., Radford, J., Connors, J., Kim, W. S., Gallamini, A., Ramchandren, R., Friedberg, J., Advani, R., Hutchings, M., Evens, A., Smolewski, P., Savage, K., Bartlett, N., Eom, H., Abramson, J., Dong, C., Campana, F., Fenton, K., Puhlmann, M., Ansell, S. 2022; 22 Suppl 2: S350

  Abstract

  CONTEXT: Overall survival (OS) benefit from upfront treatment with new over existing approaches has never been shown in first-line (1L) classical Hodgkin lymphoma (cHL). With newer therapies for relapsed/refractory disease, demonstrating improved OS with 1L therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported a long-term progression-free survival (PFS) benefit with 1L brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage Ill/IV cHL. A+AVD had a manageable long-term safety profile, with fewer second malignancies and more pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years' follow-up.INTERVENTIONS: Patients were randomized 1:1 to receive up to 6 cycles of A+AVD (n=664) or ABVD (n=670) on day 1 and 15, every 28 days.MAIN OUTCOMES MEASURES: OS was the key prespecified secondary endpoint.RESULTS: At a median follow-up of 73 months, 39 and 64 deaths occurred in A+AVD and ABVD arms, respectively; OS significantly favored A+AVD (hazard ratio [HR] 0.590; 95% confidence interval [Cl] 0.396-0.879; p = 0.009). Estimated 6-year OS rates (95% Cl) were 93.9% (91.6-95.5) vs 89.4% (86.6-91.7) with A+AVD vs ABVD, respectively, with a consistently higher OS across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1-85.0) vs 74.5% (70.8-77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% Cl 0.532-0.863]). Overall, A+AVD and ABVD had comparable long-term safety profiles. By the last follow-up, 86% (379/443) of treatment-related peripheral neuropathy cases in the A+AVD arm and 87% (249/286) in the ABVD arm either completely resolved (72% vs 79%, respectively) or were improving (14% vs 8%, respectively). Fewer second malignancies (23 vs 32) and more pregnancies (49 vs 28) were reported in the A+AVD vs ABVD arm, respectively. No new safety signals were identified.CONCLUSIONS: In this updated analysis, A+AVD treatment resulted in a 41% reduction in risk of death vs ABVD, with a manageable safety profile. These outcomes are important in advancing treatment of patients with previously untreated stage Ill/IV cHL.

  View details for DOI 10.1016/S2152-2650(22)01483-5

  View details for PubMedID 36164033

• Camidanlumab Tesirine: Updated Efficacy and Safety in an Open-Label, Multicenter, Phase 2 Study of Patients With Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL) Carlo-Stella, C., Ansell, S., Zinzani, P., Radford, J., Maddocks, K., Pinto, A., Collins, G. P., Bachanova, V., Bartlett, N., Bence-Bruckler, I., Hamadani, M., Kline, J., Mayer, J., Savage, K. J., Advani, R., Caimi, P., Casasnovas, R., Feldman, T., Hess, B., Bastos-Oreiro, M., Iyengar, S., Eisen, S., Negievich, Y., Wang, L., Wuerthner, J., Herrera, A. F. CIG MEDIA GROUP, LP. 2022: S347

  View details for Web of Science ID 000897948100357

• First-Line Brentuximab Vedotin Plus Chemotherapy Improves Overall Survival in Patients With Stage III/ IV Classical Hodgkin Lymphoma: An Updated Analysis of ECHELON-1 Straus, D., Radford, J., Connors, J., Kim, W., Gallamini, A., Ramchandren, R., Friedberg, J., Advani, R., Hutchings, M., Evens, A., Smolewski, P., Savage, K., Bartlett, N., Eom, H., Abramson, J., Dong, C., Campana, F., Fenton, K., Puhlmann, M., Ansell, S. CIG MEDIA GROUP, LP. 2022: S350

  View details for Web of Science ID 000897948100362

• Multicenter Retrospective Analysis of Single-Route Prophylaxis in Aggressive B-Cell Lymphomas Orellana-Noia, V., Reed, D., McCook, A., Sen, J., Barlow, C., Malecek, M., Watkins, M., Kahl, B., Spinner, M., Advani, R., Voorhees, T., Snow, A., Grover, N., Ayers, A., Romancik, J., Liu, Y., Huntington, S., Chavez, J., Saeed, H., Lazaryan, A., Raghunathan, V., Spurgeon, S., Ollila, T., Del Prete, C., Olszewski, A., Ayers, E., Landsburg, D., Echalier, B., Lee, J., Kamdar, M., Caimi, P., Fu, T., Liu, J., David, K., Alharthy, H., Law, J., Karmali, R., Shah, H., Stephens, D., Major, A., Rojek, A., Smith, S., Yellala, A., Kallam, A., Nakhoda, S., Khan, N., Sohail, M., Hill, B., Barrett-Campbell, O., Lansigan, F., Switchenko, J., Cohen, J., Portell, C. CIG MEDIA GROUP, LP. 2022: S381

  View details for Web of Science ID 000897948100422

• ABCL-455 Multicenter Retrospective Analysis of Single-Route Prophylaxis in Aggressive B-Cell Lymphomas. Clinical lymphoma, myeloma & leukemia Orellana-Noia, V., Reed, D., McCook, A., Sen, J., Barlow, C., Malecek, M., Watkins, M., Kahl, B., Spinner, M., Advani, R., Voorhees, T., Snow, A., Grover, N., Ayers, A., Romancik, J., Liu, Y., Huntington, S., Chavez, J., Saeed, H., Lazaryan, A., Raghunathan, V., Spurgeon, S., Ollila, T., Prete, C. D., Olszewski, A., Ayers, E., Landsburg, D., Echalier, B., Lee, J., Kamdar, M., Calmi, P., Fu, T., Liu, J., David, K., Alharthy, H., Law, J., Karmali, R., Shah, H., Stephens, D., Major, A., Rojek, A., Smith, S., Yellala, A., Kallam, A., Nakhoda, S., Khan, N., Sohail, M., Hill, B., Barrett-Campbell, O., Lansigan, F., Switchenko, J., Cohen, J., Portell, C. 2022; 22 Suppl 2: S381

  Abstract

  CONTEXT: Relapses involving the central nervous system (CNS) are uncommon among patients with diffuse large B-cell lymphoma (DLBCL) but carry very poor prognosis. Prophylaxis is heterogeneously prescribed around the time of frontline therapy, with no clear standard of care in terms of recipient selection or route of administration.DESIGN: We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline chemoimmunotherapy between 2013-2019. Primary endpoint was CNS relapse rate. Secondary endpoints included PFS, OS, and treatment-related toxicities following frontline and salvage therapies.PATIENTS: Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%).RESULTS: Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.40), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. Median OS following CNS relapse was 6.2 months (IQR 2.9-24.6) and was significantly shorter among patients achieving less than CR to first salvage therapy (HR 3.39, 95% CI 1.76-6.54, p=0.0003). Additional analyses of outcomes following CNS relapse will be presented.CONCLUSIONS: This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated; treatments following CNS relapse were heterogeneous, with poor outcomes for the vast majority of patients. Reconsideration of SCNSL prophylaxis and treatment strategies is of critical need.

  View details for DOI 10.1016/S2152-2650(22)01543-9

  View details for PubMedID 36164093

• HL-339 Camidanlumab Tesirine: Updated Efficacy and Safety in an Open-Label, Multicenter, Phase 2 Study of Patients With Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL). Clinical lymphoma, myeloma & leukemia Carlo-Stella, C., Ansell, S., Zinzani, P. L., Radford, J., Maddocks, K., Pinto, A., Collins, G. P., Bachanova, V., Bartlett, N., Bence-Bruckler, I., Hamadani, M., Kline, J., Mayer, J., Savage, K. J., Advani, R., Calmi, P., Casasnovas, R., Feldman, T., Hess, B., Bastos-Oreiro, M., Iyengar, S., Eisen, S., Negievich, Y., Wang, L., Wuerthner, J., Herrera, A. F. 2022; 22 Suppl 2: S347

  Abstract

  CONTEXT: Camidanlumab tesirine (Cami), an antibody-drug conjugate comprising a human IgG1 anti-CD25 monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer, displayed antitumor activity and manageable toxicity in a phase 1 trial in lymphoma, including R/R cHL (NCT02432235).OBJECTIVE: Present updated efficacy and safety data from a phase 2 study of Cami monotherapy in R/R cHL (NCT04052997).METHODS: Patients with R/R cHL and ≥3 prior systemic therapies including brentuximab vedotin and anti-PD-1 were enrolled.PRIMARY ENDPOINT: overall response rate (ORR). Patients received Cami 45 g/kg on Day 1 of each 3-week cycle (2 cycles), then 30 g/kg (subsequent cycles) for up to 1 year.RESULTS: Enrollment is complete (N=117). Median age was 37 years, 62% of patients were male, and 95% had an ECOG score of 0-1. Fourteen patients (12.0%) withdrew to undergo transplant (12 [10.3%] received transplant and were censored). In the all-treated population (N=117), ORR was 70.1% (82/117; 95% CI: 60.9-78.2); 33.3% (39/117) had complete response (CR). At median (range) follow-up of 10.7 (1.2-25.2+) months, the median (95% CI) duration of response (DOR) was 13.7 months (7.4-14.7) for all responders, 14.5 (7.4-not reached, NR) months and 7.9 (3.8-NR) months for patients with CR or PR. Median (95% CI) progression-free survival (PFS) was 9.1 (5.1-15.0) months. All-grade treatment-emergent AEs (TEAEs) in ≥25% of 117 patients were fatigue (38.5%), maculopapular rash (MR, 32.5%), pyrexia (29.9%), nausea (27.4%), and rash (26.5%). Grade ≥3 TEAEs in ≥5% of patients were thrombocytopenia (9.4%), anemia (8.5%), hypophosphatemia (7.7%), neutropenia (7.7%), MR (6.8%), and lymphopenia (5.1%). TEAEs considered immune-related (IR) occurred in 32.5% of patients; Grade ≥3 IR AEs (TEAEs and non-TEAEs; 8.5%). Guillain-Barre syndrome (GBS)/polyradiculopathy occurred in 8 patients (6.8%). At data cutoff, 4 cases had recovered (grade 2, n=2; grade 4, n=2); 4 had not recovered (grade 4, n=1; grade 3, n=3).CONCLUSIONS: Cami demonstrated an ORR of 70.1% (CR: 33.3%) with an encouraging median DOR of 13.7 months and median PFS of 9.1 months. Safety is consistent with prior findings, including similar incidence rates of GBS/polyradiculopathy. Abstract accepted/presented at the EHA 2022 Congress; Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group.

  View details for DOI 10.1016/S2152-2650(22)01478-1

  View details for PubMedID 36164029

• Sequential Pembrolizumab and AVD is Highly Effective at any PD-L1 Expression Level in Untreated Hodgkin Lymphoma. Blood advances Allen, P. B., Lu, X., Chen, Q., Kane, K. L., Chmiel, J. S., Barnea Slonim, L., Sukhanova, M., Savas, H., Evens, A. M., Advani, R., Pro, B., Karmali, R., Palmer, B., Bayer, R., Eisner, R. M., Mou, E., Dillehay, G., Gordon, L. I., Winter, J. N. 2022

  Abstract

  In a multicenter, phase II investigator-initiated trial of sequential pembrolizumab and AVD, nearly two-thirds of patients with untreated unfavorable or advanced stage classic Hodgkin Lymphoma (cHL) achieved PET-defined complete or near complete metabolic responses (CMR) following 3 doses of pembrolizumab monotherapy. Furthermore, all achieved CMR following 2 cycles of AVD chemotherapy and 100% of patients were alive without relapse at the time of initial publication. We now report long-term follow-up, including 3-year OS and planned correlative analyses. Thirty patients received single agent pembrolizumab every 3 weeks x 3, followed by AVD chemotherapy for 4-6 cycles depending on stage and bulk. PET/CT scan was performed after pembrolizumab monotherapy, 2 cycles of AVD, and at the end of therapy. Baseline biopsy samples were analyzed for genomic alterations of chromosome 9p24.1 and PD-1 pathway markers by immunohistochemistry. At a median follow up of 33.1 months (range, 26.0-43.0), PFS and OS remain 100%. All patients had genomic alterations in 9p24.1 and were positive for PD-L1 by immunohistochemistry. There was no relationship between response to single agent pembrolizumumab measured by decline in metabolic tumor volume and 9p24.1 alterations or PD-1 pathway H-scores. With additional follow-up, sequential pembrolizumab and AVD remains highly effective. The high response rates observed at all PD-ligand levels suggest that even low levels of PD ligand expression are sufficient for response to PD-1 blockade in untreated cHL. An international phase II trial (NCT05008224) to confirm these findings is ongoing.

  View details for DOI 10.1182/bloodadvances.2022008116

  View details for PubMedID 36083129

• Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas. The American journal of surgical pathology Singh, K., Lezama, L. S., Kurzer, J., Oak, J., Schultz, L. M., Walkush, A., Cheng, T. C., Chen, E. H., May, W. A., Chang, C., Link, M. P., Advani, R. H., Suarez, C. J., Natkunam, Y. 2022

  Abstract

  Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

  View details for DOI 10.1097/PAS.0000000000001956

  View details for PubMedID 36001451

• Genomic Profiling for Clinical Decision Making in Lymphoid Neoplasms. Blood de Leval, L., Alizadeh, A. A., Bergsagel, P. L., Campo, E., Davies, A. J., Dogan, A., Fitzgibbon, J., Horwitz, S. M., Melnick, A. M., Morice, W. G., Morin, R. D., Nadel, B., Pileri, S. A., Rosenquist, R., Rossi, D., Salaverria, I., Steidl, C., Treon, S. P., Zelenetz, A. D., Advani, R., Allen, C. E., Ansell, S. M., Chan, W. C., Cook, J. R., Cook, L. B., d'Amore, F., Dirnhofer, S., Dreyling, M., Dunleavy, K., Feldman, A., Fend, F., Gaulard, P., Ghia, P., Gribben, J. G., Hermine, O., Hodson, D. J., Hsi, E. D., Inghirami, G. G., Jaffe, E. S., Karube, K., Kataoka, K., Klapper, W., Kim, W. S., King, R. L., Ko, Y. H., LaCasce, A. S., Lenz, G., Martin-Subero, I., Piris, M. A., Pittaluga, S., Pasqualucci, L., Quintanilla-Martinez, L., Rodig, S. J., Rosenwald, A., Salles, G. A., San-Miguel, J., Savage, K. J., Sehn, L. H., Semenzato, G., Staudt, L. M., Swerdlow, S. H., Tam, C. S., Trotman, J., Vose, J., Weigert, O., Wilson, W. H., Winter, J. N., Wu, C. J., Zinzani, P. L., Zucca, E., Bagg, A., Scott, D. W. 2022

  Abstract

  With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. While the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses and epigenetic profiling will be discussed, as these will likely become important future tools for implementing precision medicine approaches in clinical decision-making for patients with lymphoid malignancies.

  View details for DOI 10.1182/blood.2022015854

  View details for PubMedID 36001803

• Response to Brentuximab Vedotin by CD30 Expression in Non-Hodgkin Lymphoma. The oncologist Jagadeesh, D., Horwitz, S., Bartlett, N. L., Kim, Y., Jacobsen, E., Duvic, M., Little, M., Trepicchio, W., Fenton, K., Onsum, M., Lisano, J., Advani, R. 2022

  Abstract

  The safety and efficacy of brentuximab vedotin (BV), an antibody-drug conjugate directed to the CD30 antigen, has been assessed in several trials in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The objective of this research was to examine the relationship between CD30 expression level and clinical response to BV.We analyzed response in patients treated with BV monotherapy in 5 prospective clinical studies in relapsed or refractory PTCL, CTCL, or B-cell NHL. CD30 expression was assessed by immunohistochemistry (IHC) using the Ber H2 antibody for 275 patients.Across all 5 studies, 140 (50.9%) patients had tumors with CD30 expression <10%, including 60 (21.8%) with undetectable CD30 by IHC. No significant differences were observed for any study in overall response rates between patients with CD30 expression ≥10% or <10%. Median duration of response was also similar in the CD30 ≥10% and <10% groups for all studies.In this analysis of studies across a range of CD30-expressing lymphomas, CD30 expression alone, as measured by standard IHC, does not predict clinical benefit from BV, making the determination of a threshold level of expression uncertain.

  View details for DOI 10.1093/oncolo/oyac137

  View details for PubMedID 35948003

• Genomic and microenvironmental landscape of stage I follicular lymphoma, compared to stage III/IV. Blood advances Los-de Vries, G. T., Stevens, W. B., van Dijk, E. v., Langois-Jacques, C., Clear, A. J., Stathi, P., Roemer, M. G., Mendeville, M., Hijmering, N. J., Sander, B., Rosenwald, A., Calaminici, M., Hoster, E., Hiddemann, W., Gaulard, P., Salles, G. A., Horn, H., Klapper, W., Xerri, L., Burton, C., Tooze, R. M., Smith, A. G., Buske, C., Scott, D. W., Natkunam, Y., Advani, R., Sehn, L. H., Raemaekers, J. M., Gribben, J. G., Kimby, E. K., Kersten, M. J., Maucort-Boulch, D., Ylstra, B., de Jong, D. 2022

  Abstract

  While the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known regarding potential biological differences between stage I and stage III/IV disease. Using next generation sequencing (NGS) and immunohistochemistry, 82 FL nodal stage I cases were analysed and compared to 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations (CNAs) and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T-cells (p=0.02) and STAT6 mutations (FDR<0.001), were more frequent in stage I FL. In contrast, PD1+ T-cells, CD68+/CD163+ macrophages (p<0.001), BCL2 translocation (BCL2trl+) (p<0.0001), KMT2D (FDR=0.003) and CREBBP (FDR=0.04) mutations were found more frequently in stage III/IV FL. By clustering we identified three clusters within stage I, and two within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with less CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more CNAs and linker histone mutations. This exploratory study shows that FL stage I is genetically heterogenous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven while BCL2trl- stage III/IV appears to be more BCL6trl driven.

  View details for DOI 10.1182/bloodadvances.2022008355

  View details for PubMedID 35816682

• The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood Campo, E., Jaffe, E. S., Cook, J. R., Quintanilla-Martinez, L., Swerdlow, S. H., Anderson, K. C., Brousset, P., Cerroni, L., de Leval, L., Dirnhofer, S., Dogan, A., Feldman, A., Fend, F., Friedberg, J. W., Gaulard, P., Ghia, P., Horwitz, S. M., King, R. L., Salles, G. A., San-Miguel, J. F., Seymour, J. F., Treon, S. P., Vose, J., Zucca, E., Advani, R., Ansell, S. M., Au, W., Barrionuevo, C., Bergsagel, P. L., Chan, W. C., Cohen, J. I., Davies, A. J., Falini, B., Ghobrial, I. M., Goodlad, J. R., Gribben, J. G., Hsi, E. D., Kahl, B. S., Kim, W. S., Kumar, S. K., LaCasce, A. S., Laurent, C., Lenz, G., Leonard, J. P., Link, M. P., Lopez-Guillermo, A., Mateos, M., Macintyre, E. A., Melnick, A. M., Morschhauser, F., Nakamura, S., Narbaitz, M., Pavlovsky, A., Pileri, S. A., Piris, M. A., Pro, B., Rajkumar, S. V., Rosen, S. T., Sander, B., Sehn, L. H., Shipp, M. A., Smith, S. M., Staudt, L. M., Thieblemont, C., Tousseyn, T., Wilson, W. H., Yoshino, T., Zinzani, P. L., Dreyling, M., Scott, D. W., Winter, J. N., Zelenetz, A. D. 2022

  Abstract

  Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have led to the current proposal. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.

  View details for DOI 10.1182/blood.2022015851

  View details for PubMedID 35653592

• Phase 1 results of a phase 1/2 trial of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination, in patients with advanced solid and hematologic cancers. Lynch, R. C., Munster, P. N., Advani, R. H., Hamadani, M., Spigel, D. R., Falchook, G., Patel, M. R., Siegel, D., Beri, N., Nowakowski, G. S., Palmisiano, N., Burness, M., Moore, K. N., Shapiro, G., Juric, D., Bradley, W. D., O'Shea, T. J., Renschler, M., Englert, J. M., Yap, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680300977

• First-line brentuximab vedotin plus chemotherapy to improve overall survival in patients with stage III/IV classical Hodgkin lymphoma: An updated analysis of ECHELON-1. Ansell, S. M., Connors, J. M., Radford, J. A., Kim, W., Gallamini, A., Ramchandren, R., Friedberg, J. W., Advani, R. H., Hutchings, M., Evens, A. M., Smolewski, P., Savage, K. J., Bartlett, N. L., Eom, H., Abramson, J. S., Dong, C., Campana, F., Fenton, K., Puhlmann, M., Straus, D. J. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301966

• Outcomes of classic Hodgkin lymphoma, relapsed within one year of diagnosis, in the era of novel agents. Desai, S., Spinner, M., David, K. A., Bachanova, V., Goyal, G., Saba, R., Dorritie, K., Azzi, J., Harris, E., Fusco, B., Sumransub, N., Hatic, H., Ibrahim, U., Iyengar, S., Rappazzo, K., Baidoun, F., Orellana-Noia, V., Diefenbach, C., Advani, R. H., Micallef, I. M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301976

• Role of Stem Cell Transplant in CD30-positive PTCL following Frontline Brentuximab Vedotin+CHP or CHOP in ECHELON-2. Blood advances Savage, K. J., Horwitz, S. M., Advani, R., Christensen, J. H., Domingo-Domenech, E., Rossi, G., Morschhauser, F., Alpdogan, O., Suh, C., Tobinai, K., Shustov, A., Trneny, M., Yuen, S. L., Zinzani, P. L., Truemper, L. H., Illidge, T. M., O'Connor, O. A., Pro, B., Miao, H., Bunn, V., Fenton, K., Fanale, M., Puhlmann, M., Iyer, S. P. 2022

  Abstract

  Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have a high relapse rate following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double blind randomized phase 3 ECHELON-2 study (NCT01777152) demonstrated an improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated, CD30-positive PTCL (ALK-negative anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) at end of treatment with frontline A+CHP or CHOP. Median PFS follow-up was 47.57 months (95% CI, 41.89-48.16). The PFS hazard ratio was 0.36 (95% CI, 0.17-0.77), equating to an 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached (95% CI, 49.81, NA), versus 55.66 months (95% CI, 19.88, NA) in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK-negative ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30-positive PTCL who achieve a CR following treatment with A+CHP.

  View details for DOI 10.1182/bloodadvances.2020003971

  View details for PubMedID 35470385

• Odronextamab, a human CD20*CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. The Lancet. Haematology Bannerji, R., Arnason, J. E., Advani, R. H., Brown, J. R., Allan, J. N., Ansell, S. M., Barnes, J. A., O'Brien, S. M., Chavez, J. C., Duell, J., Rosenwald, A., Crombie, J. L., Ufkin, M., Li, J., Zhu, M., Ambati, S. R., Chaudhry, A., Lowy, I., Topp, M. S. 2022

  Abstract

  BACKGROUND: Odronextamab is a hinge-stabilised, fully human IgG4-based CD20*CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.METHODS: This single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951.FINDINGS: From Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30).INTERPRETATION: Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.FUNDING: Regeneron Pharmaceuticals.

  View details for DOI 10.1016/S2352-3026(22)00072-2

  View details for PubMedID 35366963

• Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma. EJHaem Ribrag, V., Chavez, J. C., Boccomini, C., Kaplan, J., Chandler, J. C., Santoro, A., Corradini, P., Flinn, I. W., Advani, R., Cassier, P. A., Sangha, R., Kenkre, V. P., Isufi, I., Uttamsingh, S., Hagner, P. R., Gandhi, A. K., Shen, F., Michelliza, S., Haeske, H., Hege, K., Pourdehnad, M., Kuruvilla, J. 2022; 3 (1): 139-153

  Abstract

  There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

  View details for DOI 10.1002/jha2.375

  View details for PubMedID 35846221

• Current Frontline Treatment of Diffuse Large B-Cell Lymphoma. Oncology (Williston Park, N.Y.) Spinner, M. A., Advani, R. H. 1800; 36 (1): 51-58

  Abstract

  Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is an aggressive and biologically heterogeneous disease. Risk stratification and treatment algorithms vary based on stage of disease and bulk along with other clinical and biological factors, including the International Prognostic Index, cell of origin, and other molecular subsets. Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard of care and cures more than 60% of patients. The role of radiotherapy is largely restricted to patients with limited-stage disease. In elderly patients, geriatric assessments of baseline fitness and functional status help optimize therapy based on the balance of efficacy and toxicity. While numerous randomized trials have failed to improve upon R-CHOP, a recent press release from the POLARIX trial (NCT03274492) suggests that adding polatuzumab vedotin (Polivy) to rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) improves progression-free survival and may replace R-CHOP in eligible patients. Ongoing trials are exploring frontline therapy that integrates other novel agents, including various small molecules, bispecific antibodies, and chimeric antigen receptor T-cell therapy, with promising preliminary results. Defining a population of patients with high-risk disease in whom R-CHOP is not effective is critical. Patient selection based on refining molecular subsets, quantitative PET metrics such as metabolic tumor volume, and dynamic risk assessments using interim PET and circulating tumor DNA analysis may allow for a personalized, response-adapted approach that will further improve outcomes in DLBCL.

  View details for DOI 10.46883/2022.25920940

  View details for PubMedID 35089671

• Anti-CD79B Antibody-Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study. Clinical cancer research : an official journal of the American Association for Cancer Research Herrera, A. F., Patel, M. R., Burke, J. M., Advani, R., Cheson, B. D., Sharman, J. P., Penuel, E., Polson, A. G., Liao, C. D., Li, C., Schuth, E., Vaze, A., Samineni, D., Elstrom, R., Cooper, J., Diefenbach, C. 1800

  Abstract

  PURPOSE: Targeting CD79B using antibody-drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB{trade mark, serif} technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast to ADCs with heterogeneous loads.PATIENTS AND METHODS: This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following {greater than or equal to}1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3-4.8 mg/kg); 9 received combination therapy (3.6-4.8 mg/kg) with rituximab.RESULTS: Fifty-four (90%) patients experienced adverse events related to study drug, the most common of which were blurred vision, fatigue, corneal deposits, neutropenia, nausea, and peripheral neuropathy. 4.8 mg/kg was the highest dose tested and the recommended phase II dose. The pharmacokinetic profile was linear at doses {greater than or equal to}1.2 mg/kg. Response rate in all-treated patients (N=60) was 47% (n=28), including 17 complete responses (28%) and 11 partial responses (18%). The median duration of response (15.2 months) was the same for all responders (n=28) and patients with DLBCL (n=20).CONCLUSIONS: DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging anti-tumor activity advocates continuation of investigations into novel ADC technologies.

  View details for DOI 10.1158/1078-0432.CCR-21-3261

  View details for PubMedID 34980599

• NCCN Guidelines Insights: Hodgkin Lymphoma, Version 2.2022. Journal of the National Comprehensive Cancer Network : JNCCN Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Armand, P., Bello, C. M., Benitez, C. M., Chen, W., Dabaja, B., Daly, M. E., Gordon, L. I., Hansen, N., Herrera, A. F., Hochberg, E. P., Johnston, P. B., Kaminski, M. S., Kelsey, C. R., Kenkre, V. P., Khan, N., Lynch, R. C., Maddocks, K., McConathy, J., Metzger, M., Morgan, D., Mulroney, C., Pullarkat, S. T., Rabinovitch, R., Rosenspire, K. C., Seropian, S., Tao, R., Torka, P., Winter, J. N., Yahalom, J., Yang, J. C., Burns, J. L., Campbell, M., Sundar, H. 2022; 20 (4): 322-334

  Abstract

  Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

  View details for DOI 10.6004/jnccn.2022.0021

  View details for PubMedID 35390768

• Increased double-negative alpha beta plus T cells reveal adult-onset autoimmune lymphoproliferative syndrome in a patient with IgG4-related disease HAEMATOLOGICA Brar, N., Spinner, M. A., Baker, M. C., Advani, R. H., Natkunam, Y., Lewis, D. B., Silva, O. 2022; 107 (1): 347-350

  View details for DOI 10.3324/haematol.2021.279297

  View details for Web of Science ID 000740550800043

• CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Pre-Established Immunity. Blood cancer discovery Shree, T., Shankar, V., Lohmeyer, J. J., Czerwinski, D. K., Schroers-Martin, J. G., Rodriguez, G. M., Beygi, S., Kanegai, A. M., Corbelli, K. S., Gabriel, E., Kurtz, D. M., Khodadoust, M. S., Gupta, N. K., Maeda, L. S., Advani, R. H., Alizadeh, A. A., Levy, R. 2022

  Abstract

  To obtain a deeper understanding of poor responses to COVID-19 vaccination in lymphoma patients, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies post-vaccination, compared to 100% of controls. Evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.

  View details for DOI 10.1158/2643-3230.BCD-21-0222

  View details for PubMedID 35015688

• Outcomes Among Classical Hodgkin Lymphoma Patients After an Interim PET Scan: A Real-World Experience. Clinical lymphoma, myeloma & leukemia Hamid, M. S., Rutherford, S. C., Jang, H., Kim, S., Patel, K., Bartlett, N. L., Malecek, M., Watkins, M. P., Maddocks, K. J., Bond, D. A., Feldman, T. A., Magarelli, G., Advani, R. H., Spinner, M. A., Evens, A. M., Shah, M., Ahmed, S., Stephens, D. M., Allen, P., Tees, M. T., Karmali, R., Cheson, B. D., Yazdy, M. S., Strouse, C., Bailey, N. A., Pagel, J. M., Ramchandren, R. 1800

  Abstract

  INTRODUCTION: The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients.PATIENTS AND METHODS: Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed.RESULTS: A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation.CONCLUSION: A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.

  View details for DOI 10.1016/j.clml.2021.12.012

  View details for PubMedID 35093285

• The ECHELON-2 Trial: 5-year results of a randomized, phase 3 study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology Horwitz, S., O'Connor, O. A., Pro, B., Trumper, L., Iyer, S., Advani, R., Bartlett, N. L., Christensen, J. H., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W. S., Feldman, T., Menne, T., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Shustov, A., Huttmann, A., Savage, K. J., Yuen, S., Zinzani, P. L., Miao, H., Bunn, V., Fenton, K., Fanale, M., Puhlmann, M., Illidge, T. 1800

  Abstract

  BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with CHOP or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival vs cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL.PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase 3 study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. This trial is registered with ClinicalTrials.gov (NCT01777152).RESULTS: A total of 452 patients were randomized (1:1) to 6 or 8 cycles of A+CHP (N=226) or CHOP (N=226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% (95% confidence interval [CI]: 42.8, 59.4) with A+CHP vs 43.0% (95% CI: 35.8, 50.0) with CHOP (hazard ratio=0.70; 95% CI: 0.53, 0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3, 75.9) with A+CHP vs 61.0% (95% CI: 54.0, 67.3) with CHOP (hazard ratio=0.72; 95% CI: 0.53, 0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the overall response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP.CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS vs CHOP, with a manageable safety profile, including continued resolution or improvement of PN.

  View details for DOI 10.1016/j.annonc.2021.12.002

  View details for PubMedID 34921960

• The Echelon-2 Trial: 5-Year Exploratory Subgroup Analyses of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A plus CHP) Vs CHOP in Frontline Treatment of Pts with CD30-Positive Peripheral T-Cell Lymphoma Horwitz, S. M., Savage, K. J., Timillidge, Plyer, S., Advani, R., Shustov, A. R., Bartlett, N. L., Pro, B., Jacobsen, E. D., Koch, R., Eva, D., Fanale, M. A., Fenton, K., Campana, F., Dong, C., Truemper, L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-145124

  View details for Web of Science ID 000736398800133

• Novel Salvage Regimens Lead to Better Response and Survival in Relapsed Refractory Classic Hodgkin Lymphoma after Autologous Stem Cell Transplant Desai, S. H., Spinner, M. A., David, K. A., Bachanova, V., Goyal, G., Azzi, J., Dorritie, K., Kenkre, V. P., Chang, C., Arai, S., Fusco, B., Sumransub, N., Hactic, H., Ibrahim, U., Harris, E., Maurer, M. J., Rappazzo, K. C., Orellana-Noia, V. M., Diefenbach, C. S., Raya, S., Nowakowski, G. S., Advani, R., Micallef, I. N. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-149880

  View details for Web of Science ID 000736398803176

• Frontline Treatment with Single Agent Pembrolizumab (PEM) Followed By AVD Chemotherapy for Classic Hodgkin Lymphoma: Updated Results and Correlative Analysis Allen, P., Chen, Q. C., Lu, X., O'Shea, K., Chmiel, J., Sukhanova, M., Slonim, L., Savas, H., Mou, E., Pro, B., Evens, A. M., Palmer, B., Advani, R., Gordon, L. I., Winter, J. N. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-147042

  View details for Web of Science ID 000736398801008

• Time Since Last Anti-CD20 Treatment Is a Major Determinant of Sars-Cov-2 Vaccine Response in a Large Cohort of Patients with B-Cell Lymphoma Shree, T., Shankar, V., Czerwinski, D. K., Rodriguez, G., Beygi, S., Schroers-Martin, J. G., Advani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Kurtz, D. M., Corbelli, K. S., Gabriel, E., Kanegai, A. M., Alizadeh, A. A., Levy, R. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153901

  View details for Web of Science ID 000736413900065

• Final Results from a Phase 2 Study of Tipifarnib in Subjects with Relapsed or Refractory Peripheral T-Cell Lymphoma Witzig, T. E., Sokol, L., Kim, W., de la Cruz Vicente, F., Caballero, D., Advani, R., de Ona, R., Marin Niebla, A., Jose Terol, M., Domenech Eva, D., Bendris, N., Mackey Ahsan, J., Leoni, M., Foss, F. M. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-147279

  View details for Web of Science ID 000736398802161

• Venetoclax in Previously Treated Waldenstrom Macroglobulinemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Castillo, J. J., Allan, J. N., Siddiqi, T., Advani, R. H., Meid, K., Leventoff, C., White, T. P., Flynn, C. A., Sarosiek, S., Branagan, A. R., Demos, M. G., Guerrera, M. L., Kofides, A., Liu, X., Munshi, M., Tsakmaklis, N., Xu, L., Yang, G., Patterson, C. J., Hunter, Z. R., Davids, M. S., Furman, R. R., Treon, S. P. 2021: JCO2101194

  Abstract

  PURPOSE: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenstrom macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.PATIENTS AND METHODS: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.RESULTS: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P-mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.CONCLUSION: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.

  View details for DOI 10.1200/JCO.21.01194

  View details for PubMedID 34793256

• Characteristics and Outcome of Extranodal NK/T-cell Lymphoma in North America: A Retrospective Multi-Institutional Experience. Clinical lymphoma, myeloma & leukemia Bennani, N. N., Tun, A. M., Carson, K. R., Geiger, J. L., Maeda, L. S., Savage, K. J., Rose, J., Pinter-Brown, L., Lunning, M. A., Abramson, J. S., Bartlett, N. L., Vose, J. M., Evens, A. M., Smith, S. M., Horwitz, S. M., Ansell, S. M., Advani, R. H. 2021

  Abstract

  BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinical data from non-Asian countries are lacking. It is unclear whether outcomes and disease natural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers.PATIENTS AND METHODS: We retrospectively identified patients with newly-diagnosed CD56+ENKTL and studied disease characteristics and clinical outcomes.RESULTS: One hundred and twenty-one patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treated with combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) or radiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV disease and were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up for the entire cohort was 51 months. Patients with stage I/II disease, compared to those with stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs 19% (P=.03) and overall survival (OS) 59% vs. 29% (P= .004). Outcomes were similar for stage I/II patients who received CMT vs. RT alone with 2-year PFS (53% vs. 47%; P= .91) and OS (67% vs. 67%; P= .58). No significant differences in outcomes were noted based on race/ethnicity.CONCLUSIONS: This series represents a large experience of ENKTL treated at several major North American academic centers. Our data are consistent with Asian studies: (1) majority of patients present with early-stage disease; (2) overall poor outcome regardless of race/ethnicity; (3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.

  View details for DOI 10.1016/j.clml.2021.10.018

  View details for PubMedID 34848181

• Optimizing First-Line Therapy for Advanced- Stage Classic Hodgkin Lymphoma Advani, R. H. HARBORSIDE PRESS. 2021: 1335-1338

  View details for DOI 10.6004/jnccn.2021.5111

  View details for Web of Science ID 000731434000005

• Characteristics and Outcome of Extranodal NK/T-Cell Lymphoma in North America: A Retrospective Multi-Institutional Experience. Clinical lymphoma, myeloma & leukemia Bennani, N. N., Tun, A. M., Carson, K. R., Geiger, J. L., Maeda, L. S., Savage, K. J., Rose, J., Pinter-Brown, L., Lunning, M. A., Abramson, J. S., Bartlett, N. L., Vose, J. M., Evens, A. M., Smith, S. M., Horwitz, S. M., Ansell, S. M., Advani, R. H. 2021

  Abstract

  BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinicaldata from non-Asian countries are lacking. It is unclear whether outcomes and diseasenatural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers.PATIENTS AND METHODS: We retrospectively identified patients with newly-diagnosedCD56 + ENKTL and studied disease characteristics and clinical outcomes.RESULTS: 121 patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treatedwith combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) orradiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV diseaseand were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up forthe entire cohort was 51 months. Patients with stage I/II disease, compared to thosewith stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs19% (p=0.03) and overall survival (OS) 59% vs 29% (p=0.004). Outcomes were similarfor stage I/II patients who received CMT vs RT alone with 2-year PFS (53% vs 47%;p=0.91) and OS (67% vs 67%; p=0.58). No significant differences in outcomes werenoted based on race/ethnicity.CONCLUSIONS: This series represents a large experience of ENKTL treated at several major North American academic centers.OUR DATA ARE CONSISTENT WITH ASIAN STUDIES: 1) majority of patients present with early-stage disease; 2) overall poor outcome regardless of race/ethnicity; 3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.

  View details for DOI 10.1016/j.clml.2021.10.004

  View details for PubMedID 34794912

• ECHELON-2 (NCT01777152), A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF BRENTUXIMAB VEDOTIN plus CHP VS CHOP IN PREVIOUSLY UNTREATED PATIENTS WITH CD30-POSITIVE PERIPHERAL T-CELL LYMPHOMA: 5-YEAR RESULTS Zinzani, P. L., Illidge, T., Horwitz, S. M., O'Connor, O. A., Pro, B., Iyer, S. P., Advani, R., Bartlett, N. L., Christensen, J. H., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W. S., Feldman, T. A., Menne, T., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Huttmann, A., Savage, K. J., Yuen, S., Miao, H., Bunn, V., Fenton, K., Fanale, M. A., Puhlmann, M., Trumper, L. FERRATA STORTI FOUNDATION. 2021: 3

  View details for Web of Science ID 000719458000005

• BRENTUXIMAB VEDOTIN PLUS CHEMOTHERAPY FOR PATIENTS WITH PREVIOUSLY UNTREATED, STAGE III OR IV CLASSICAL HODGKIN LYMPHOMA: 5-YEAR UPDATE OF THE PHASE 3 ECHELON-1 STUDY (NCT01712490) Picardi, M., Straus, J., Dlugosz-Danecka, M., Connors, J. M., Illes, A., Lech-Maranda, E., Feldman, T., Smolewski, P., Savage, K. J., Bartlett, N. L., Walewski, J., Ramchandren, R., Zinzani, P. L., Hutchings, M., Munoz, J., Kim, W. S., Advani, R., Ansell, S. M., Gallamini, A., Liu, R., Little, M., Fenton, K., Fanale, M., Radford, J. FERRATA STORTI FOUNDATION. 2021: 44

  View details for Web of Science ID 000719458000070

• Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study Ramchandren, R., Dlugosz-Danecka, M., Connors, J. M., Radford, J., Illes, A., Picardi, M., Lech-Maranda, E., Feldman, T., Smolewski, P., Savage, K. J., Bartlett, N. L., Walewski, J., Zinzani, P., Hutchings, M., Munoz, J., Kim, W., Advani, R., Ansell, S. M., Gallamini, A., Alekseev, S., Lee, H., Liu, R., Little, M., Fenton, K., Fanale, M., Straus, D. J. CIG MEDIA GROUP, LP. 2021: S371

  View details for Web of Science ID 000691910500287

• ECHELON-2, (NCT01777152), 5-year results of a randomised, double-blind, phase 3 study of frontline brentuximab vedotin plus CHP vs CHOP in patients with CD30-positive peripheral T-cell lyphoma Truemper, L., O'Connor, O. A., Pro, B., Illidge, T., Advani, R., Bartlett, N. L., Christensen, J. H., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W. S., Feldman, T., Menne, T., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S. P., Huettmann, A., Savage, K. J., Yuen, S., Iyer, S., Zinzani, P. L., Miao, H., Bunn, Fenton, K., Fanale, M., Puhlmann, M., Horwitz, S. KARGER. 2021: 128

  View details for Web of Science ID 000760622600234

• Patterns of Care for Elderly Patients with Peripheral T-Cell Lymphoma: A Report from the International T-Cell Project 1.0 Skrypets, T., Civallero, M., Manni, M., Vose, J., Dlouhy, I., Pileri, S., Elena Cabrera, M. E., Hitz, F., Inghirami, G., Bobillo, S., Marino, D., Advani, R., Stelitano, C., Federico, M. CIG MEDIA GROUP, LP. 2021: S415

  View details for Web of Science ID 000691910500370

• The ECHELON-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A plus CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma Iyer, S., Truemper, L., O'Connor, O. A., Pro, B., Illidge, T., Advani, R., Bartlett, N. L., Christensen, J., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W., Feldman, T., Menne, T., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Shustov, A., Huettmann, A., Savage, K. J., Yuen, S., Zinzani, P., Miao, H., Bunn, V., Fenton, K., Fanale, M., Puhlmann, M., Horwitz, S. CIG MEDIA GROUP, LP. 2021: S411

  View details for Web of Science ID 000691910500363

• Treatment Strategies in Nodular Lymphocyte Predominant Hodgkin Lymphoma Advani, R. CIG MEDIA GROUP, LP. 2021: S168-S169

  View details for Web of Science ID 000691910500064

• Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma. Blood advances Orellana-Noia, V. M., Isaac, K., Malecek, M., Bartlett, N. L., Voorhees, T. J., Grover, N. S., Hwang, S. R., Bennani, N. N., Hu, R., Hill, B. T., Mou, E., Advani, R., Carter, J., David, K. A., Ballard, H. J., Svoboda, J., Churnetski, M. C., Magarelli, G., Feldman, T., Cohen, J. B., Evens, A. M., Portell, C. 2021

  Abstract

  We performed a multicenter retrospective analysis across 10 US academic medical centers (2010 - 2018) to evaluate current treatment patterns and outcomes in patients age ≥60 with classical Hodgkin lymphoma (cHL). Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 14% had ECOG performance status (PS) 2-4, and 12% had documented loss of ≥1 activity of daily living (ADLs). Medical comorbidities were assessed by the Cumulative Illness Rating Scale - Geriatric (CIRS-G), where n=44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; HR 2.13, p=0.007) and overall survival (OS; HR=2.52, P=0.02). Most patients (n=203, 83%) received conventional chemotherapy regimens, including ABVD (56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P=0.0007) and OS (HR 0.31, p=0.0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, p=0.63; OS HR 0.73, p=0.55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28 vs 12%, p=0.016) or documented geriatric syndrome (28 vs 13%, p=0.02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, p=0.02) and higher mortality from causes other than disease or treatment in those with high CIRS-G or geriatric syndromes. These data suggest conventional chemotherapy regimens be considered standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

  View details for DOI 10.1182/bloodadvances.2021004645

  View details for PubMedID 34448831

• Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study. Annals of hematology Kim, W. S., Oki, Y., Kim, S. J., Yoon, S. E., Ardeshna, K. M., Lin, Y., Ruan, J., Porcu, P., Brammer, J. E., Jacobsen, E. D., Yoon, D. H., Suh, C., Suarez, F., Radford, J., Budde, L. E., Kim, J. S., Bachy, E., Lee, H. J., Bollard, C. M., Jaccard, A., Kang, H. J., Inman, S., Murray, M., Combs, K. E., Lee, D. Y., Advani, R., Gunter, K. C., Rooney, C. M., Heslop, H. E. 2021

  Abstract

  We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.

  View details for DOI 10.1007/s00277-021-04558-0

  View details for PubMedID 34304287

• Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project. Blood Advani, R. H., Skrypets, T., Civallero, M., Spinner, M. A., Manni, M., Kim, W. S., Shustov, A. R., Horwitz, S. M., Hitz, F., Cabrera, M. E., Dlouhy, I., Vassallo, J., Pileri, S. A., Inghirami, G., Montoto, S., Vitolo, U., Radford, J., Vose, J. M., Federico, M. 2021; 138 (3): 213-220

  Abstract

  Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.

  View details for DOI 10.1182/blood.2020010387

  View details for PubMedID 34292324

• Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial LANCET HAEMATOLOGY Straus, D. J., Dlugosz-Danecka, M., Connors, J. M., Alekseev, S., Illes, A., Picardi, M., Lech-Maranda, E., Feldman, T., Smolewski, P., Savage, K. J., Bartlett, N. L., Walewski, J., Ramchandren, R., Zinzani, P., Hutchings, M., Munoz, J., Lee, H., Kim, W., Advani, R., Ansell, S. M., Younes, A., Gallamini, A., Liu, R., Little, M., Fenton, K., Fanale, M., Radford, J. 2021; 8 (6): E410-E421

  View details for Web of Science ID 000655263700010

• DLBCL-Morph: Morphological features computed using deep learning for an annotated digital DLBCL image set. Scientific data Vrabac, D., Smit, A., Rojansky, R., Natkunam, Y., Advani, R. H., Ng, A. Y., Fernandez-Pol, S., Rajpurkar, P. 2021; 8 (1): 135

  Abstract

  Diffuse Large B-Cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Though histologically DLBCL shows varying morphologies, no morphologic features have been consistently demonstrated to correlate with prognosis. We present a morphologic analysis of histology sections from 209 DLBCL cases with associated clinical and cytogenetic data. Duplicate tissue core sections were arranged in tissue microarrays (TMAs), and replicate sections were stained with H&E and immunohistochemical stains for CD10, BCL6, MUM1, BCL2, and MYC. The TMAs are accompanied by pathologist-annotated regions-of-interest (ROIs) that identify areas of tissue representative of DLBCL. We used a deep learning model to segment all tumor nuclei in the ROIs, and computed several geometric features for each segmented nucleus. We fit a Cox proportional hazards model to demonstrate the utility of these geometric features in predicting survival outcome, and found that it achieved a C-index (95% CI) of 0.635 (0.574,0.691). Our finding suggests that geometric features computed from tumor nuclei are of prognostic importance, and should be validated in prospective studies.

  View details for DOI 10.1038/s41597-021-00915-w

  View details for PubMedID 34017010

• First-in-human phase I/II study of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination in patients with advanced solid and hematologic cancers. Lynch, R. C., Bendell, J. C., Advani, R. H., Falchook, G., Munster, P. N., Patel, M. R., Gutierrez, M., Burness, M., Palmisiano, N., Hamadani, M., Bradley, W. D., O'Shea, T. J., Doleman, S., Renschler, M., Englert, J. M., Yap, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.3006

  View details for Web of Science ID 000708120601183

• 18F-Fluorothymidine PET is an early and superior predictor of progression-free survival following chemoimmunotherapy of diffuse large B cell lymphoma: a multicenter study. European journal of nuclear medicine and molecular imaging Minamimoto, R., Fayad, L., Vose, J., Meza, J., Advani, R., Hankins, J., Mottaghy, F., Macapinlac, H., Heinzel, A., Juweid, M. E., Quon, A. 2021

  Abstract

  PURPOSE: To determine whether interim 3'-deoxy-3'-[18F]fluorothymidine (iFLT) PET/CT is a superior predictor of progression-free survival (PFS) compared with interim 18F-fluorodeoxyglucose (iFDG) PET/CT in patients with diffuse large B cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH).METHODS: Ninety-two prospectively enrolled patients with DLBCL underwent both FLT-PET/CT and FDG-PET/CT 18-24days after two cycles of R-CHOP/R-EPOCH. Deauville-criteria, PERCIST1.0, standardized uptake value (SUV), total lesion glycolysis (TLG), and metabolic tumor volume were used to interpret iFDG-PET/CT while dichotomous visual interpretation was used to interpret iFLT-PET/CT and the results were compared with the 3- and 5-year PFS.RESULTS: iFLT-PET/CT was negative in 67 (73%) and positive in 25 (27%) patients. iFDG-PET/CT by Deauville criteria was negative (Deauville scores [DS] of 1-3) in 53 (58%) and positive (DS=4-5) in 39 (42%) patients. Of the 67 iFLT-PET/CT-negative patients, 7 (10.4%) progressedat a median of 14.1months whereas 14/25 (56.0%) iFLT-PET/CT-positive patientsprogressed at a median of 7.8months (P<.0001). Of the 53 Deauville-negative patients, 9 (17.0%) progressedat a median of 14.1months whereas 12/39 (30.8%) Deauville-positive patients progressedat a median of 5.6months (P=.11). In multivariate analysis, including iFLT-PET/CT, PERCIST, interim TLG, and interim SUVmax, only iFLT-PET/CT was an independent predictor for 3- and 5-year PFS (P<.0001 and P=.001, respectively).CONCLUSIONS: In patients with DLBCL given R-CHOP/R-EPOCH, iFLT-PET/CT is a superior independent predictor of outcome compared with iFDG-PET/CT.

  View details for DOI 10.1007/s00259-021-05353-9

  View details for PubMedID 33909086

• Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood Advani, R., Moskowitz, A. J., Bartlett, N. L., Vose, J., Ramchandren, R., Feldman, T., LaCasce, A. S., Christian, B., Ansell, S. M., Moskowitz, C. H., Brown, L., Zhang, C., Taft, D., Ansari, S., Sacchi, M., Ho, L., Herrera, A. F. 2021

  Abstract

  This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed or refractory classical Hodgkin lymphoma. In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2-4. In part 3, both study drugs were dosed same day for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (N=91) was 85%, with 67% achieving a complete response. At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI]: 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns.

  View details for DOI 10.1182/blood.2020009178

  View details for PubMedID 33827139

• Brentuximab vedotin plus chemotherapy for patients with previously untreated, Stage III or IV classical Hodgkin lymphoma: 5-year update of the phase 3 ECHELON-1 study (NCT01712490) Radford, J., Dlugosz-Danecka, M., Connors, J. M., Illes, A., Picardi, M., Lech-Maranda, E., Feldman, T., Smolewski, P., Savage, K. J., Bartlett, N. L., Walewski, J., Ramchandren, R., Zinzani, P., Hutchings, M., Munoz, J., Kim, W., Advani, R., Ansell, S. M., Younes, A., Gallamini, A., Liu, R., Little, M., Fenton, K., Fanale, M., Straus, D. J. WILEY. 2021: 145-147

  View details for Web of Science ID 000645412200190

• ECHELON-2 (NCT01777152), a randomized, double-blind, phase 3 study of brentuximab vedotin plus cyclophosphamide doxorubicin and prednisone versus cyclophosphamide, doxorubicin, vincristine and prednisone in previously untreated patients with CD30-positive peripheral T-cell lymphoma: 5-year results Illidge, T., Horwitz, S. M., O'Connor, O. A., Pro, B., Iyer, S. P., Advani, R., Bartlett, N. L., Christensen, J., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W., Feldman, T. A., Menne, T., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Huettmann, A., Savage, K. J., Yuen, S., Zinzani, P., Miao, H., Bunn, V., Fenton, K., Fanale, M. A., Puhlmann, M., Truemper, L. WILEY. 2021: 38-40

  View details for Web of Science ID 000645412200040

• Primary Mediastinal B cell Lymphoma in the Positron-Emission Tomography Era Executive Summary of the American Radium SocietyTM Appropriate Use Criteria. International journal of radiation oncology, biology, physics Hoppe, B. S., Advani, R., Milgrom, S. A., Bakst, R. L., Ballas, L. K., Dabaja, B. S., Flowers, C. R., Ha, C. S., Mansur, D. B., Metzger, M. L., Pinnix, C. C., Plastaras, J. P., Roberts, K. B., Smith, S. M., Terezakis, S. A., Kirwan, J. M., Constine, L. S. 2021

  Abstract

  BARCKGROUND: Primary mediastinal B cell lymphoma(PMBCL) is a highly curable subtype of non-Hodgkin lymphoma that is predominantly diagnosed in adolescents and young adults. Consequently, long-term treatment-related morbidity is critical to consider when devising treatment strategies that include different chemoimmunotherapy strategies with or without radiotherapy. Furthermore, adaptive approaches using the end-of-chemotherapy (EOC)positron emission tomography (PET)/computed tomography (CT) scanning may help determine which patients may benefit from additional therapies. We aimed to develop evidence-based guidelines for treating these patients.METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) guideline using PubMed database. The ARS expert committee made up of radiation oncologists, hematoligists, and pediatric oncologists developed consensus guidelines using the modifited DELPHI framework.RESULTS: Nine studies were identified that met the full criteria for inclusion based on reporting outcomes on patients with primary mediastinal B cell lymphoma with EOC PET/CT response scored with the 5 point Deauville scale. These studies formed the evidence for these guidelines in managing patients with PMBCL according to the EOC PET response, including after a 5PDS of 1-3, 4, 5, and for patients with relapsed and refractory disease. The expert group also developed guidance on radiation simulation, treatment planning, and plan evaluation based on expert opinion.CONCLUSIONS: Various treatment approaches exist in the management of PMBCL, including different chemoimmunotherapy regimens, the use of consolidative radiotherapy, and adaptive approaches based on EOC PET/CT response. These guidelines can be used by practitioners to provide appropriate treatment according to different disease scenarios.

  View details for DOI 10.1016/j.ijrobp.2021.03.035

  View details for PubMedID 33774076

• Correlation of 18-fluorodeoxyglucose PET/computed tomography parameters and clinical features to predict outcome for diffuse large B-cell lymphoma. Nuclear medicine communications Baratto, L., Wu, F., Minamimoto, R., Hatami, N., Liang, T., Sabile, J., Advani, R. H., Mittra, E. 2021

  Abstract

  PURPOSE: To determine if the correlation between different metabolic parameters along with clinical features can create an improved model of prognostication for diffuse large B-cell lymphoma (DLBCL) patients.METHODS: We retrospectively evaluated 89 patients with DLBCL. All patients had a baseline and an interim 18F-FDG PET/CT. Seventy-nine also had an end-of-treatment PET/CT (EOT-PET). For each scan, we collected standardized uptake value (SUVmax, SUVmean, SUVpeak), metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVmaxsum, SUVmeansum, MTVsum, and TLGsum. These metabolic parameters were combined with clinical features in order to identify a new prognostic model. The predictive value of interim PET and EOT-PET using Deauville score was also determined.RESULTS: Baseline SUVmaxsum and SUVmeansum were significantly correlated to overall survival (OS) (P value=0.012 and 0.011, respectively). The percentage change of MTV and TLG sum from baseline to EOT was predictive of progression-free survival (PFS) (P value=0.003 and 0.022, respectively). The combination of either Deauville score at the EOT and SUVmaxsum at baseline significantly predicted OS (P value <0.001); Eastern Cooperative Oncology Group performance status, presence of extranodal disease and percentage change of MTVsum from baseline to EOT were significant predictors of PFS (P value=0.001).CONCLUSIONS: SUVmaxsum and SUVmeansum at baseline and percentage change in MTV and TLG sum from baseline to EOT are predictors of outcome in DLBCL patients. These metabolic parameters combined to Deauville score and some clinical features could be used together to stratify patients.

  View details for DOI 10.1097/MNM.0000000000001398

  View details for PubMedID 33741852

• Stage I-II diffuse large B-cell lymphoma treated with rituximab and chemotherapy with or without radiotherapy. Leukemia & lymphoma Binkley, M. S., Hiniker, S. M., Younes, S., Yoo, C., Wignarajah, A., Jin, M., Guo, H. H., Gupta, N. K., Natkunam, Y., Advani, R. H., Hoppe, R. T. 2021: 1–15

  Abstract

  We set to identify prognostic factors in a retrospective cohort of consecutive patients with stage I-II diffuse large B-cell lymphoma treated with rituximab-chemotherapy with or without radiotherapy from 2001 through 2017 at our institution. We identified 143 patients with median follow-up of 7.7years. The majority were male (59.4%), had stage II (53.1%), had stage-modified IPI 0-1 (smIPI, 58.1%), and had non-bulky disease (<7cm, 68.5%). 99 patients (69.2%) received rituximab-chemotherapy followed by radiotherapy, and 44 patients (30.8%) received rituximab-chemotherapy alone. The 5-year progression-free survival (PFS) and overall survival (OS) were 81.2% and 88.9%, respectively. The 5-year PFS for those with smIPI 0-1 versus 2-4 was 89.5% versus 69.7%, respectively (P=0.005). Bulky disease (≥7cm) was associated with worse PFS and OS on univariable and multivariable analyses (P<0.05). Patients with smIPI 0-1 without bulky disease have excellent outcomes. However, patients with smIPI 2-4 or bulky disease have a high risk of progression.

  View details for DOI 10.1080/10428194.2021.1876859

  View details for PubMedID 33622155

• Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma. Blood advances Merryman, R. W., Redd, R. A., Nishihori, T. n., Chavez, J. n., Nieto, Y. n., Darrah, J. M., Rao, U. n., Byrne, M. T., Bond, D. A., Maddocks, K. J., Spinner, M. A., Advani, R. H., Ballard, H. J., Svoboda, J. n., Singh, A. K., McGuirk, J. P., Modi, D. n., Ramchandren, R. n., Romancik, J. n., Cohen, J. B., Frigault, M. J., Chen, Y. B., Serritella, A. V., Kline, J. n., Ansell, S. n., Nathan, S. n., Rahimian, M. n., Joyce, R. M., Shah, M. n., David, K. A., Park, S. n., Beaven, A. W., Habib, A. n., Bachanova, V. n., Nakhoda, S. n., Khan, N. n., Lynch, R. C., Smith, S. D., Ho, V. T., LaCasce, A. n., Armand, P. n., Herrera, A. F. 2021; 5 (6): 1648–59

  Abstract

  Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

  View details for DOI 10.1182/bloodadvances.2020003556

  View details for PubMedID 33710337

• The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Cancer cell Steen, C. B., Luca, B. A., Esfahani, M. S., Azizi, A., Sworder, B. J., Nabet, B. Y., Kurtz, D. M., Liu, C. L., Khameneh, F., Advani, R. H., Natkunam, Y., Myklebust, J. H., Diehn, M., Gentles, A. J., Newman, A. M., Alizadeh, A. A. 2021

  Abstract

  Biological heterogeneity in diffuse large B cell lymphoma (DLBCL) is partly driven by cell-of-origin subtypes and associated genomic lesions, but also by diverse cell types and cell states in the tumor microenvironment (TME). However, dissecting these cell states and their clinical relevance at scale remains challenging. Here, we implemented EcoTyper, a machine-learning framework integrating transcriptome deconvolution and single-cell RNA sequencing, to characterize clinically relevant DLBCL cell states and ecosystems. Using this approach, we identified five cell states of malignant B cells that vary in prognostic associations and differentiation status. We also identified striking variation in cell states for 12 other lineages comprising the TME and forming cell state interactions in stereotyped ecosystems. While cell-of-origin subtypes have distinct TME composition, DLBCL ecosystems capture clinical heterogeneity within existing subtypes and extend beyond cell-of-origin and genotypic classes. These results resolve the DLBCL microenvironment at systems-level resolution and identify opportunities for therapeutic targeting (https://ecotyper.stanford.edu/lymphoma).

  View details for DOI 10.1016/j.ccell.2021.08.011

  View details for PubMedID 34597589

• NCCN Guidelines Insights: B-Cell Lymphomas, Version 5.2021. Journal of the National Comprehensive Cancer Network : JNCCN Zelenetz, A. D., Gordon, L. I., Chang, J. E., Christian, B., Abramson, J. S., Advani, R. H., Bartlett, N. L., Budde, L. E., Caimi, P. F., De Vos, S., Dholaria, B., Fakhri, B., Fayad, L. E., Glenn, M. J., Habermann, T. M., Hernandez-Ilizaliturri, F., Hsi, E., Hu, B., Kaminski, M. S., Kelsey, C. R., Khan, N., Krivacic, S., LaCasce, A. S., Lim, M., Narkhede, M., Rabinovitch, R., Ramakrishnan, P., Reid, E., Roberts, K. B., Saeed, H., Smith, S. D., Svoboda, J., Swinnen, L. J., Tuscano, J., Vose, J. M., Dwyer, M. A., Sundar, H. 2021; 19 (11): 1218-1230

  Abstract

  In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

  View details for DOI 10.6004/jnccn.2021.0054

  View details for PubMedID 34781267

• Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. The Lancet. Haematology Straus, D. J., Długosz-Danecka, M., Connors, J. M., Alekseev, S., Illés, Á., Picardi, M., Lech-Maranda, E., Feldman, T., Smolewski, P., Savage, K. J., Bartlett, N. L., Walewski, J., Ramchandren, R., Zinzani, P. L., Hutchings, M., Munoz, J., Lee, H. J., Kim, W. S., Advani, R., Ansell, S. M., Younes, A., Gallamini, A., Liu, R., Little, M., Fenton, K., Fanale, M., Radford, J. 2021; 8 (6): e410-e421

  Abstract

  Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population.ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing.Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50).With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma.Millennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.

  View details for DOI 10.1016/S2352-3026(21)00102-2

  View details for PubMedID 34048680

• Increased double-negative αβ+ T-cells reveal adult-onset autoimmune lymphoproliferative syndrome in a patient with IgG4-related disease. Haematologica Brar, N., Spinner, M. A., Baker, M. C., Advani, R. H., Natkunam, Y., Lewis, D. B., Silva, O. 2021

  Abstract

  Not available.

  View details for DOI 10.3324/haematol.2021.278772

  View details for PubMedID 34474549

• Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions. Blood Orellana-Noia, V. M., Reed, D., McCook, A. A., Sen, J. M., Barlow, C. M., Malecek, M. K., Watkins, M. P., Kahl, B. S., Spinner, M. A., Advani, R., Voorhees, T. J., Snow, A., Grover, N. S., Ayers, A. A., Romancik, J., Liu, Y., Huntington, S. F., Chavez, J. C., Saeed, H., Lazaryan, A., Raghunathan, V., Spurgeon, S. E., Ollila, T. A., Del Prete, C., Olszewski, A., Ayers, E. C., Landsburg, D. J., Echalier, B., Lee, J., Kamdar, M., Caimi, P. F., Fu, T., Liu, J., David, K. A., Alharthy, H., Law, J. Y., Karmali, R., Shah, H. R., Stephens, D. M., Major, A., Rojek, A. E., Smith, S. M., Yellala, A., Kallam, A., Nakhoda, S., Khan, N., Sohail, M. A., Hill, B. T., Barrett-Campbell, O., Lansigan, F., Switchenko, J. M., Cohen, J. B., Portell, C. A. 2021

  Abstract

  Prophylaxis is commonly used to prevent central nervous system (CNS) relapse in diffuse large B cell lymphoma, with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013-2019. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated and reconsideration of prophylaxis strategies in DLBCL is of critical need.

  View details for DOI 10.1182/blood.2021012888

  View details for PubMedID 34570876

• Outcomes of adults with lymphoma treated with nonmyeloablative TLI-ATG and radiation boost to high risk or residual disease before allogeneic hematopoietic cell transplant. Bone marrow transplantation Dworkin, M. L., Jiang, A. L., Von Eyben, R., Spinner, M. A., Advani, R. H., Lowsky, R., Hiniker, S. M., Hoppe, R. T. 2021

  Abstract

  We evaluated the impact on survival of antithymocyte globulin conditioning (TLI-ATG) with radiation (RT) boost to high risk or residual disease before allogeneic hematopoietic cell transplant (allo-HCT) for adults with lymphoma (excluding mycosis fungoides and low-grade NHL other than SLL/CLL). Of 251 evaluable patients, 36 received an RT boost within 3 months of allo-HCT at our institution from 2001 to 2016. At the time of TLI-ATG, patients who received boost vs no boost had a lower rate of CR (11% vs 47%, p = 0.0003), higher rates of bulky disease (22% vs 4%, p < 0.0001), extranodal disease (39% vs 5%, p < 0.0001), and positive PET (75% vs 28%, p < 0.00001). In the boost group, the median (range) largest axial lesion diameter was 5.2 cm (1.8-22.3). Median follow-up was 50.2 months (range: 1-196). There was no significant difference in OS, time to recurrence, or time to graft failure with vs without boost. A trend toward higher percent donor CD3+ chimerism was seen with vs without boost (p = 0.0819). The worst boost-related toxicity was grade 2 dermatitis. RT boost may help successfully mitigate the risk of high risk or clinically evident residual disease in adults with lymphoma undergoing allo-HCT.

  View details for DOI 10.1038/s41409-021-01495-4

  View details for PubMedID 34671121

• Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kumar, A. n., Casulo, C. n., Advani, R. H., Budde, E. n., Barr, P. M., Batlevi, C. L., Caron, P. n., Constine, L. S., Dandapani, S. V., Drill, E. n., Drullinsky, P. n., Friedberg, J. W., Grieve, C. n., Hamilton, A. n., Hamlin, P. A., Hoppe, R. T., Horwitz, S. M., Joseph, A. n., Khan, N. n., Laraque, L. n., Matasar, M. J., Moskowitz, A. J., Noy, A. n., Palomba, M. L., Schöder, H. n., Straus, D. J., Vemuri, S. n., Yang, J. n., Younes, A. n., Zelenetz, A. D., Yahalom, J. n., Moskowitz, C. H. 2021: JCO2100108

  Abstract

  To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma.In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4-negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4.Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering-defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible.BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4-negative patients.

  View details for DOI 10.1200/JCO.21.00108

  View details for PubMedID 33909449

• Outcomes and Prognostic Factors in Angioimmunoblastic T cell Lymphoma: Final Report from the International TCell Project. Blood Advani, R. n., Skrypets, T. n., Civallero, M. n., Spinner, M. A., Manni, M. n., Kim, W. n., Shustov, A. n., Horwitz, S. M., Hitz, F. n., Cabrera, M. E., Dlouhy, I. n., Vassallo, J. n., Pileri, S. A., Inghirami, G. G., Montoto, S. n., Vitolo, U. n., Radford, J. n., Vose, J. n., Federico, M. n. 2021

  Abstract

  Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary endpoints were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced stage disease. Eighty-one percent received anthracycline-based regimens and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ³60 years, ECOG performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low, intermediate, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared to only 6% for patients with POD24 (p<0.0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need and novel therapeutic approaches are required.

  View details for DOI 10.1182/blood.2020010387

  View details for PubMedID 33786592

• Effect of CD47 Blockade on Vascular Inflammation. The New England journal of medicine Jarr, K. U., Nakamoto, R. n., Doan, B. H., Kojima, Y. n., Weissman, I. L., Advani, R. H., Iagaru, A. n., Leeper, N. J. 2021; 384 (4): 382–83

  View details for DOI 10.1056/NEJMc2029834

  View details for PubMedID 33503349

• Nodular lymphocyte predominant Hodgkin lymphoma: executive summary of the American radium society appropriate use criteria. Leukemia & lymphoma Ballas, L. K., Metzger, M. L., Milgrom, S. A., Advani, R., Bakst, R. L., Dabaja, B. S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mansur, D. B., Pinnix, C. C., Plastaras, J. P., Roberts, K. B., Smith, S. M., Terezakis, S. A., Constine, L. S. 2020: 1–14

  Abstract

  This guideline for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) by the American Radium Society was developed by a multidisciplinary expert panel of medical, pediatric, and radiation oncologists convened to formulate guidelines for evaluation and treatment. The guideline development was based on an in-depth literature review and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of the recommendations by the panel. Given the scarcity of compelling data for strong recommendations for a rare lymphoma that has been shown to be more indolent than classical Hodgkin lymphoma, in instances where evidence is not available or equivocal, expert opinion guided the recommendations. Four clinical variants exemplify common scenarios and represent the consensus recommendations for patients with nodular lymphocyte Hodgkin lymphoma. A summary of the available published literature is also presented.

  View details for DOI 10.1080/10428194.2020.1852559

  View details for PubMedID 33274673

• Exploratory Analysis of Brentuximab Vedotin Plus CHP (A plus CHP) as Frontline Treatment for Patients with CD30-Expressing PERIPHERAL T-Cell Lymphomas (Echelon-2): Impact of Consolidative Stem Cell Transplant Trneny, M., Savage, K. J., Horwitz, S. M., Advani, R., Christensen, J. H., Domingo-Domenech, E., Rossi, G., Morschhauser, F., Alpdogan, O., Suh, C., Tobinai, K., Shustov, A. R., Yuen, S., Zinzani, P., Trumper, L., Illidge, T., O'Connor, O., Pro, B., Little, M., Bunn, V., Fenton, K., Manley, T., Iyer, S. P. SPRINGERNATURE. 2020: 115–16

  View details for Web of Science ID 000600556200110

• Controversies in the Management of Early-Stage Hodgkin Lymphoma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Advani, R. H. 2020; 18 (12): 1748–50

  View details for DOI 10.6004/jnccn.2020.5033

  View details for Web of Science ID 000605166600004

• Partial response or better at sixmonths is prognostic of superior progression-free survival in Waldenstrom macroglobulinaemia patients treated with ibrutinib. British journal of haematology Castillo, J. J., Abeykoon, J. P., Gustine, J. N., Zanwar, S., Mein, K., Flynn, C. A., Demos, M. G., Guerrera, M. L., Kofides, A., Liu, X., Munshi, M., Tsakmaklis, N., King, R., Yang, G., Hunter, Z. R., Advani, R. H., Palomba, M. L., Ansell, S. M., Gertz, M. A., Kapoor, P., Treon, S. P. 2020

  Abstract

  Ibrutinib is associated with durable responses in patients with Waldenstrom macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P=0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P=0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P=0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P=0·01] and validation cohorts (HR 0·18; P=0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

  View details for DOI 10.1111/bjh.17225

  View details for PubMedID 33207010

• Consensus treatment recommendations from the tenth International Workshop for Waldenstrom Macroglobulinaemia LANCET HAEMATOLOGY Castillo, J. J., Advani, R. H., Branagan, A. R., Buske, C., Dimopoulos, M. A., D'Sa, S., Kersten, M., Leblond, V., Minnema, M. C., Owen, R. G., Palomba, M., Talaulikar, D., Tedeschi, A., Trotman, J., Varettoni, M., Vos, J. M., Treon, S. P., Kastritis, E. 2020; 7 (11): E827–E837

  View details for Web of Science ID 000581050200017

• Outcomes Of Adult Patients With Lymphoma Treated With Nonmyeloablative Total Lymphoid Irradiation For Stem Cell Transplant (SCT) Conditioning With A Boost To High Risk Or Gross Disease Dworkin, M. L., Hiniker, S. M., Von Eyben, R., Spinner, M. A., Advani, R. H., Lowsky, R., Hoppe, R. T. ELSEVIER SCIENCE INC. 2020: E752–E753

  View details for Web of Science ID 000582521502485

• Long-Term Outcomes For Stage I-II Diffuse Large B-Cell Lymphoma Treated With Rituximab And Chemotherapy With Or Without Radiotherapy Binkley, M. S., Hiniker, S. M., Younes, S., Yoo, C., Wignarajah, K., Jin, M., Guo, H. H., Natkunam, Y., Advani, R. H., Hoppe, R. T. ELSEVIER SCIENCE INC. 2020: E758

  View details for Web of Science ID 000582521502497

• Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. The Lancet. Haematology Cheson, B. D., Bartlett, N. L., LaPlant, B., Lee, H. J., Advani, R. J., Christian, B., Diefenbach, C. S., Feldman, T. A., Ansell, S. M. 2020

  Abstract

  BACKGROUND: Hodgkin lymphoma is potentially curable. However, 15-35% of older patients (ie, >60 years) have a lower response rate, worse survival outcomes, and greater toxicity than younger patients. Brentuximab vedotin and nivolumab exhibit activity in patients with relapsed or refractory Hodgkin lymphoma. We therefore aimed to evaluate the safety and efficacy of brentuximab vedotin and nivolumab in untreated older patients with Hodgkin lymphoma or in younger patients considered unsuitable for standard ABVD (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy.METHODS: We did a multicentre, single-arm, phase 2 trial at eight cancer centres in the USA. Previously untreated patients with classic Hodgkin lymphoma were eligible for study enrolment if they were 60 years or older, or younger than 60 years but considered unsuitable for standard chemotherapy because of a cardiac ejection fraction of less than 50%, pulmonary diffusion capacity of less than 80%, or a creatinine clearance of 30 mL/min or more but less than 60 mL/min, or those who refused chemotherapy. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received brentuximab vedotin at 1·8 mg/kg (dose cap at 180 mg) and nivolumab at 3 mg/kg both intravenously every 21 days for 8 cycles. The primary endpoint was the overall response, defined as a partial metabolic response or complete metabolic response at the end of 8 cycles of treatment. A per protocol analysis was done including all patients who received treatment in the activity and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02758717.FINDINGS: Between May 13, 2016, and Jan 30, 2019, the study accrued 46 patients. The median age was 71·5 years (IQR 64-77), with two (4%) of 46 patients younger than 60 years. Median follow-up was 21·2 months (IQR 15·6-29·9), and 35 (76%) of 46 patients completed all 8 cycles of therapy. At the interim analysis on Oct 11, 2019, the first 25 evaluable patients had an overall response rate of 64% ([95% CI 43-82] 16 of 25 patients; 13 [52%] had a complete metabolic response and three [12%] had a partial metabolic response). The trial was closed to accrual on Oct 14, 2019, after the interim analysis failed to meet the predefined criteria. In all 46 evaluable patients, 22 (48%) patients achieved a complete metabolic response and six (13%) achieved a partial metabolic response (overall response rate 61% [95% CI 45-75]). 14 (30%) of 46 patients had 16 dose adjustments, primarily due to neurotoxicity. 22 (48%) of 46 patients had peripheral neuropathy (five [11%] patients had grade 3 peripheral neuropathy). Grade 4 adverse events included increased aminotranferases (one [2%] of 46), increased lipase or amylase (two [4%]), and pancreatitis (one [2%]). One (2%) patient died from cardiac arrest, possibly treatment related.INTERPRETATION: Although the trial did not meet the prespecified activity criteria, brentuximab vedotin plus nivolumab is active in older patients with previously untreated Hodgkin lymphoma with comorbidities. The regimen was also well tolerated in the majority of patients in this older population. Future trials should be based on optimising the dose and schedule, perhaps combined with other targeted agents that might permit chemotherapy-free strategies in older patients with Hodgkin lymphoma.FUNDING: Seattle Genetics and Bristol Myers Squibb.

  View details for DOI 10.1016/S2352-3026(20)30275-1

  View details for PubMedID 33010817

• Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial LANCET HAEMATOLOGY Diefenbach, C. S., Hong, F., Ambinder, R. F., Cohen, J. B., Robertson, M. J., David, K. A., Advani, R. H., Fenske, T. S., Barta, S. K., Palmisiano, N. D., Svoboda, J., Morgan, D. S., Karmali, R., Sharon, E., Streicher, H., Kahl, B. S., Ansell, S. M. 2020; 7 (9): E660–E670

  View details for Web of Science ID 000564050500017

• Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial. The Lancet. Haematology Diefenbach, C. S., Hong, F., Ambinder, R. F., Cohen, J. B., Robertson, M. J., David, K. A., Advani, R. H., Fenske, T. S., Barta, S. K., Palmisiano, N. D., Svoboda, J., Morgan, D. S., Karmali, R., Sharon, E., Streicher, H., Kahl, B. S., Ansell, S. M. 2020; 7 (9): e660–e670

  Abstract

  BACKGROUND: Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We evaluated the safety and activity of combinations of brentuximab vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma.METHODS: In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab vedotin 1·8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort D) or 1·8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort G) or 1·8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipilimumab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01896999. The phase 2, randomised portion of the trial is still enrolling.FINDINGS: Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were excluded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3-4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11 (50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53-92) in the ipilimumab group, 89% (65-99) in the nivolumab group, and 82% (60-95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34-78%) in the ipilimumab group, 61% (36-83%) in the nivolumab group, and 73% (50-89%) in the triplet therapy group. With a median follow-up of 2·6 years (IQR 1·8-2·9) in the ipilimumab group, 2·4 years (2·2-2·6) in the nivolumab group, and 1·7 years (1·6-1·9) in the triplet therapy group, median progression-free survival is 1·2 years (95% CI 1·7-not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups.INTERPRETATION: There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial (NCT01896999).FUNDING: Eastern Cooperative Oncology Group-American College of Radiology Imaging Network and the National Cancer Institute of the National Institutes of Health.

  View details for DOI 10.1016/S2352-3026(20)30221-0

  View details for PubMedID 32853585

• Angioimmunoblastic T-Cell Lymphoma: Report on 282 Cases from the Prospective International T-Cell Lymphoma Project Skrypets, T., Civallero, M., Manni, M., Pileri, S., Weisenburger, D. D., Ko, Y., Inghirami, G., Bargetzi, M., Gabus, R., Bobillo Varela, S., Horwitz, S. M., Pavlovsky, A., Thieblemont, C., De Souza, C., Milone, J., Kim, W., Montoto, S., Carson, K., Vose, J. M., Federico, M., Advani, R. H. CIG MEDIA GROUP, LP. 2020: S253–S254

  View details for Web of Science ID 000564055100226

• Consensus Statement on the Management of Waldenstrom Macroglobulinemia Patients During the COVID-19 Pandemic. HemaSphere Talaulikar, D., Advani, R. H., Branagan, A. R., Buske, C., Dimopoulos, M. A., D'Sa, S., Kersten, M. J., Leblond, V., Minnema, M. C., Owen, R. G., Palomba, M. L., Tedeschi, A., Trotman, J., Varettoni, M., Vos, J. M., Treon, S. P., Kastritis, E., Castillo, J. J. 2020; 4 (4): e433

  Abstract

  In the light of the COVID-19 pandemic, the International Workshop on Waldenstrom Macroglobulinemia (IWWM) Treatment Recommendations Panel felt the need to provide a consensus statement for the management of Waldenstrom Macroglobulinemia (WM) patients during this challenging time. We followed the current recommendations by the American Society of Hematology, which have been modified accordingly to fit the specific realities associated with the management of WM. In this Consensus Statement, the Panel addresses questions related to treatment initiation, preferred therapies, minimizing visit to clinics and infusions centers, supportive care and guidance for WM patients in clinical trials. Finally, we also provide information on timing and appropriateness of testing and management of COVID-19 infected patients, as well as ways to get physicians and patients involved in registry studies that could help others.

  View details for DOI 10.1097/HS9.0000000000000433

  View details for PubMedID 32803133

• A 3-Arm Randomized Phase II Study of Bendamustine/Rituximab with Bortezomib Induction or Lenalidomide Continuation in Untreated Follicular Lymphoma: ECOG-ACRIN E2408. Clinical cancer research : an official journal of the American Association for Cancer Research Evens, A. M., Hong, F., Habermann, T. M., Advani, R. H., Gascoyne, R. D., Witzig, T. E., Quon, A., Ranheim, E. A., Ansell, S. M., Cheema, P. S., Dy, P. A., O'Brien, T. E., Winter, J. N., Cescon, T. P., Chang, J. E., Kahl, B. 2020

  Abstract

  PURPOSE: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL).PATIENTS AND METHODS: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01332968).RESULTS: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received 6 cycles, respectively. CR rate with BR vs. BVR induction was 62% vs. 75% (P=0.04). One-year DFS rates with BR-R vs. BR-LR were 85% vs. 67%, respectively (P=0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR vs. BR were neutropenia and sensory neuropathy (12% vs. <1%); 83% of the latter with intravenous bortezomib. The most common grade 3-4 AEs related to LR vs. rituximab maintenance were neutropenia 66% vs. 21% (P<0.0001) and febrile neutropenia 10% vs. 2% (P=0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P=0.36) with OS rates of 87%, 90%, and 84%, respectively (P=0.79). For prognostication, CR rate and POD-24 were associated with survival.CONCLUSIONS: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction are recommended in untreated FL.

  View details for DOI 10.1158/1078-0432.CCR-20-1345

  View details for PubMedID 32532790

• Long-term outcomes of patients with unfavorable stage I-II classic Hodgkin lymphoma treated with Stanford V chemotherapy and limited field irradiation. Leukemia & lymphoma Weil, C. R., Qian, Y., Von Eyben, R., Daadi, S. E., Corbelli, K. S., Rosenberg, S. A., Advani, R. H., Hoppe, R. T. 2020: 1–7

  Abstract

  Management of stage I-II unfavorable risk Hodgkin lymphoma (HL) strives to reduce toxicity while maintaining tumor control. Compared to ABVD or BEACOPP, Stanford V chemotherapy contains less doxorubicin and bleomycin. We report long-term outcomes of patients with stage I-II classic HL with European risk factors treated with Stanford V combined modality therapy (CMT). From our institutional cancer registry, we identified 168 patients with ≥1 European risk factor treated with 8-12weeks of Stanford V CMT and consolidative radiotherapy between 1990 and 2016. Outcomes were analyzed after classification by EORTC and GHSG unfavorable criteria. With median follow-up of 8.4years, 10-year overall survival and progression-free survival for the entire cohort were 95% and 88%, respectively. Thirteen of 18 relapses were salvaged successfully. There were no cases of MDS or AML after primary therapy. Long-term outcomes of stage I-II unfavorable risk HL treated with Stanford V CMT are comparable to ABVD or BEACOPP regimens.

  View details for DOI 10.1080/10428194.2020.1768385

  View details for PubMedID 32476541

• Phase II, multicenter trial of nivolumab (Nivo) and brentuximab vedotin (BV) in patients (Pts) with untreated Hodgkin lymphoma (HL) over the age of 60 years or unable to receive standard ABVD chemotherapy: Results of a study of Academic and Community Cancer Research United (ACCRU) RU051505I. Cheson, B. D., Bartlett, N. L., LaPlant, B., Lee, H., Advani, R. H., Christian, B., Diefenbach, C., Feldman, T., Ansell, S. M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303235

• Mantle cell lymphoma: initial report from the North American Mantle Cell Lymphoma Consortium. Fu, K., Yu, G., Bi, C., Cheng, H., Smith, L., Yuan, J., Naushad, H., Link, B. K., Nichols, C. R., Barr, P. M., Kahl, B. S., Stewart, D., Barta, S. K., Beaven, A., Advani, R. H., Martin, P., Greiner, T., Weisenburger, D., Armitage, J. O., Vose, J. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303255

• Utility of Routine Surveillance Laboratory Testing in Detecting Relapse in Patients With Classic Hodgkin Lymphoma in First Remission: Results From a Large Single-Institution Study. JCO oncology practice Lynch, R. C., Sundaram, V., Desai, M., Henry, S., Wood, D., Daadi, S., Hoppe, R. T., Advani, R. 2020: JOP1900733

  Abstract

  PURPOSE: Classic Hodgkin lymphoma is highly curable with contemporary therapy. Although the limited role of surveillance imaging to detect early relapse for patients in complete remission at the end of therapy is well established, there is a paucity of data regarding role of laboratory testing in this setting.METHODS: Patients with newly diagnosed classic Hodgkin lymphoma uniformly treated with the Stanford V regimen from 1998-2014 and in complete remission for at least 3 months were identified in a single-center institutional database. Laboratory tests categorized by Common Terminology Criteria for Adverse Events v4.03 as grade 2 or higher were considered abnormal. Primary analysis included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of surveillance laboratory tests for predicting relapse in the first 3 years after end of treatment.RESULTS: Among 235 eligible patients, 24 (10.2%) patients ultimately relapsed. In the first 3 years after end of therapy, the mean number of surveillance blood draws per patient was 7.1, (range, 1-13). These 1,661 surveillance blood draws included 4,684 individual laboratory tests, comprising 1,609 CBCs, 1,578 metabolic panels, and 1,497 erythrocyte sedimentation rates. None of the biopsies confirming relapses were prompted by any abnormal laboratory finding. The sensitivity of any surveillance laboratory test for detecting relapse within 3 years of end of treatment was 72.7% (95% CI, 49.8% to 89.3%), specificity 22.6% (95% CI, 17.2% to 28.9%), yielding a PPV of 8.9% (95% CI, 7.0% to 11.3%) and NPV of 88.9% (95% CI, 79% to 94%).CONCLUSION: Our study found limited clinically meaningful utility for routine surveillance laboratory testing in detecting relapse in patients with complete remission at end of treatment. Our results warrant consideration of modifications to current practice guidelines.

  View details for DOI 10.1200/JOP.19.00733

  View details for PubMedID 32369413

• Response to brentuximab vedotin plus CHP according to CD30 expression in the ECHELON-2 trial Illidge, T., Horwitz, S., Iyer, S., Bartlett, N., Kim, W. S., Belada, D., Feldman, T., Illes, A., Jacobsen, E., Huettmann, A., Zinzani, P. L., O'Connor, O., Mckay, P., Trepicchio, W., Miao, H., Fenton, K., Onsum, M., Manley, T., Advani, R. WILEY. 2020: 111–12

  View details for Web of Science ID 000528597400151

• Brentuximab vedotin plus chemotherapy for stage III/IV classical Hodgkin lymphoma: 4-year update of the ECHELON-1 study Radford, J., Bartlett, N., Straus, D., Dlugosz-Danecka, M., Alekseev, S., Illes, A., Lech-Maranda, E., Feldman, T., Smolewski, P., Savage, K., Walewski, J., Ramchandren, R., Zinzani, P. L., Hutchings, M., Connors, J., Munoz, J., Kim, W. S., Advani, R., Ansell, S., Younes, A., Gallamini, A., Miao, H., Liu, R., Fenton, K., Forero-Torres, A., Picardi, M. WILEY. 2020: 101–2

  View details for Web of Science ID 000528597400137

• The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. British journal of haematology Fowler, N. H., Nastoupil, L., De Vos, S., Knapp, M., Flinn, I. W., Chen, R., Advani, R. H., Bhatia, S., Martin, P., Mena, R., Davis, R. E., Neelapu, S. S., Eckert, K., Ping, J., Co, M., Beaupre, D. M., Neuenburg, J. K., Palomba, M. L. 2020

  Abstract

  This phase 2 study evaluated the activity and safety of ibrutinib, a Bruton's tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular lymphoma. Patients received once-daily ibrutinib 560mg continuously plus once-weekly rituximab 375mg/m2 for 4weeks beginning Week 1 (Arm 1, n=60) or Week 9 (following an 8-week ibrutinib lead-in) to explore biomarkers (Arm 2, n=20). The primary endpoint was the best overall response rate (ORR). The median age was 58years; most had an Eastern Cooperative Oncology Group Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow-up of 34months in Arm 1 and 29months in Arm 2, ORRs were 85% [95% confidence interval (CI) 73-93] and 75% (95% CI 51-91), respectively, with complete responses in 40% and 50%. The median duration of response was not reached in either arm; 30-month progression-free and overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3/4) haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab was active and tolerable in first-line follicular lymphoma.

  View details for DOI 10.1111/bjh.16424

  View details for PubMedID 32180219

• POPULATION PHARMACOKINETICS OF MAGROLIMAB (5F9, HU5F9--G4) IN PATIENTS WITH SOLID TUMORS AND LYMPHOMAS. Agoram, B., Jin, C., Wang, B., Sikic, B., Advani, R., Chao, M., Takimoto, C. WILEY. 2020: S85

  View details for Web of Science ID 000513341300292

• Three-year outcomes with brentuximab vedotin plus bendamustine as first salvage therapy in relapsed or refractory Hodgkin lymphoma. British journal of haematology LaCasce, A. S., Bociek, R. G., Sawas, A., Caimi, P., Agura, E., Matous, J., Ansell, S. M., Crosswell, H. E., Islas-Ohlmayer, M., Behler, C., Cheung, E., Forero-Torres, A., Vose, J., O'Connor, O. A., Josephson, N., Wang, Y., Advani, R. 2020

  View details for DOI 10.1111/bjh.16499

  View details for PubMedID 32048731

• Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia. The Lancet. Haematology Castillo, J. J., Advani, R. H., Branagan, A. R., Buske, C. n., Dimopoulos, M. A., D'Sa, S. n., Kersten, M. J., Leblond, V. n., Minnema, M. C., Owen, R. G., Palomba, M. L., Talaulikar, D. n., Tedeschi, A. n., Trotman, J. n., Varettoni, M. n., Vos, J. M., Treon, S. P., Kastritis, E. n. 2020; 7 (11): e827–e837

  Abstract

  Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.

  View details for DOI 10.1016/S2352-3026(20)30224-6

  View details for PubMedID 33091356

• Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Treon, S. P., Meid, K. n., Gustine, J. n., Yang, G. n., Xu, L. n., Liu, X. n., Patterson, C. J., Hunter, Z. R., Branagan, A. R., Laubach, J. P., Ghobrial, I. M., Palomba, M. L., Advani, R. n., Castillo, J. J. 2020: JCO2000555

  Abstract

  We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM).Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity.The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL (P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88MutCXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88MutCXCR4WT and MYD88MutCXCR4Mut WM, respectively (P = .02). In patients with MYD88WT, the median PFS was 0.4 years (P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management.Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

  View details for DOI 10.1200/JCO.20.00555

  View details for PubMedID 32931398

• Brentuximab vedotin with chemotherapy for Stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood Straus, D. J., Długosz-Danecka, M. n., Alekseev, S. n., Illes, A. n., Picardi, M. n., Lech-Maranda, E. n., Feldman, T. n., Smolewski, P. n., Savage, K. J., Bartlett, N. L., Walewski, J. n., Ramchandren, R. n., Zinzani, P. L., Hutchings, M. n., Connors, J. M., Radford, J. n., Munoz, J. n., Kim, W. S., Advani, R. n., Ansell, S. M., Younes, A. n., Miao, H. n., Liu, R. n., Fenton, K. n., Forero, A. n., Gallamini, A. n. 2020

  Abstract

  The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with AVD (A+AVD) exhibited superior modified PFS versus ABVD for the frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL) (NCT01712490; 2011-005450-60). Maturing data from positron emission tomography (PET)-adapted trials highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET2(-) patients. We present here an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. 1334 patients with stage III or IV cHL were randomized 1:1 to receive six cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET scan after cycle 2 (PET2) was required. At a median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2(-) patients aged <60 years were 87.2% versus 81.0%, respectively. A beneficial trend in PET2(+) patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% versus 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy (PN) on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL which is consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or exposure to bleomycin.

  View details for DOI 10.1182/blood.2019003127

  View details for PubMedID 31945149

• Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics. Blood advances Torka, P. n., Kothari, S. K., Sundaram, S. n., Li, S. n., Medeiros, L. J., Ayers, E. C., Landsburg, D. J., Bond, D. A., Maddocks, K. J., Giri, A. n., Hess, B. n., Pham, L. Q., Advani, R. n., Liu, Y. n., Barta, S. K., Vose, J. M., Churnetski, M. C., Cohen, J. B., Burkart, M. n., Karmali, R. n., Zurko, J. n., Mehta, A. n., Olszewski, A. J., Lee, S. n., Hill, B. T., Burns, T. F., Lansigan, F. n., Rabinovich, E. n., Peace, D. n., Groman, A. n., Attwood, K. n., Hernandez-Ilizaliturri, F. J. 2020; 4 (2): 253–62

  Abstract

  There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.

  View details for DOI 10.1182/bloodadvances.2019000875

  View details for PubMedID 31945157

• Checkpoint blockade treatment sensitises relapsed/refractory non-Hodgkin lymphoma to subsequent therapy. British journal of haematology Carreau, N. A., Armand, P. n., Merryman, R. W., Advani, R. H., Spinner, M. A., Herrera, A. F., Ramchandren, R. n., Hamid, M. S., Assouline, S. n., Santiago, R. n., Wagner-Johnston, N. n., Paul, S. n., Svoboda, J. n., Bair, S. M., Barta, S. K., Nathan, S. n., Karmali, R. n., Torka, P. n., David, K. n., Lansigan, F. n., Persky, D. n., Godfrey, J. n., Chavez, J. C., Xia, Y. n., Diefenbach, C. n. 2020

  Abstract

  Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.

  View details for DOI 10.1111/bjh.16756

  View details for PubMedID 32430944

• Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma. The oncologist Merryman, R. W., Carreau, N. A., Advani, R. H., Spinner, M. A., Herrera, A. F., Chen, R. n., Tomassetti, S. n., Ramchandren, R. n., Hamid, M. n., Assouline, S. n., Santiago, R. n., Nina Wagner-Johnston, N. n., Paul, S. n., Svoboda, J. n., Bair, S. M., Barta, S. K., Liu, Y. n., Nathan, S. n., Karmali, R. n., Burkart, M. n., Torka, P. n., David, K. A., Wei, C. n., Lansigan, F. n., Emery, L. n., Persky, D. n., Smith, S. M., Godfrey, J. n., Chavez, J. n., Cohen, J. B., Troxel, A. B., Diefenbach, C. n., Armand, P. n. 2020

  Abstract

  Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB - 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median 17.5m vs 6.1m, p=0.035) and longer time-to-subsequent treatment failure (TTSTF), defined as time from initial ICB progression to failure of subsequent treatment (median 34.6m vs 9.9m, p=0.003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

  View details for DOI 10.1634/theoncologist.2020-0040

  View details for PubMedID 32275786

• Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Armand, P., Bello, C. M., Benitez, C. M., Bierman, P. J., Boughan, K. M., Dabaja, B., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Herrera, A. F., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Lynch, R. C., Maddocks, K., McConathy, J., McKinney, M., Metzger, M., Morgan, D., Mulroney, C., Rabinovitch, R., Rosenspire, K. C., Seropian, S., Tao, R., Winter, J. N., Yahalom, J., Burns, J. L., Ogba, N. 2020; 18 (6): 755–81

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

  View details for DOI 10.6004/jnccn.2020.0026

  View details for PubMedID 32502987

• Stage I-II Nodular Lymphocyte-Predominant Hodgkin Lymphoma: a Multi-institutional Experience of Adult Patients by ILROG. Blood Binkley, M. S., Rauf, M. S., Milgrom, S. A., Pinnix, C. C., Tsang, R. W., Dickinson, M. n., Ng, A. n., Roberts, K. B., Gao, S. n., Balogh, A. G., Ricardi, U. n., Levis, M. n., Casulo, C. n., Stolten, M. n., Specht, L. n., Plastaras, J. P., Wright, C. n., Kelsey, C. R., Brady, J. L., Mikhaeel, N. G., Hoppe, B. S., Terezakis, S. n., Picardi, M. n., Della Pepa, R. n., Kirova, Y. n., Akhtar, S. n., Maghfoor, I. n., Koenig, J. L., Jackson, C. n., Song, E. n., Sehgal, S. n., Advani, R. n., Natkunam, Y. n., Constine, L. S., Eich, H. T., Wirth, A. n., Hoppe, R. T. 2020

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment for stage I-II NLPHL is undefined. We conducted a multi-center retrospective study including patients ≥16 years with stage I-II NLPHL diagnosed from 1995-2018 receiving all forms of management including radiotherapy (RT), combined modality therapy (CMT=RT+chemotherapy), chemotherapy (CT), observation after excision, rituximab and RT, and single agent rituximab (R). End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age 39 years, 72.3% being male, and 54.9% having stage I disease. Median follow up was 5.5 years (IQR=3.1-10.1). 5-year PFS and OS for the entire cohort were 87.1% (95%CI=83.6-90.0%) and 98.3% (95%CI=96.4-99.2%), respectively. Primary management was RT alone (n=257, 46.0%), CMT (n=184, 32.9%), CT alone (n=47, 8.4%), observation (n=37, 6.6%), rituximab and RT (n=19, 3.4%), and rituximab alone (n=15, 2.7%). 5-year PFS rates were 91.1% (95%CI=85.3-94.7%) after RT, 90.5% (95%CI=84.8-94.1%) after CMT, 77.8% (95%CI=61.3-88.0%) after chemotherapy, 73.5% (95%CI=50.6-87.0%) after observation, 80.8% (95%CI=41.0-95.1%) after rituximab and RT, and 38.5% (95%CI=14.0-62.8%) after rituximab alone. For the RT cohort but not the CMT cohort, variant immunoarchitectural pattern and number of sites>2 were associated with worse PFS (P<0.05). Overall, 21 patients (3.8%) developed large cell transformation, with a significantly higher transformation rate for those with variant immunoarchitectural pattern (P=0.049) and number of involved sites >2 (P=0.0006). OS for patients with stage I-II NLPHLwas excellent following all managements.

  View details for DOI 10.1182/blood.2019003877

  View details for PubMedID 32211877

• Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial. The Journal of experimental medicine Frank, M. J., Khodadoust, M. S., Czerwinski, D. K., Haabeth, O. A., Chu, M. P., Miklos, D. B., Advani, R. H., Alizadeh, A. A., Gupta, N. K., Maeda, L. S., Reddy, S. A., Laport, G. G., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Weng, W. K., Sheehan, K. n., Faham, M. n., Okada, A. n., Moore, A. H., Phillips, D. L., Wapnir, I. L., Brody, J. D., Levy, R. n. 2020; 217 (9)

  Abstract

  Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

  View details for DOI 10.1084/jem.20191712

  View details for PubMedID 32558897

• Long-Term Outcomes of Patients with Early-Stage Non-Bulky Hodgkin Lymphoma Treated with Combined Modality Therapy on the Stanford V Trials (The G4 and G5 Studies). International journal of radiation oncology, biology, physics Mou, E. n., Advani, R. H., von Eyben, R. n., Rosenberg, S. A., Hoppe, R. T. 2020

  Abstract

  Combined modality therapy (CMT) is standard therapy for early-stage Hodgkin lymphoma (ESHL). We previously reported excellent outcomes with the abbreviated Stanford V regimen. Herein we report updated results with median follow-up >10 years on survival, therapy-related late effects, and impact of disease risk factors on patient outcomes.The XXXXXX and YYYYYY studies enrolled patients with stage I-IIA non-bulky ESHL. Patients received eight weeks of Stanford V chemotherapy followed by 30 Gy modified involved-field radiotherapy (mIFRT) (XXXXXX) or Stanford V-C + 20 Gy mIFRT (YYYYYY). Patients were categorized as favorable or unfavorable risk per German Hodgkin Study Group (GHSG) criteria and outcomes between groups compared.129 patients were enrolled (68 favorable and 61 unfavorable risk). In the XXXXXX study (n = 87), at median follow-up of 19.7 years, 5-, 10-, and 15-year PFS and OS were 95.4%/97.7%, 91.8%/96.5%, and 91.8%/95.3%, respectively. In the YYYYYY study (n = 42), at median follow-up of 13.5 years, the 5-, 10-, and 15-year PFS and OS were 92.9%/100%, 92.9%/100%, and 88.4%/91.9%, respectively. PFS (p = 0.86) and OS (p = 0.86) were not significantly different between studies. There were also no significant differences between studies in patients with favorable or unfavorable risk for PFS (F: p = 0.53; U: p = 0.96), OS (F: p = 0.99; U: p = 0.78), secondary malignancies (F: p = .74; U: p = 1.0), and cardiovascular complications (F: no cases; U: p = 1.0).The XXXXXX and YYYYYY studies achieve high rates of durable remission. 20 versus 30 Gy mIFRT and cyclophosphamide substituted for mechlorethamine did not compromise nodal control, PFS, or OS in both favorable and unfavorable risk disease. These results support the efficacy of CMT in early-stage disease and lower-dose radiotherapy in patients with favorable and non-bulky unfavorable ESHL.

  View details for DOI 10.1016/j.ijrobp.2020.12.039

  View details for PubMedID 33385495

• CD20-Negative Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A 20-Year Consecutive Case Series From a Tertiary Cancer Center. Archives of pathology & laboratory medicine Menke, J. R., Spinner, M. A., Natkunam, Y. n., Warnke, R. A., Advani, R. H., Gratzinger, D. A. 2020

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma.To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution.A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted.Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naïve, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease.NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyte-rich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation.

  View details for DOI 10.5858/arpa.2020-0135-OA

  View details for PubMedID 32991677

• Pembrolizumab followed by AVD in untreated early unfavorable and advanced stage classical Hodgkin lymphoma. Blood Allen, P. B., Savas, H. n., Evens, A. M., Advani, R. n., Palmer, B. n., Pro, B. n., Karmali, R. n., Mou, E. n., Bearden, J. n., Dillehay, G. n., Bayer, R. n., Eisner, R. M., Chmiel, J. S., O'Shea, K. L., Gordon, L. I., Winter, J. N. 2020

  Abstract

  Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase II investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients > 18 years of age with untreated early unfavorable or advanced stage disease were eligible for treatment. Thirty patients with either early unfavorable (n=12) or advanced (n=18) stage cHL were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4-6 cycles depending on stage and bulk. Twelve had either large mediastinal masses and/or bulky disease (>10 cm). Following pembrolizumab monotherapy, 11 patients (37%) demonstrated CMR's, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography/computed tomography scanning (PET-CT) had >90% reductions in metabolic tumor volume. All patients achieved CMR following 2 cycles of AVD and maintained their responses at end of treatment. With a median follow-up of 22.5 months (range: 14.2-30.6) there have been no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well-tolerated. The most common immune-related adverse events were grade 1 rash (n=6), and grade 2 infusion reactions (n=4). One patient had a reversible grade 4 transaminitis and a second had a reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD proved both highly effective and safe in newly diagnosed cHL patients including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

  View details for DOI 10.1182/blood.2020007400

  View details for PubMedID 32992341

• Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy. The oncologist Carreau, N. A., Pail, O. n., Armand, P. n., Merryman, R. n., Advani, R. H., Spinner, n. n., Herrera, A. F., Chen, R. n., Tomassetti, S. n., Ramchandren, R. n., Hamid, n. n., Assouline, S. n., Santiago, R. n., Wagner-Johnston, N. n., Paul, S. n., Svoboda, J. n., Bair, S. M., Barta, S. K., Liu, Y. n., Nathan, S. n., Karmali, R. n., Burkart, M. n., Torka, P. n., David, K. n., Wei, C. n., Lansigan, F. n., Emery, L. n., Persky, D. n., Smith, S. n., Godfrey, J. n., Chavez, J. n., Xia, Y. n., Troxel, n. n., Diefenbach, C. n. 2020

  Abstract

  Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued due to progression or side effects, it is unclear how successful further therapies will be. Moreover, there is no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis we investigated whether exposure to CBT could sensitize HL to subsequent therapy.Seventeen centers across the US and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression free survival (PFS), duration of response (DOR), and overall survival (OS).Eighty-one patients were included. Seventy-two percent had stage 3-4 disease, and the population was heavily pretreated with a median of 4 therapies before CBT. Most patients (65%) discontinued CBT due to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen.In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.Relapsed and refractory (R/R) Hodgkin lymphoma (HL) presents a clinical challenge, and better treatment strategies are greatly desired to prevent these patients from ultimately succumbing to their disease. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy usage in R/R HL may sensitize patients their subsequent treatment. This approach may potentially be used to extend the number of options patients have or to bridge them to transplant. Prospective data is warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

  View details for DOI 10.1634/theoncologist.2020-0167

  View details for PubMedID 32720734

• T follicular helper phenotype predicts response to histone deacetylase inhibitors in relapsed/refractory peripheral T-cell lymphoma. Blood advances Ghione, P. n., Faruque, P. n., Mehta-Shah, N. n., Seshan, V. n., Ozkaya, N. n., Bhaskar, S. n., Yeung, J. n., Spinner, M. A., Lunning, M. n., Inghirami, G. n., Moskowitz, A. n., Galasso, N. n., Ganesan, N. n., van der Weyden, C. n., Ruan, J. n., Prince, H. M., Trotman, J. n., Advani, R. n., Dogan, A. n., Horwitz, S. n. 2020; 4 (19): 4640–47

  Abstract

  Histone deacetylase inhibitors (HDACi) are active agents for peripheral T-cell lymphoma (PTCL). Anecdotally angioimmunoblastic T-cell lymphoma (AITL) appears to respond better than PTCL-not otherwise specified (NOS) to HDACi. The new World Health Organization classification shows that a subgroup of PTCL carries similarities in phenotype and gene expression profiling to AITL, comparable to T follicular helper (TFH) cells. The disease might behave similarly to AITL when treated with HDACi. We analyzed 127 patients with AITL or PTCL-NOS treated with HDACi at relapse as a single agent or in combination. We re-reviewed the pathology of all PTCL-NOS to identify the TFH phenotype. Patients received HDACi at relapse as a single agent in 97 cases (76%, 59 TFH, 38 non-TFH) or in combination in 30 cases (24%, 18 TFH, 12 non-TFH) including duvelisib, lenalidomide, lenalidomide plus carfilzomib, and pralatrexate. Seven PTCL-NOS had TFH phenotype; 2 PTCL-NOS were reclassified as AITL. Overall response rate (ORR) was 56.5% (28.9% complete response [CR]) in TFH and 29.4% (19.6% CR) in non-TFH phenotype patients (P = .0035), with TFH phenotype being an independent predictor of ORR (P = .009). Sixteen patients sufficiently responded to HDACi or HDACi in combination with another agent to proceed directly to allogeneic transplantation; 1 of 16 responded to donor lymphocyte infusion (12 TFH, 4 non-TFH). Our results, although retrospective, support that HDACi, as a single agent or in combination, may have superior activity in TFH-PTCL compared with non-TFH PTCL. This differential efficacy could help inform subtype-specific therapy and guide interpretation of HDACi trials.

  View details for DOI 10.1182/bloodadvances.2020002396

  View details for PubMedID 33002132

• Improved Outcomes for Relapsed/Refractory Classic Hodgkin Lymphoma Following Autologous Stem Cell Transplantation in the Era of Novel Agents Sica, R., Spinner, M. A., Tamaresis, J. S., Advani, R. H., Johnston, L. J., Lowsky, R., Meyer, E. H., Miklos, D. B., Muffly, L. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Negrin, R. S., Arai, S. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131532

  View details for Web of Science ID 000577160403295

• Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL) Bannerji, R., Allan, J. N., Arnason, J. E., Brown, J. R., Advani, R. H., Barnes, J. A., Ansell, S. M., O'Brien, S. M., Chavez, J., Duell, J., David, K. A., Martin, P., Joyce, R. M., Charnas, R., Ambati, S. R., Adriaens, L., Ufkin, M., Zhu, M., Li, J., Gasparini, P., Ibrahim, A., Jankovic, V., Fiaschi, N., Aina, O., Zhang, W., Deering, R. P., Hamon, S., Thurston, G., Murphy, A. J., Weinreich, D. M., Yancopoulos, G. D., Lowy, I., Sternberg, D., Topp, M. S. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-122451

  View details for Web of Science ID 000518218500601

• An Exploratory Analysis of Brentuximab Vedotin Plus CHP (A plus CHP) in the Frontline Treatment of Patients with CD30+Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative Stem Cell Transplant Savage, K. J., Horwitz, S. M., Advani, R. H., Christensen, J. H., Domingo-Domenech, E., Rossi, G., Morschhauser, F., Alpdogan, O., Suh, C., Tobinai, K., Shustov, A. R., Trneny, M., Yuen, S., Zinzani, P., Truemper, L., Illidge, T., O'Connor, O., Pro, B., Little, M., Bunn, V., Fenton, K., Manley, T., Iyer, S. P. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-122781

  View details for Web of Science ID 000518218500567

• Proof of Concept for Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study Witzig, T. E., Sokol, L., Foss, F. M., Kim, W., Jacobsen, E., De La Cruz, M., Caballero, D., Advani, R. H., Roncero, J., Ona, R., Niebla, A., Izquierdo, A., Terol, M., Domingo-Domenech, E., Piris, M. A., Rodriguez, M., Bolognese, J., Kessler, L., Mishra, V., Curry, R., Kurman, M., Scholz, C., Gualberto, A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-128513

  View details for Web of Science ID 000518218500571

• Brentuximab Vedotin and Nivolumab for Relapsed or Refractory Classic Hodgkin Lymphoma: Long-Term Follow-up Results from the Single-Arm Phase 1/2 Study Moskowitz, A. J., Advani, R. H., Bartlett, N. L., Vose, J. M., Ramchandren, R., Feldman, T. A., LaCasce, A. S., Christian, B. A., Ansell, S. M., Moskowitz, C. H., Brown, L., Taft, D., Ansari, S., Zak, D. E., Sacchi, M., Manley, T., Herrera, A. F. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-122576

  View details for Web of Science ID 000518218500563

• Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies Garofalo, A., Schroers-Martin, J. G., Soo, J., Kurtz, D. M., Sworder, B., Liu, C., Pinsky, B. A., Luikart, H., Advani, R. H., Natkunam, Y., Khush, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131602

  View details for Web of Science ID 000518218500906

• An Atlas of Clinically-Distinct Tumor Cellular Ecosystems in Diffuse Large B Cell Lymphoma Steen, C. B., Luca, B. A., Esfahani, M., Nabet, B. Y., Sworder, B., Farshidfar, F., Shamardani, K., Kurtz, D. M., Liu, C., Advani, R. H., Natkunam, Y., Myklebust, J., Diehn, M., Gentles, A., Newman, A. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129461

  View details for Web of Science ID 000518218500530

• Fitness and Anthracycline Use in Front-Line Therapy for Older Patients with Classical Hodgkin Lymphoma: A US Multi-Center Retrospective Analysis Orellana-Noia, V. M., Isaac, K., Wages, N. A., Malecek, M., Bartlett, N. L., Voorhees, T. J., Grover, N. S., Hwang, S. R., Bennani, N., Hu, R., Hill, B. T., Mou, E., Advani, R. H., Carter, J., David, K. A., Ballard, H. J., Svoboda, J., Magarelli, G., Feldman, T. A., Churnetski, M. C., Cohen, J. B., Evens, A. M., Portell, C. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-123572

  View details for Web of Science ID 000577164602050

• Outcome of Autologous Stem Cell Transplantation Following PD-(L)1 Based Salvage Therapy for Multiply Relapsed Patients with Classic Hodgkin Lymphoma Merryman, R. W., Redd, R. A., Nieto, Y., Rao, U., Byrne, M. T., Bond, D. A., Maddocks, K. J., Ballard, H. J., Svoboda, J., Singh, A. K., McGuirk, J. P., Darrah, J., Spinner, M. A., Advani, R. H., Romancik, J., Cohen, J. B., Frigault, M. J., Chen, Y., Rahimian, M., Joyce, R. M., Shah, M., David, K. A., Lynch, R. C., Smith, S. D., Ho, V. T., Armand, P., Herrera, A. F. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-123088

  View details for Web of Science ID 000577164603303

• Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma (cHL): 4-Year Update of the Echelon-1 Study Bartlett, N. L., Straus, D. J., Dlugosz-Danecka, M., Alekseev, S., Illes, A., Lech-Maranda, E., Feldman, T. A., Smolewski, P., Savage, K. J., Walewski, J., Ramchandren, R., Zinzani, P., Hutchings, M., Connors, J. M., Radford, J., Munoz, J., Kim, W., Advani, R. H., Ansell, S. M., Younes, A., Gallamini, A., Miao, H., Liu, R., Fenton, K., Forero-Torres, A., Picardi, M. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-124116

  View details for Web of Science ID 000577164602049

• North American Practice Patterns for PET-2 Positive Hodgkin Lymphoma Hamid, M., Rutherford, S. C., Kim, S., Bartlett, N. L., Malecek, M., Watkins, M., Maddocks, K. J., Bond, D. A., Feldman, T. A., Magarelli, G., Advani, R. H., Spinner, M. A., Ahmed, S., Stephens, D. M., Allen, P., Patel, K., Tees, M. T., Karmali, R., Cheson, B. D., Yazdy, M., Strouse, C., Pagel, J. M., Ramchandren, R. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131276

  View details for Web of Science ID 000577160402106

• A Pilot Study of Brentuximab Vedotin Combined with AVD Chemotherapy and Radiotherapy in Patients with Newly Diagnosed Early Stage, Unfavorable Risk Hodgkin Lymphoma Kumar, A., Casulo, C., Advani, R. H., Budde, L. E., Barr, P. M., Batlevi, C., Caron, P., Constine, L. S., Dandapani, S., Drill, E., Drullinsky, P., Friedberg, J. W., Grieve, C., Hamilton, A., Hamlin, P. A., Hoppe, R. T., Horwitz, S. M., Matasar, M. J., McCall, S., Moskowitz, A. J., Noy, A., Palomba, M., Schoder, H., Straus, D. J., Vemuri, S., Yang, J. C., Younes, A., Zelenetz, A. D., Yahalom, J., Moskowitz, C. H. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-123150

  View details for Web of Science ID 000577160406215

• Incidence and Outcomes of Rare T cell Lymphomas from the T Cell Project: Hepatosplenic, Enteropathy Associated and Peripheral Gamma Delta T cell Lymphomas. American journal of hematology Foss, F. M., Horwitz, S. M., Civallero, M., Bellei, M., Marcheselli, L., Kim, W. S., Cabrera, M. E., Dlouhy, I., Nagler, A., Advani, R. H., Pesce, E. A., Ko, Y., Montoto, S., Chiattone, C., Moskowitz, A., Spina, M., Cesaretti, M., Biasoli, I., Federico, M. 2019

  Abstract

  The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T -cell lymphoma (EATL), and PGDTCLs (PGDTCL) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n=31), enteropathy associated (n=65), and PGDTCLs (n=19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20-40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and 4 patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3years ranged from 28-40% for these rare subtypes, and the overall survival at 3years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ajh.25674

  View details for PubMedID 31709579

• Updates in Treatment Strategies for Hodgkin Lymphoma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Advani, R. H. 2019; 17 (11): 1411–13

  Abstract

  Several options are available for frontline treatment of advanced-stage Hodgkin lymphoma (HL) and treatment of relapsed HL, each with inherent advantages and disadvantages. Clinicians must balance risk with benefit for the individual patient. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Ranjana H. Advani summarized the current frontline treatment options for advanced-stage HL and outlined novel and emerging agents that may be incorporated as therapy options for relapsed disease.

  View details for DOI 10.6004/jnccn.2019.5027

  View details for Web of Science ID 000499644200003

  View details for PubMedID 31766016

• Multicenter prospective phase II study of venetoclax in patients with previously treated Waldenstrom macroglobulinemia Castillo, J., Allan, J., Siddiqi, T., Advani, R., Keezer, A., Gustine, J., Meid, K., Dubeau, T., Lam, J., Xu, L., Yang, G., Hunter, Z., Furman, R., Davids, M., Treon, S. CIG MEDIA GROUP, LP. 2019: E39–E40

  View details for DOI 10.1016/j.clml.2019.09.060

  View details for Web of Science ID 000491229800060

• Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Rosenwald, A., Bens, S., Advani, R., Barrans, S., Copie-Bergman, C., Elsensohn, M., Natkunam, Y., Calaminici, M., Sander, B., Baia, M., Smith, A., Painter, D., Pham, L., Zhao, S., Ziepert, M., Jordanova, E. S., Molina, T. J., Kersten, M. J., Kimby, E., Klapper, W., Raemaekers, J., Schmitz, N., Jardin, F., Stevens, W. B., Hoster, E., Hagenbeek, A., Gribben, J. G., Siebert, R., Gascoyne, R. D., Scott, D. W., Gaulard, P., Salles, G., Burton, C., de Jong, D., Sehn, L. H., Maucort-Boulch, D. 2019: JCO1900743

  Abstract

  PURPOSE: MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene.METHODS: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes.RESULTS: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001).CONCLUSION: The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.

  View details for DOI 10.1200/JCO.19.00743

  View details for PubMedID 31498031

• Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry. Acta haematologica Lansigan, F., Horwitz, S. M., Pinter-Brown, L. C., Rosen, S. T., Pro, B., Hsi, E. D., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M., Shustov, A. R., Advani, R. H., Feldman, T., Lechowicz, M. J., Smith, S. M., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Park, S. I., Foss, F. M. 2019: 1–11

  Abstract

  BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data.OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease.METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days.RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months.CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

  View details for DOI 10.1159/000500666

  View details for PubMedID 31315113

• Correction: First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget Byrd, J. C., Smith, S., Wagner-Johnston, N., Sharman, J., Chen, A. I., Advani, R., Augustson, B., Marlton, P., Commerford, S. R., Okrah, K., Liu, L., Murray, E., Penuel, E., Ward, A. F., Flinn, I. W. 2019; 10 (38): 3827–30

  Abstract

  [This corrects the article DOI: 10.18632/oncotarget.24310.].

  View details for DOI 10.18632/oncotarget.27011

  View details for PubMedID 31217910

• B-Cell Lymphomas, Version 3.2019 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Gordon, L. I., Abramson, J. S., Advani, R. H., Bartlett, N. L., Caimi, P. F., Chang, J. E., Chavez, J. C., Christian, B., Fayad, L. E., Glenn, M. J., Habermann, T. M., Harris, N., Hernandez-Ilizaliturri, F., Kaminski, M. S., Kelsey, C. R., Khan, N., Krivacic, S., LaCasce, A. S., Mehta, A., Nademanee, A., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K. B., Smith, S. D., Snyder, E. D., Swinnen, L. J., Vose, J. M., Dwyer, M. A., Sundar, H. 2019; 17 (6): 651–61

  Abstract

  Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

  View details for DOI 10.6004/jnccn.2019.0029

  View details for Web of Science ID 000473277200004

  View details for PubMedID 31200358

• Response to A+CHP by CD30 expression in the ECHELON-2 trial. Advani, R. H., Horwitz, S. M., Iyer, S., Bartlett, N. L., Kim, W., Tilly, H., Belada, D., Feldman, T., Illes, A., Jacobsen, E. D., Huettmann, A., Zinzani, P., O'Connor, O. A., Trepicchio, W. L., Miao, H. H., Rao, S., Onsum, M., Manley, T., Illidge, T. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806300

• Longitudinal toxicity analysis with novel summary metrics of lenalidomide maintenance in follicular lymphoma in ECOG-ACRIN 2408. Thanarajasingam, G., Dueck, A. C., Novotny, P. J., Habermann, T., Advani, R. H., Gascoyne, R. D., Witzig, T. E., Quon, A., Ranheim, E., Kahl, B. S., Evens, A. M., Hong, F. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.6511

  View details for Web of Science ID 000487345806065

• Response to brentuximab vedotin by CD30 expression: Results from five trials in PTCL, CTCL, and B-cell lymphomas. Jagadeesh, D., Horwitz, S. M., Bartlett, N. L., Advani, R. H., Jacobsen, E. D., Duvic, M., Gautam, A., Rao, S., Onsum, M., Fanale, M., Kim, Y. H. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806305

• Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS) LANCET HAEMATOLOGY Morschhauser, F., Flinn, I. W., Advani, R., Sehn, L. H., Diefenbach, C., Kolibaba, K., Press, O. W., Salles, G., Tilly, H., Chen, A. I., Assouline, S., Cheson, B. D., Dreyling, M., Hagenbeek, A., Zinzani, P., Jones, S., Cheng, J., Lu, D., Penuel, E., Hirata, J., Wenger, M., Chu, Y., Sharman, J. 2019; 6 (5): E254–E265

  View details for DOI 10.1016/S2352-3026(19)30026-2

  View details for Web of Science ID 000466131400008

• The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study CANCER Park, S. I., Horwitz, S. M., Foss, F. M., Pinter-Brown, L. C., Carson, K. R., Rosen, S. T., Pro, B., Hsi, E. D., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M., Advani, R. H., Feldman, T., Lechowicz, M., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Shustov, A. R., COMPLETE Investigators 2019; 125 (9): 1507–17

  View details for DOI 10.1002/cncr.31861

  View details for Web of Science ID 000465035900017

• Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). The Lancet. Haematology Morschhauser, F., Flinn, I. W., Advani, R., Sehn, L. H., Diefenbach, C., Kolibaba, K., Press, O. W., Salles, G., Tilly, H., Chen, A. I., Assouline, S., Cheson, B. D., Dreyling, M., Hagenbeek, A., Zinzani, P. L., Jones, S., Cheng, J., Lu, D., Penuel, E., Hirata, J., Wenger, M., Chu, Y., Sharman, J. 2019

  Abstract

  BACKGROUND: Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma.METHODS: In this phase 2 randomised study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomisation scheme, to receive R-pola or R-pina (375 mg/m2 rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumour response. The study is registered with ClinicalTrials.gov, number NCT01691898, and is closed to accrual.FINDINGS: 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event).INTERPRETATION: R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola.FUNDING: F Hoffmann-La Roche.

  View details for PubMedID 30935953

• Prognostic Value of Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma Reply JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019; 37 (9): 755-+

  View details for DOI 10.1200/JCO.18.01907

  View details for Web of Science ID 000462408300010

• Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma CLINICAL CANCER RESEARCH Ramchandren, R., Advani, R. H., Ansell, S. M., Bartlett, N. L., Chen, R., Connors, J. M., Feldman, T., Forero-Torres, A., Friedberg, J. W., Gopal, A. K., Gordon, L. I., Kuruvilla, J., Savage, K. J., Younes, A., Engley, G., Manley, T. J., Fenton, K., Straus, D. J. 2019; 25 (6): 1718–26

  View details for DOI 10.1158/1078-0432.CCR-18-2435

  View details for Web of Science ID 000461476000006

• CD20-negative nodular lymphocyte-predominant Hodgkin lymphoma is enriched for variant patterns and shows aggressive clinical features Menke, J., Spinner, M., Shrestha, B., Advani, R., Natkunam, Y., Gratzinger, D. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102345

• CD20-negative nodular lymphocyte-predominant Hodgkin lymphoma is enriched for variant patterns and shows aggressive clinical features Menke, J., Spinner, M., Shrestha, B., Advani, R., Natkunam, Y., Gratzinger, D. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915501104

• Reply to J. Wang et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019: JCO1801907

  View details for PubMedID 30753108

• CD47 Blockade and Rituximab in Non-Hodgkin's Lymphoma REPLY NEW ENGLAND JOURNAL OF MEDICINE Advani, R., Volkmer, J., Chao, M. P. 2019; 380 (5): 497–98

  View details for Web of Science ID 000457135700019

• The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study. Cancer Park, S. I., Horwitz, S. M., Foss, F. M., Pinter-Brown, L. C., Carson, K. R., Rosen, S. T., Pro, B., Hsi, E. D., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M., Advani, R. H., Feldman, T., Lechowicz, M. J., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Shustov, A. R. 2019

  Abstract

  BACKGROUND: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1.METHODS: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis.RESULTS: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89).CONCLUSIONS: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

  View details for PubMedID 30694529

• Brentuximab Vedotin Plus Chemotherapy in North American Patients with Newly Diagnosed Stage III or IV Hodgkin Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research Ramchandren, R., Advani, R. H., Ansell, S. M., Bartlett, N. L., Chen, R., Connors, J. M., Feldman, T., Forero, A., Friedberg, J. W., Gopal, A. K., Gordon, L. I., Kuruvilla, J., Savage, K. J., Younes, A., Engley, G., Manley, T. J., Fenton, K., Straus, D. J. 2019

  Abstract

  PURPOSE: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).EXPERIMENTAL DESIGN: ECHELON-1 is a global, open-label, randomized phase 3 study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD+bleomycin) as frontline therapy in subjects with Stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on Days 1 and 15 of each 28‑day cycle for up to 6 cycles.RESULTS: The NA subgroup consisted of 497 subjects in the A+AVD (n=250) and ABVD (n=247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint (modified progression-free survival [PFS] per independent review) demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR=0.60; P=.012). For PFS, the risk of progression or death was also reduced (HR=0.50; P=.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared to ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.CONCLUSIONS: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for Stage III or IV cHL patients.

  View details for PubMedID 30617130

• CD47 Blockade and Rituximab in Non-Hodgkin's Lymphoma. The New England journal of medicine Advani, R., Volkmer, J., Chao, M. P. 2019; 380 (5): 497–98

  View details for PubMedID 30699313

• The ECHELON-2 trial: Results of a randomised, double-blind, active-controlled phase 3 study of brentuximab vedotin and CHP (A plus CHP) vs CHOP in the frontline treatment of patients (pts) with CD30(+) peripheral T-cell lymphomas (PTCLs) Truemper, L., O'Connor, O. A., Pro, B., Illidge, T. M., Advani, R. H., Bartlett, N. L., Christensen, H. J., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W. S., Feldman, T. A., Lennard, A., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Shustov, A. R., Huettmann, A., Savage, K. J., Yuen, S., Iyer, S., Zinzani, P. L., Hua, Z., Little, M., Rao, S., Woolery, J., Manley, T., Horwitz, S. M. KARGER. 2019: 23

  View details for Web of Science ID 000568159600053

• Prognostic factors and patterns of failure in advanced stage Hodgkin lymphoma treated with combined modality therapy RADIOTHERAPY AND ONCOLOGY Moding, E. J., Advani, R., Rosenberg, S. A., Hoppe, R. T. 2018; 129 (3): 507–12

  View details for DOI 10.1016/j.radonc.2018.06.033

  View details for Web of Science ID 000452272800015

• Prognostic factors and patterns of failure in advanced stage Hodgkin lymphoma treated with combined modality therapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Moding, E. J., Advani, R., Rosenberg, S. A., Hoppe, R. T. 2018; 129 (3): 507–12

  Abstract

  BACKGROUND AND PURPOSE: The role of irradiation to non-bulky and bulky sites of disease in advanced stage Hodgkin lymphoma is controversial. We aimed to review the long-term outcomes of patients treated with combined modality therapy to clarify the role of consolidative radiotherapy.MATERIALS AND METHODS: Patients with stage III or IV Hodgkin lymphoma treated with Stanford V chemotherapy and consolidative radiotherapy to initial sites of disease ≥5 cm were analyzed retrospectively to determine patient outcomes, patterns of failure, and factors associated with treatment failure.RESULTS: A total of 170 patients were analyzed. Overall survival was 91.2%, freedom from progression was 80.6%, and progression-free survival was 78.9% at 10 years. 5 patients (2.9%) had refractory disease and 27 patients (15.9%) relapsed after treatment. Only an International Prognostic Score (IPS) greater than 2 predicted disease progression. 19 out of 27 relapses occurred exclusively outside of the radiation treatment field, and 17 out of 27 relapses occurred exclusively at original sites of disease. However, only 11 of 170 patients (6.5%) relapsed exclusively at original, non-bulky sites of disease not treated with radiation therapy. The cumulative incidence of local failure at 10 years was 4.6% for unirradiated sites and 2.6% for irradiated sites.CONCLUSION: Patients with advanced stage Hodgkin lymphoma treated with combined modality therapy including consolidative radiotherapy to bulky disease sites had excellent long-term outcomes. Given the low frequency of isolated failures at initial sites, our results suggest that selective radiation therapy to sites at high risk of relapse may be feasible.

  View details for PubMedID 30539763

• Risk-adapted therapy for advanced-stage Hodgkin lymphoma. Hematology. American Society of Hematology. Education Program Spinner, M. A., Advani, R. H. 2018; 2018 (1): 200–206

  Abstract

  More than 80% of patients with advanced-stage Hodgkin lymphoma are now cured with contemporary treatment approaches. The ongoing challenge is how to further improve outcomes by identifying both high-risk patients who may benefit from more intensive frontline therapy to reduce the risk of relapse as well as lower-risk patients who may do just as well with less intensive therapy. Numerous trials have used an interim positron emission tomography (PET) response-adapted approach to evaluate early escalation or deescalation of therapy for patients with a positive or negative interim PET scan, respectively. Recent trials have incorporated novel agents, including brentuximab vedotin (BV) and the immune checkpoint inhibitors, in the frontline setting. Based on results of the ECHELON-1 trial, the Food and Drug Administration approved BV in combination with adriamycin, vinblastine, and dacarbazine chemotherapy for stage III to IV Hodgkin lymphoma. Improved methods to assess higher risk at diagnosis using quantitative PET metrics, such as metabolic tumor volume and total lesion glycolysis, and incorporation of emerging biomarkers may further refine patient selection for more intensive upfront therapy. The ultimate goal is to achieve the highest level of efficacy for an individual patient while minimizing the short- and long-term toxicities.

  View details for PubMedID 30504311

• Multicenter Prospective Phase II Study of Venetoclax in Patients with Previously Treated Waldenstrom Macroglobulinemia Castillo, J. J., Gustine, J., Meid, K., Dubeau, T., Keezer, A., Allan, J. N., Furman, R. R., Siddiqi, T., Advani, R., Lam, J., Hunter, Z. R., Yang, G., Xu, L., Davids, M. S., Treon, S. P. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-112325

  View details for Web of Science ID 000454842800088

• Emerging Clinical Activity of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Follicular Lymphoma (FL), Diffuse Large B-Cell Lymphoma (DLBCL), and Other B-Cell Non-Hodgkin Lymphoma (B-NHL) Subtypes Bannerji, R., Arnason, J. E., Advani, R., Brown, J. R., Allan, J. N., Ansell, S. M., Barnes, J., O'Brien, S. M., Chavez, J. C., Duell, J., Lowy, I., Charnas, R., Sternberg, D., Ambati, S., Adriaens, L., Ufkin, M., Yan, X., Li, J., Navarro, M., Gasparini, P., Jankovic, V., Fiaschi, N., Zhang, W., Hamon, S., Thurston, G., Topp, M. S. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113328

  View details for Web of Science ID 000454837605066

• A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Research Group (E4412: Arms G-I) Diefenbach, C., Hong, F., Ambinder, R. F., Cohen, J. B., Robertson, M., David, K. A., Advani, R. H., Fenske, T. S., Barta, S., Palmisano, N., Svoboda, J., Morgan, D., Karmali, R., Kahl, B. S., Ansell, S. M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-115390

  View details for Web of Science ID 000454837602057

• The Prognostic Impact of Baseline Positron Emission Tomography (PET) Imaging in Untreated High Risk (HR) Follicular Lymphoma (FL): Analysis from E2408, the Bortezomib Induction or Novel Imid (R) Continuation (BIONIC) Study Baratto, L., Jegede, O., Hong, F., Habermann, T. M., Advani, R., Gascoyne, R. D., Kostakoglu, L., Witzig, T. E., Ranheim, E. A., Kahl, B. S., Quon, A., Evens, A. M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113247

  View details for Web of Science ID 000454837605004

• Outcomes of Patients with Limited-Stage Aggressive Large B-Cell Lymphoma with MYC Rearrangement with and without BCL2 and/or BCL6 Rearrangements: A Retrospective Analysis from 15 US Academic Centers Kothari, S. K., Li, S., Medeiros, L., Ayers, E. C., Landsburg, D. J., Bond, D. A., Maddocks, K. J., Giri, A., Hess, B. T., Pham, L. Q., Advani, R., Liu, Y., Barta, S., Vose, J. M., Churnetski, M. C., Cohen, J. B., Burkart, M., Karmali, R., Zurko, J., Mehta, A., Olszewski, A. J., Lee, S. S., Hill, B. T., Burns, T. F., Lansigan, F., Rabinovich, E., Peace, D., Groman, A., Attwood, K., Hernandez-Ilizaliturri, F. J., Torka, P. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-111530

  View details for Web of Science ID 000454837601160

• Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classic Hodgkin Lymphoma: Part 3 (Concurrent Dosing) Results and Updated Progression-Free Survival Results from Parts 1 and 2 (Staggered Dosing) Advani, R. H., Moskowitz, A. J., Bartlett, N. L., Vose, J. M., Ramchandren, R., Feldman, T. A., LaCasce, A. S., Christian, B. A., Ansell, S. M., Moskowitz, C. H., Fenton, K., Ogden, C., Taft, D., Zak, D. E., Sacchi, M., Galderisi, F., Herrera, A. F. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110002

  View details for Web of Science ID 000454837605012

• A Phase II Study(A)over-cap of Sequential Pembrolizumab (PEM)(A)over-cap Followed(A)over-cap By AVD for Frontline Treatment(A)over-cap of Classical Hodgkin Lymphoma (CHL): Quantifying Response Following(A)over-cap PEM Monotherapy(A)over-cap with FDG-PLT-Derived Metabolic Tumor Volume and Total Lesion Glycolysis Savas, H., Allen, P., Evens, A. M., Pro, B., Dillehay, G., Rademaker, A., Palmer, B., Advani, R., Gordon, L. I., Winter, J. N. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113836

  View details for Web of Science ID 000454837605028

• The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A plus CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+Peripheral T-Cell Lymphomas Horwitz, S. M., O'Connor, O. A., Pro, B., Illidge, T. M., Fanale, M. A., Advani, R. H., Bartlett, N. L., Christensen, J., Morschhauser, F., Domingo-Domenech, E., Rossi, G., Kim, W., Feldman, T. A., Lennard, A., Belada, D., Illes, A., Tobinai, K., Tsukasaki, K., Yeh, S., Shustov, A. R., Huettmann, A., Savage, K. J., Yuen, S., Zinzani, P., Hua, Z., Little, M., Rao, S., Woolery, J., Manley, T., Truemper, L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110563

  View details for Web of Science ID 000454837603027

• Checkpoint Blockade Therapy May Sensitize Aggressive and Indolent Non-Hodgkin Lymphoma to Subsequent Therapy Carreau, N. A., Pail, O., Armand, P., Merryman, R. W., Advani, R. H., Spinner, M. A., Herrera, A. F., Chen, R. W., Tomassetti, S., Ramchandren, R., Hamid, M., Assouline, S., Santiago, R., Wagner-Johnston, N. D., Paul, S., Svoboda, J., Bair, S. M., Barta, S., Liu, Y., Nathan, S., Burkart, M., Karmali, R., Torka, P., David, K. A., Wei, C., Lansigan, F., Emery, L., Persky, D., Smith, S. M., Chavez, J. C., Xia, Y., Troxel, A. B., Diefenbach, C. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117448

  View details for Web of Science ID 000454837600147

• Longitudinal Adverse Event Assessment of the Combination of Ipilimumab, Nivolumab and Brentuximab Vedotin in Relapsed / Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412: Arms A-F) Hong, F., Thanarajasingam, G., Ansell, S. M., Ambinder, R. F., Cohen, J. B., Robertson, M., David, K. A., Advani, R. H., Fenske, T. S., Barta, S., Palmisiano, N., Svoboda, J., Morgan, D., Karmali, R., Witzig, T. E., Dueck, A. C., Novotny, P., Kahl, B. S., Diefenbach, C. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119372

  View details for Web of Science ID 000454837602001

• No Utility of Routine Laboratory Testing during Surveillance in Detecting Relapse in Patients with Classic Hodgkin Lymphoma in First Remission Lynch, R. C., Sundaram, V., Desai, M., Henry, S., Wood, D., Daadi, S., Corbelli, K. S., Rosenberg, S., Hoppe, R. T., Advani, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113156

  View details for Web of Science ID 000454837601324

• Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma Jin, M. C., Schroers-Martin, J. G., Kurtz, D. M., Buedts, L., Esfahani, M. S., Macaulay, C., Sworder, B., Soo, J., Glover, C., Roschewski, M., Wilson, W. H., Duhrsen, U., Huettmann, A., Rossi, D., Gaidano, G., Westin, J. R., Maeda, L. S., Advani, R. H., Vandenberghe, P., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119140

  View details for Web of Science ID 000454842800039

• Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing Schroers-Martin, J. G., Garofalo, A., Soo, J., Jin, M. C., Kurtz, D. M., Buedts, L., Duehrsen, U., Huettmann, A., Cottereau, A., Meignan, M., Casasnovas, O., Westin, J. R., Gaidano, G., Rossi, D., Roschewski, M., Wilson, W. H., Advani, R. H., Vandenberghe, P., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119905

  View details for Web of Science ID 000454842800062

• A Longitudinal Toxicity over Time (ToxT) Analysis of Bortezomib When Added to Bendamustine-Rituximab (BR) in Previously Untreated High Risk (HR) Follicullar Lymphoma (FL) from in E2408 Hong, F., Evens, A. M., Novotny, P. J., Habermann, T. M., Advani, R. H., Gascoyne, R. D., Witzig, T. E., Quon, A., Ranheim, E. A., Dueck, A. C., Kahl, B. S., Thanarajasingam, G. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117249

  View details for Web of Science ID 000454842803182

• Modern principles in the management of nodular lymphocyte-predominant Hodgkin lymphoma. British journal of haematology Spinner, M. A., Varma, G., Advani, R. H. 2018

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a unique rare subtype of Hodgkin lymphoma (HL) which differs clinically, pathologically and biologically from classic HL, warranting a nuanced approach to treatment. CD20 expression by malignant lymphocyte-predominant cells, a tendency for late relapses, and the risk of transformation to aggressive large B-cell lymphoma are characteristic features with important implications for treatment and follow-up. Recognition of histopathological variant patterns is also critical, with important implications for prognosis and treatment. The optimal management for NLPHL is unclear and opinions differ as to whether treatment paradigms should be similar to, or differ from, those for classic HL. Therapy differs for early versus advanced stage disease and for frontline versus relapsed or refractory disease. Potential treatment strategies include radiotherapy, combined modality therapy, chemotherapy, rituximab and watchful waiting. Given the excellent overall survival of NLPHL, treatment choices should be geared towards reducing long-term toxicity and optimizing survivorship. In this review, we provide an overview of the current literature and discuss modern principles in the management of NLPHL.

  View details for PubMedID 30485408

• Risk-adapted therapy for advanced-stage Hodgkin lymphoma HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM Spinner, M. A., Advani, R. H. 2018: 200–206

  View details for DOI 10.1182/asheducation-2018.1.200

  View details for Web of Science ID 000451862100026

• Prognostic Factors and Patterns of Failure in Advanced Stage Hodgkin Lymphoma Treated with Stanford V and Radiation Therapy Moding, E. J., Advani, R. H., Rosenberg, S. A., Hoppe, R. T. ELSEVIER SCIENCE INC. 2018: S189–S190

  View details for DOI 10.1016/j.ijrobp.2018.07.077

  View details for Web of Science ID 000447811602642

• The Outcomes of Patients with Unfavorable Stage I-II Classic Hodgkin Lymphoma Treated with Stanford V Chemotherapy and Limited Irradiation Weil, C., Qian, Y., Von Eyben, R., Daadi, S. E., Corbelli, K. S., Rosenberg, S. A., Advani, R. H., Hoppe, R. T. ELSEVIER SCIENCE INC. 2018: S189

  View details for DOI 10.1016/j.ijrobp.2018.07.076

  View details for Web of Science ID 000447811602641

• Novel Approaches in Waldenstrom Macroglobulinemia. Hematology/oncology clinics of North America Spinner, M. A., Varma, G., Advani, R. H. 2018; 32 (5): 875–90

  Abstract

  Recent advances in the understanding of Waldenstrom macroglobulinemia (WM) biology have paved the way for development of a plethora of novel therapeutic strategies. The success of ibrutinib in WM has shifted treatment paradigms away from conventional chemoimmunotherapy approaches. Recognition of high-risk genomic subgroups as well as mechanisms of acquired resistance to ibrutinib have led to targeting of additional pathways. In this article, the authors review ongoing and emerging trials of novel therapies in WM that target the B-cell receptor pathway beyond ibrutinib, toll-like receptor pathway, chemokine signaling, apoptotic pathway, chromatin remodeling, protein transport, the immune microenvironment, and CD19-directed immunotherapy.

  View details for PubMedID 30190025

• Novel Approaches in Waldenstrom Macroglobulinemia HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Spinner, M. A., Varma, G., Advani, R. H. 2018; 32 (5): 875-+

  View details for DOI 10.1016/j.hoc.2018.05.014

  View details for Web of Science ID 000445988300013

• Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018; 36 (28): 2845-+

  View details for DOI 10.1200/JCO.2018.78.5246

  View details for Web of Science ID 000451485300005

• Impact of ibrutinib dose intensity on patient outcomes in previously treated Waldenstrom macroglobulinemia HAEMATOLOGICA Castillo, J. J., Gustine, J. N., Meid, K., Dubeau, T. E., Xu, L., Yang, G., Hunter, Z. R., Advani, R., Palomba, L., Treon, S. P. 2018; 103 (10): E466–E468

  View details for PubMedID 29773590

• Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation CLINICAL CANCER RESEARCH Aghighi, M., Theruvath, A. J., Pareek, A., Pisani, L. L., Alford, R., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D., Luna-Fineman, S., Advani, R., Spunt, S. L., Daldrup-Link, H. E. 2018; 24 (17): 4110–18

  View details for DOI 10.1158/1078-0432.CCR-18-0673

  View details for Web of Science ID 000444040400008

• Circulating tumor DNA (ctDNA) in B-cell lymphoma Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. M., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Green, M. R., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Davis, R., Levy, R., Ohgami, R. S., Kunder, C. A., Rossi, D., Westin, J., Diehn, M., Alizadeh, A. A. WILEY. 2018: 16–17

  View details for Web of Science ID 000444944200019

• Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018: JCO2018785246

  Abstract

  Purpose Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. Patients and Methods We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. Results Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. Conclusion Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

  View details for PubMedID 30125215

• New Treatment Algorithms in Hodgkin Lymphoma: Too Much or Too Little? American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Spinner, M. A., Advani, R. H., Connors, J. M., Azzi, J., Diefenbach, C. 2018; 38: 626-636

  Abstract

  Hodgkin lymphoma treatment continues to evolve as new means of assessing response to treatment, new appreciation of important risk factors, and more effective therapeutic agents become available. Treatment algorithms integrating functional imaging now provide the opportunity to modify therapy during its delivery, allowing adjustment of duration and intensity of chemotherapy and rationale identification of patients who may benefit from the addition of therapeutic irradiation. Novel agents, including the antibody drug conjugate brentuximab vedotin and checkpoint inhibitors such as nivolumab and pembrolizumab can improve the effectiveness of treatment while keeping toxicity within acceptable limits. Carefully designed clinical trials permit the identification of superior approaches in which efficacy is enhanced and toxicity minimized. Clinicians treating patients with Hodgkin lymphoma now have access to novel treatment approaches, which will require detailed assessment of each patient and careful discussion of the goals and risks of treatment at the time of planning primary treatment, again during delivery of that treatment as data indicating ongoing effectiveness become available, at the conclusion of initial intervention, and, when the need arises, at the time of recurrence of disease.

  View details for DOI 10.1200/EDBK_200679

  View details for PubMedID 30231319

• Immune toxicity in post autologous transplant patients treated with brentuximab vedotin in combination with immune checkpoint blockade. Diefenbach, C., Hong, F., Ambinder, R. F., Cohen, J., David, K., Advani, R. H., Robertson, M. J., Fenske, T. S., Barta, S. K., Palmisano, N., Svoboda, J., Morgan, D. S., Karmali, R., Kahl, B., Ansell, S. M. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for Web of Science ID 000442916003027

• Prognostication of older Hodgkin lymphoma (HL) patients (pts): Findings from a multicenter phase II study. Evens, A. M., Advani, R. H., Fanale, M. A., Smith, S. M., Helenowski, I. B., Bociek, G., Klein, A., Winter, J. N., Gordon, L. I., Hamlin, P. A. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.7540

  View details for Web of Science ID 000442916003006

• Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. Ramchandren, R., Advani, R. H., Ansell, S. M., Bartlett, N. L., Chen, R. W., Feldman, T., Forero-Torres, A., Friedberg, J. W., Gopal, A. K., Gordon, L. I., Kuruvilla, J., Savage, K. J., Straus, D. J., Younes, A., Fenton, K., Manley, T., Engley, G., Connors, J. M. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.7541

  View details for Web of Science ID 000442916003007

• Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas BLOOD Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Uttarwar, M., Lee, S., Ren, H., Kennedy, D. A., Shustov, A. R. 2018; 131 (19): 2120–24

  Abstract

  This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30+ peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.

  View details for PubMedID 29507077

• The Role of Radiation Therapy in Patients With Relapsed or Refractory Hodgkin Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Constine, L. S., Yahalom, J., Ng, A. K., Hodgson, D. C., Wirth, A., Milgrom, S. A., Mikhaeel, N., Eich, H., Illidge, T., Ricardi, U., Dieckmann, K., Moskowitz, C. H., Advani, R., Mauch, P. M., Specht, L., Hoppe, R. T. 2018; 100 (5): 1100–1118

  Abstract

  Relapsed and refractory Hodgkin lymphoma (HL) challenges clinicians to devise treatment strategies that are effective and safe. This problem is particularly prominent in an era when de-escalation trials are designed to minimize therapeutic toxicities in both early- and advanced-stage disease. Radiation therapy is the single most effective treatment modality for HL, and its integration into salvage regimens, or its independent use in select patients, must be understood to maximize our success in treating these patients. The complexity of treating relapsed or refractory HL derives from the spectrum of primary treatment approaches currently in use that creates heterogeneity in both treatment exposure and the potential toxicities of salvage therapy. Patients can have relapsed or refractory disease after limited or aggressive primary therapy (with or without radiation therapy), at early or delayed time points, with limited or extensive disease volumes, and with varying degrees of residual morbidity from primary therapy. Their response to salvage systemic therapy can be partial or complete, and the use of consolidative stem cell transplantation is variably applied. New biologics and immunotherapeutic approaches have broadened but also complicated salvage treatment approaches. Through all of this, radiation therapy remains an integral component of treatment for many patients, but it must be used effectively and judiciously. The purpose of this review is to describe the different treatment scenarios and provide guidance for radiation dose, volume, and timing in patients with relapsed or refractory HL.

  View details for PubMedID 29722655

• NCCN Guidelines (R) Insights Hodgkin Lymphoma, Version 1.2018 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Armand, P., Bello, C. M., Benitez, C. M., Bierman, P. J., Chen, R., Dabaja, B., Dean, R., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Maddocks, K., Maloney, D. G., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Rabinovitch, R., Seropian, S., Tao, R., Winter, J. N., Yahalom, J., Burns, J. L., Ogba, N. 2018; 16 (3): 245–54

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

  View details for DOI 10.6004/jnccn.2018.0013

  View details for Web of Science ID 000427032100007

  View details for PubMedID 29523663

• First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget Byrd, J. C., Smith, S., Wagner-Johnston, N., Sharman, J., Chen, A. I., Advani, R., Augustson, B., Marlton, P., Renee Commerford, S., Okrah, K., Liu, L., Murray, E., Penuel, E., Ward, A. F., Flinn, I. W. 2018; 9 (16): 13023–35

  Abstract

  GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15% of patients regardless of causality included fatigue (37%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), headache (20%), and abdominal pain, cough, and dizziness (16%, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23% and -44%). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.

  View details for PubMedID 29560128

• Phase II study of rituximab given in conjunction with standard chemotherapy in primary central nervous system lymphoma (PCNSL): a trial of the ECOG-ACRIN cancer research group (E1F05) ONCOTARGET Swinnen, L. J., O'Neill, A., Imus, P. H., Gujar, S., Schiff, D., Kleinberg, L. R., Advani, R. H., Dunbar, E. M., Moore, D., Grossman, S. A. 2018; 9 (1): 766–73

  Abstract

  Therapy of primary CNS lymphoma (PCNSL) has focused on multi-agent chemotherapy designed to cross the blood brain barrier. Rituximab has demonstrated activity in PCNSL. E1F05 is an ECOG-ACRIN multicenter phase 2 prospective trial of rituximab with high-dose methotrexate (HD-MTX)-based chemotherapy similar to the RTOG 93-10 regimen, omitting radiotherapy.Immunocompetent patients with newly diagnosed PCNSL received HD-MTX 3.5g/m2 with vincristine every two weeks for 5 doses; procarbazine for 7 days in weeks 1, 5, and 9; cytarabine 3g/m2/day IV for 2 days in weeks 11 and 14; a dexamethasone taper over 6 weeks; and rituximab 375mg/m2 IV infusion 3 times per week for weeks 1-4. Subjects with CSF involvement received intrathecal methotrexate 12mg every two weeks.Twenty-six patients were enrolled; median age was 57. Sixteen subjects (65%) completed treatment per protocol; the most common reason for discontinuation was adverse events, and 2 subjects discontinued due to progressive disease (PD). Complete response (CR) + unconfirmed CR (CRu) was 16/25 (64%), overall response rate was 20/25 (80%), and 4/25(16%) had PD as best response. Median progression free survival (PFS) was 34 months, and median overall survival has not been reached at 40 months' median follow up. Two year PFS was 63%. The most common grade 3-4 toxicities were hematologic.The addition of rituximab to multi-agent chemotherapy is well tolerated. Outcomes are comparable to or better than those seen in RTOG 93-10, which included RT. These and other results suggest rituximab has activity in the CNS. [ECOG-ACRIN E1F05].NCT00335140, clinicaltrials.gov.

  View details for DOI 10.18632/oncotarget.22332

  View details for Web of Science ID 000419615500062

  View details for PubMedID 29416652

  View details for PubMedCentralID PMC5787508

• Advances in the Management of Primary Mediastinal Large B-Cell Lymphoma CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Advani, R. H. 2018; 16 (1): 33–34

  View details for Web of Science ID 000425929300005

  View details for PubMedID 29741502

• New Treatment Algorithms in Hodgkin Lymphoma: Too Much or Too Little? American Society of Clinical Oncology Education Book Spinner, M. A., Advani, R. H., Connors, J. M., Azzi, J., Diefenbach, C. 2018; 38: 626-636

  View details for DOI 10.1200/EDBK_200679

• Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation. Clinical cancer research : an official journal of the American Association for Cancer Research Aghighi, M. n., Theruvath, A. J., Pareek, A. n., Pisani, L. n., Alford, R. n., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D. n., Luna-Fineman, S. n., Advani, R. H., Spunt, S. L., Daldrup-Link, H. E. 2018

  Abstract

  Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.In a first-in-patient, IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies.

  View details for PubMedID 29764855

• Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis CANCER Henderson, T. O., Parsons, S. K., Wroblewski, K. E., Chen, L., Hong, F., Smith, S. M., McNeer, J. L., Advani, R. H., Gascoyne, R. D., Constine, L. S., Horning, S., Bartlett, N. L., Shah, B., Connors, J. M., Leonard, J. I., Kahl, B. S., Kelly, K. M., Schwartz, C. L., Li, H., Friedberg, J. W., Friedman, D. L., Gordon, L. I., Evens, A. M. 2018; 124 (1): 136–44

  Abstract

  There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL).Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study.Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study.Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2018;124:136-44. © 2017 American Cancer Society.

  View details for PubMedID 28902390

• Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma BLOOD Pro, B., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M., Connors, J. M., Fenton, K., Huebner, D., Pinelli, J. M., Kennedy, D. A., Shustov, A. 2017; 130 (25): 2709–17

  Abstract

  This pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.

  View details for PubMedID 28974506

• KLHL6 Is Preferentially Expressed in Germinal Center-Derived B-Cell Lymphomas AMERICAN JOURNAL OF CLINICAL PATHOLOGY Kunder, C. A., Roncador, G., Advani, R. H., Gualco, G., Bacchi, C. E., Sabile, J. M., Lossos, I. S., Nie, K., Tibshirani, R., Green, M. R., Alizadeh, A. A., Natkunam, Y. 2017; 148 (6): 465–76

  Abstract

  KLHL6 is a recently described BTB-Kelch protein with selective expression in lymphoid tissues and is most strongly expressed in germinal center B cells.Using gene expression profiling as well as immunohistochemistry with an anti-KLHL6 monoclonal antibody, we have characterized the expression of this molecule in normal and neoplastic tissues. Protein expression was evaluated in 1,058 hematopoietic neoplasms.Consistent with its discovery as a germinal center marker, KLHL6 was positive mainly in B-cell neoplasms of germinal center derivation, including 95% of follicular lymphomas (106/112). B-cell lymphomas of non-germinal center derivation were generally negative (0/33 chronic lymphocytic leukemias/small lymphocytic lymphomas, 3/49 marginal zone lymphomas, and 2/66 mantle cell lymphomas).In addition to other germinal center markers, including BCL6, CD10, HGAL, and LMO2, KLHL6 immunohistochemistry may prove a useful adjunct in the diagnosis and future classification of B-cell lymphomas.

  View details for PubMedID 29140403

• Clinical Practice Recommendations on Indication and Timing of Hematopoietic Cell Transplantation in Mature T Cell and NK/T Cell Lymphomas: An International Collaborative Effort on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Kharfan-Dabaja, M. A., Kumar, A., Ayala, E., Hamadani, M., Reimer, P., Gisselbrecht, C., d'Amore, F., Jantunen, E., Ishida, T., Bazarbachi, A., Foss, F., Advani, R., Fenske, T. S., Lazarus, H. M., Friedberg, J. W., Aljurf, M., Sokol, L., Tobinai, K., Tse, E., Burns, L. J., Chavez, J. C., Reddy, N. M., Suzuki, R., Ahmed, S., Nademanee, A., Mohty, M., Gopal, A. K., Fanale, M. A., Pro, B., Moskowitz, A. J., Sureda, A., Perales, M., Carpenter, P. A., Savani, B. N. 2017; 23 (11): 1826–38

  Abstract

  Recognizing the significant biological and clinical heterogeneity of mature T cell and natural killer (NK)/T cell lymphomas, the American Society for Blood and Marrow Transplantation invited experts to develop clinical practice recommendations related to the role of autologous hematopoietic cell transplantation (auto-HCT) and allogeneic HCT (allo-HCT) for specific histological subtypes. We used the GRADE methodology to aid in moving from evidence to decision making and ultimately to generating final recommendations. Auto-HCT in front-line consolidation is recommended in peripheral T cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma-anaplastic lymphoma kinase (ALCL-ALK)-negative, NK/T cell (disseminated), enteropathy-associated T cell lymphoma (EATL), and hepatosplenic lymphomas. Auto-HCT in relapsed-sensitive disease is recommended for NK/T cell (localized and disseminated), EATL, subcutaneous panniculitis-like T cell, and ALCL-ALK-positive lymphomas. Auto-HCT is also recommended for PTCL-NOS, AITL, and ALCL-ALK-negative lymphomas if not performed as front-line therapy. Auto-HCT in refractory (primary or relapsed) disease is not recommended for any of the histological subtypes discussed. Allo-HCT in front-line consolidation is recommended for NK/T cell (disseminated), adult T cell leukemia/lymphoma (ATLL; acute and lymphoma type), and hepatosplenic lymphomas. Allo-HCT for relapsed-sensitive disease is recommended for PTCL-NOS, AITL, ALCL-ALK-negative, ALCL-ALK-positive, NK/T cell (localized and disseminated), ATLL (acute, lymphoma type, smoldering/chronic), mycosis fungoides/Sezary syndrome (advanced stage IIB-IVB or tumor stage/extracutaneous), EATL, subcutaneous panniculitis-like T cell, and hepatosplenic lymphoma. Allo-HCT in refractory (primary or relapsed refractory) disease is recommended for any aforementioned histological subtypes. Emerging novel therapies will likely be incorporated into the pretransplantation, peritransplantation, and post-transplantation algorithms (auto-HCT or allo-HCT) with the goals of optimizing efficacy and improving outcomes. We acknowledge that there are unique clinical scenarios not covered by these recommendations that may require individualized decisions.

  View details for PubMedID 28797780

• Clinical Impact of the 2016 Update to the WHO Lymphoma Classification (vol 18, 45, 2017) CURRENT TREATMENT OPTIONS IN ONCOLOGY Lynch, R. C., Gratzinger, D., Advani, R. H. 2017; 18 (10): 60

  View details for PubMedID 28861885

• Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG) ANNALS OF ONCOLOGY Dabaja, B. S., Zelenetz, A. D., Ng, A. K., Tsang, R. W., Qi, S., Allen, P. K., Hodgson, D., Ricardi, U., Hoppe, R. T., Advani, R., Mauch, P. M., Constine, L. S., Specht, L., Li, Y., Terezakis, S. A., Wirth, A., Reinartz, G., Eich, H. T., Aleman, B. P., Barr, P., Yahalom, J. 2017; 28 (9): 2185–90

  Abstract

  Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease.In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival.Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively.Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

  View details for PubMedID 28911068

• Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium HAEMATOLOGICA Stevens, W. C., Mendeville, M., Redd, R., Clear, A. J., Bladergroen, R., Calaminici, M., Rosenwald, A., Hoster, E., Hiddemann, W., Gaulard, P., Xerri, L., Salles, G., Klapper, W., Pfreundschuh, M., Jack, A., Gascoyne, R. D., Natkunam, Y., Advani, R., Kimby, E., Sander, B., Sehn, L. H., Hagenbeek, A., Raemaekers, J., Gribben, J., Kersten, M., Ylstra, B., Weller, E., de Jong, D. 2017; 102 (8): 1413–23

  Abstract

  In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death <2 years versus long remission, response duration of >5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (P=0.006), gain of chromosome 18 (P=0.002), low percentages of CD8+ cells (P=0.011) and CD163+ areas (P=0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.

  View details for PubMedID 28411252

• PRELIMINARY RESULTS FROM AN OPEN-LABEL, PHASE II STUDY OF TIPIFARNIB IN RELAPSED OR REFRACTORY PERIPHERAL T-CELL LYMPHOMA Witzig, T., Sokol, L., Jacobsen, E., Advani, R., Mondejar, R., Piris, M., Burrows, F., Melvin, C., Mishra, V., Scholz, C., Gualberto, A. FERRATA STORTI FOUNDATION. 2017: 222

  View details for Web of Science ID 000404127002064

• The landscape of new drugs in lymphoma NATURE REVIEWS CLINICAL ONCOLOGY Younes, A., Ansell, S., Fowler, N., Wilson, W., de Vos, S., Seymour, J., Advani, R., Forero, A., Morschhauser, F., Kersten, M. J., Tobinai, K., Zinzani, P. L., Zucca, E., Abramson, J., Vose, J. 2017; 14 (6): 335-346

  Abstract

  The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.

  View details for DOI 10.1038/nrclinonc.2016.205

  View details for Web of Science ID 000401612500004

• Subsequent primary malignancies after diffuse large B-cell lymphoma in the modern treatment era. British journal of haematology Tao, L., Clarke, C. A., Rosenberg, A. S., Advani, R. H., Jonas, B. A., Flowers, C. R., Keegan, T. H. 2017

  Abstract

  With the addition of rituximab and other treatment advances, survival after diffuse large B-cell lymphoma (DLBCL) has improved, but subsequent primary malignancies (SPMs) have emerged as an important challenge for DLBCL survivorship. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPMs among 23 879 patients who survived at least 1 year after a first primary DLBCL diagnosed during 1989-2012, compared to the general population in California. Cumulative incidence (CMI) of SPMs, accounting for the competing risk of death, also was calculated. We found that the incidence of acute myeloid leukaemia (AML) nearly doubled in the post-rituximab era [SIR (95% CI) 4·39 (2·51-7·13) pre- (1989-2000) and 8·70 (6·62-11·22) post-rituximab (2001-2012)]. Subsequent thyroid cancer was rare pre-rituximab, but increased substantially after 2001 [0·66 (0·08-2·37) vs. 2·27(1·44-3·41)]. The 5-year CMI for all SPMs (4·77% pre- vs. 5·41% post-rituximab, P = 0·047), AML (0·15% vs. 0·41%, P = 0·003), thyroid cancer (0·03% vs. 0·15%, P = 0·003) and melanoma (0·25% vs. 0·42%, P = 0·020) were greater in DLBCL patients diagnosed in the post- versus pre-rituximab period. This study provides insight into the changing pattern of SPM occurrence after the introduction of rituximab, which may elucidate the aetiology of SPMs and should guide future cancer surveillance efforts among DLBCL patients.

  View details for DOI 10.1111/bjh.14638

  View details for PubMedID 28542862

• Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma. Jin, M. C., Kurtz, D., Esfahani, M., Scherer, F., Craig, A. M., Soo, J., Khodadoust, M., Saganty, R., Chabon, J. J., Schroers-Martin, J., Stehr, H., Advani, R. H., Rossi, D., Gaidano, G., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7507

  View details for Web of Science ID 000411931708176

• Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA. Soo, J., Kurtz, D., Scherer, F., Craig, A. M., Jin, M. C., Westin, J. R., Rossi, D., Gaidano, G., Advani, R. H., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7538

  View details for Web of Science ID 000411931709025

• Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Benitez, C. M., Bernat, K., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Maloney, D. G., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Poppe, M., Rabinovitch, R., Seropian, S., Smith, M., Winter, J. N., Yahalom, J., Burns, J., Ogba, N., Sundar, H. 2017; 15 (5): 608-638

  Abstract

  This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

  View details for PubMedID 28476741

• Hodgkin Lymphoma Version 1.2017 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Benitez, C. M., Bernat, K., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Maloney, D. G., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Poppe, M., Rabinovitch, R., Seropian, S., Smith, M., Winter, J. N., Yahalom, J., Burns, J., Ogba, N., Sundar, H. 2017; 15 (5): 608-638

  Abstract

  This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

  View details for Web of Science ID 000401120200011

• International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Annals of oncology Younes, A., HILDEN, P., Coiffier, B., Hagenbeek, A., Salles, G., Wilson, W., Seymour, J. F., Kelly, K., Gribben, J., Pfreunschuh, M., Morschhauser, F., Schoder, H., Zelenetz, A. D., Rademaker, J., Advani, R., Valente, N., Fortpied, C., Witzig, T. E., Sehn, L. H., Engert, A., Fisher, R. I., Zinzani, P., Federico, M., Hutchings, M., Bollard, C., Trneny, M., Elsayed, Y. A., Tobinai, K., Abramson, J. S., Fowler, N., Goy, A., Smith, M., Ansell, S., Kuruvilla, J., Dreyling, M., Thieblemont, C., Little, R. F., Aurer, I., Van Oers, M. H., Takeshita, K., Gopal, A., Rule, S., de Vos, S., Kloos, I., Kaminski, M. S., Meignan, M., Schwartz, L. H., Leonard, J. P., Schuster, S. J., Seshan, V. E. 2017

  Abstract

  In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) or bidimensional tumor measurements on computerized tomography (CT) scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47,828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials, and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

  View details for DOI 10.1093/annonc/mdx097

  View details for PubMedID 28379322

• A Prospective Cohort Study of Patients With Peripheral T-Cell Lymphoma in the United States CANCER Carson, K. R., Horwitz, S. M., Pinter-Brown, L. C., Rosen, S. T., Pro, B., Hsi, E. D., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M. A., Shustov, A. R., Advani, R. H., Feldman, T. A., Lechowicz, M. J., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Park, S. I., Foss, F. M. 2017; 123 (7): 1174-1183

  Abstract

  Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States.Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided.Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]).To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30416

  View details for Web of Science ID 000397760100015

• Improving care with portfolio of physician-led cancer quality measures at an academic center Porter, J., Smith, A., Winget, M., Rosenthal, E., Seshadri, S., Vetteth, Y., Kiamanesh, E. F., Badwe, A., Advani, R. H., Buyyounouski, M. K., Coutre, S., Dorigo, O., Ganjoo, K. N., Johnston, L. J., Recht, L., Shrager, J. B., Skinner, E. C., Swetter, S. M., Visser, B. C., Blayney, D. W. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for Web of Science ID 000443301600049

• NCCN Guidelines (R) Insights Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia, Version 1.2017 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Wierda, W. G., Zelenetz, A. D., Gordon, L. I., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Caimi, P., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Martin, M. G., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Snyder, E. D., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Dwyer, M. A., Sundar, H. 2017; 15 (3): 293-311

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

  View details for Web of Science ID 000395889300004

• NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia, Version 1.2017. Journal of the National Comprehensive Cancer Network Wierda, W. G., Zelenetz, A. D., Gordon, L. I., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Caimi, P., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Martin, M. G., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Snyder, E. D., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Dwyer, M. A., Sundar, H. 2017; 15 (3): 293-311

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

  View details for PubMedID 28275031

• Phase I Study of the Anti-CD22 Antibody-Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research Advani, R. H., Lebovic, D., Chen, A., Brunvand, M., Goy, A., Chang, J. E., Hochberg, E., Yalamanchili, S., Kahn, R., Lu, D., Agarwal, P., Dere, R. C., Hsieh, H., Jones, S., Chu, Y., Cheson, B. D. 2017; 23 (5): 1167-1176

  Abstract

  Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167-76. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-0772

  View details for PubMedID 27601593

• Acquired mutations associated with ibrutinib resistance in Waldenstrom Macroglobulinemia. Blood Xu, L., Tsakmaklis, N., Yang, G., Chen, J. G., Liu, X., Demos, M., Kofides, A., Patterson, C. J., Meid, K., Gustine, J., Dubeau, T., Palomba, M. L., Advani, R., Castillo, J. J., Furman, R. R., Hunter, Z. R., Treon, S. P. 2017

  Abstract

  Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4(WHIM) mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. We sequenced sorted CD19(+) lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays that we developed for Bruton tyrosine kinase (BTK) mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naïve disease. Targeted next-generation sequencing was used to validate AS-PCR findings, assess for other BTK mutations, and other targets in B-cell receptor and MYD88 signaling. Among the 6 progressing patients, 3 had BTK(Cys481) variants that included BTK(Cys481Ser(c.1635G>C and c.1634T>A)) and BTK(Cys481Arg(c.1634T>C)) Two of these patients had multiple BTK mutations. Screening of 38 additional patients on ibrutinib without clinical progression identified BTK(Cys481) mutations in 2 (5.1%) individuals, both of whom subsequently progressed. BTK(Cys481) mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutated MYD88 as a tumor marker, BTK(Cys481) mutations were subclonal, with a highly variable clonal distribution. Targeted deep-sequencing confirmed AS-PCR findings, and identified an additional BTK(Cys481Tyr(c.1634G>A)) mutation in the 2 patients with multiple other BTK(Cys481) mutations, as well as CARD11(Leu878Phe(c.2632C>T)) and PLCγ2(Tyr495His(c.1483T>C)) mutations. Four of the 5 patients with BTK(C481) variants were CXCR4 mutated. BTK(Cys481) mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutated CXCR4.

  View details for DOI 10.1182/blood-2017-01-761726

  View details for PubMedID 28235842

• T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment. Journal of the National Cancer Institute Casulo, C., O'Connor, O., Shustov, A., Fanale, M., Friedberg, J. W., Leonard, J. P., Kahl, B. S., Little, R. F., Pinter-Brown, L., Advani, R., Horwitz, S. 2017; 109 (2)

  Abstract

  Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and aggressive non-Hodgkin's lymphomas. Despite progress in the last several years resulting in a deeper understanding of PTCL biology and pathogenesis, there is currently no accepted single standard of care for newly diagnosed patients, and for those with relapsed or refractory disease, prognosis is dismal. The National Cancer Institute convened a Clinical Trials Planning Meeting to advance the national clinical trial agenda in lymphoma. The objective was to identify unmet needs specific to five major lymphoma subtypes and develop strategies to address them. This consensus statement reviews recent advances in the molecular and genetic characterization of PTCL that may inform novel treatments, proposes strategies to test novel therapies in the relapsed setting with the hopes of rapid advancement into frontline trials, and underscores the need for the identification and development of active and biologically rational therapies to cure PTCL at higher rates, with iterative biomarker evaluation.

  View details for DOI 10.1093/jnci/djw248

  View details for PubMedID 28040682

• Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States. Clinical lymphoma, myeloma & leukemia Hsi, E. D., Horwitz, S. M., Carson, K. R., Pinter-Brown, L. C., Rosen, S. T., Pro, B., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M., Collie, A. M., Gruver, A. M., Grzywacz, B. J., Turakhia, S., Shustov, A. R., Advani, R. H., Feldman, T., Lechowicz, M. J., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Park, S. I., Foss, F. M. 2017

  Abstract

  With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States.A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01).The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

  View details for DOI 10.1016/j.clml.2016.10.001

  View details for PubMedID 28209473

• Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study. The Lancet. Haematology Furman, R. R., Eradat, H. A., DiRienzo, C. G., Hofmeister, C. C., Hayman, S. R., Leonard, J. P., Coleman, M., Advani, R., Chanan-Khan, A., Switzky, J., Liao, Q. M., Shah, D., Jewell, R. C., Lisby, S., Lin, T. S. 2017; 4 (1): e24-e34

  Abstract

  The development of more effective and safer treatments, especially non-chemotherapeutics, is needed for patients with Waldenström's macroglobulinaemia. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström's macroglobulinaemia.We did a phase 2, open-label, single-arm study at six centres (hospitals and cancer clinics) in the USA. Patients aged at least 18 years who were diagnosed with untreated or relapsed Waldenström's macroglobulinaemia and required treatment, received up to three cycles of weekly ofatumumab for 5 weeks. For cycle 1, patients received one of two treatment regimens. Group A received ofatumumab 300 mg during week 1 followed by 1000 mg during weeks 2-4. Because of the acceptable safety of the 1000 mg dose in treatment group A and clinical activity of the 2000 mg dose established in chronic lymphocytic leukaemia, the study was amended on Dec 9, 2009, to change cycle 1 for group B who received ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 5-16 for treatment group A and during weeks 6-16 for treatment group B (no treatment was given during this follow-up). Patients in both groups with stable disease or a minor response after 16 weeks were eligible to then receive a redosing cycle of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 6-16 after the redosing cycle (no treatment was given during this follow-up). Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. The primary endpoint for this study was the proportion of patients who achieved an overall response (complete responses plus partial responses plus minor responses) after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8. This trial is registered at www.ClinicalTrials.gov, NCT00811733, and is now complete.Between March 17, 2009, and Feb 24, 2011, we enrolled and assigned 37 patients to treatment (15 in treatment group A and 22 in treatment group B). All 37 were included in the efficacy and safety analyses. 19 (51%, 95% CI 34·4-68·1) of 37 patients achieved an overall response after cycle 1 and 22 (59%, 42·1-75·2) of 37 achieved an overall response after the redosing cycle; 15 (41%) with partial responses, seven (19%) with minor responses. 13 patients received treatment cycle 2; ten (77%) of the 13 achieved a response. All 37 patients had at least one adverse event; 16 (43%) patients had events of grade 3 or more (30 grade 3, one grade 4). The most common grade 3 or 4 adverse events were infusion reactions (four [11%] of 37), chest pain (two [5%] of 37), haemolysis (two [5%] of 37), and neutropenia (two [5%] of 37). Two (9%) of 22 patients (both in treatment group B) had an IgM flare. 12 patients reported serious adverse events; haemolysis and pyrexia were the most common (each occurring in two [5%] of 37 patients).A high proportion of patients achieved an overall response with ofatumumab monotherapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström's macroglobulinaemia, especially those with high IgM concentrations.GlaxoSmithKline and Genmab.

  View details for DOI 10.1016/S2352-3026(16)30166-1

  View details for PubMedID 27914971

• Clinical Impact of the 2016 Update to the WHO Lymphoma Classification. Current treatment options in oncology Lynch, R. C., Gratzinger, D. n., Advani, R. H. 2017; 18 (7): 45

  Abstract

  The 2016 revision of the WHO classification of lymphoid neoplasms includes new entities along with a clearer definition of provisional and definitive subtypes based on better understanding of the molecular drivers of lymphomas. These changes impact current treatment paradigms and provide a framework for future clinical trials. Additionally, this update recognizes several premalignant or predominantly indolent entities and underscores the importance of avoiding unnecessarily aggressive treatment in the latter subsets.

  View details for PubMedID 28670664

• Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center Porter, J. B. 2017; 13 (8): e673-e682

  Abstract

  Development and implementation of robust reporting processes to systematically provide quality data to care teams in a timely manner is challenging. National cancer quality measures are useful, but the manual data collection required is resource intensive, and reporting is delayed. We designed a largely automated measurement system with our multidisciplinary cancer care programs (CCPs) to identify, measure, and improve quality metrics that were meaningful to the care teams and their patients.Each CCP physician leader collaborated with the cancer quality team to identify metrics, abiding by established guiding principles. Financial incentive was provided to the CCPs if performance at the end of the study period met predetermined targets. Reports were developed and provided to the CCP physician leaders on a monthly or quarterly basis, for dissemination to their CCP teams.A total of 15 distinct quality measures were collected in depth for the first time at this cancer center. Metrics spanned the patient care continuum, from diagnosis through end of life or survivorship care. All metrics improved over the study period, met their targets, and earned a financial incentive for their CCP.Our quality program had three essential elements that led to its success: (1) engaging physicians in choosing the quality measures and prespecifying goals, (2) using automated extraction methods for rapid and timely feedback on improvement and progress toward achieving goals, and (3) offering a financial team-based incentive if prespecified goals were met.

  View details for DOI 10.1200/JOP.2017.021139

  View details for PubMedCentralID PMC5880618

• How to Provide Gadolinium-Free PET/MR Cancer Staging of Children and Young Adults in Less than 1 h: the Stanford Approach. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Muehe, A. M., Theruvath, A. J., Lai, L. n., Aghighi, M. n., Quon, A. n., Holdsworth, S. J., Wang, J. n., Luna-Fineman, S. n., Marina, N. n., Advani, R. n., Rosenberg, J. n., Daldrup-Link, H. E. 2017

  Abstract

  To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h.In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [(18)F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests.Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [(18)F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %).Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.

  View details for PubMedID 28721605

• Dramatic Response with Single-Agent Ibrutinib in Multiply Relapsed Marginal Zone Lymphoma with MYD88(L265P) Mutation CASE REPORTS IN ONCOLOGY Lynch, R. C., Advani, R. H. 2017; 10 (3): 813–18

  Abstract

  The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.

  View details for PubMedID 29070995

• Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry LEUKEMIA & LYMPHOMA Bartlett, N. L., Smith, M. R., Siddiqi, T., Advani, R. H., O'Connor, O. A., Sharman, J. P., Feldman, T., Savage, K. J., Shustov, A. R., Diefenbach, C. S., Oki, Y., Palanca-Wessels, M. C., Uttarwar, M., Li, M., Yang, J., Jacobsen, E. D. 2017; 58 (7): 1607-1616

  Abstract

  This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

  View details for DOI 10.1080/10428194.2016.1256481

  View details for Web of Science ID 000399474000013

• The landscape of new drugs in lymphoma. Nature reviews. Clinical oncology Younes, A., Ansell, S., Fowler, N., Wilson, W., de Vos, S., Seymour, J., Advani, R., Forero, A., Morschhauser, F., Kersten, M. J., Tobinai, K., Zinzani, P. L., Zucca, E., Abramson, J., Vose, J. 2016

  Abstract

  The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.

  View details for DOI 10.1038/nrclinonc.2016.205

  View details for PubMedID 28031560

• A prospective cohort study of patients with peripheral T-cell lymphoma in the United States. Cancer Horwitz, S. M., Pinter-Brown, L. C., Rosen, S. T., Pro, B., Hsi, E. D., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M. A., Shustov, A. R., Advani, R. H., Feldman, T. A., Lechowicz, M. J., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Park, S. I., Foss, F. M. 2016

  Abstract

  Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States.Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided.Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]).To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30416

  View details for PubMedID 27911989

• Molecular Basis of Ibrutinib Resistance in Waldenstrom's Macroglobulinemia Xu, L., Tsakmaklis, N., Yang, G., Chen, J. G., Liu, X., Chen, J., Demos, M., Patterson, C. J., Dubeau, T., Meid, K., Gustine, J., Castillo, J. J., Advani, R. H., Palomba, M., Furman, R. R., Hunter, Z., Treon, S. P. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446802082

• Title: A Phase I Study with an Expansion Cohort of the Combination of Ipilimumab and Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412 Arms D and E) Diefenbach, C. S., Hong, F., David, K. A., Cohen, J., Robertson, M., Advani, R., Palmisiano, N. D., Ambinder, R. F., Kahl, B. S., Ansell, S. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803137

• Preliminary Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma Herrera, A. F., Bartlett, N. L., Ramchandren, R., Vose, J. M., Moskowitz, A. J., Feldman, T. A., LaCasce, A. S., Ansell, S. M., Moskowitz, C. H., Fenton, K., Kato, K., Fong, A., Advani, R. H. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803139

• Phase 1 Study of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, in Patients with CD20+B-Cell Malignancies Previously Treated with CD20-Directed Antibody Therapy Bannerji, R., Brown, J. R., Advani, R. H., Arnason, J., O'Brien, S. M., Allan, J. N., Chavez, J. C., Barnes, J. A., Joyce, R., Ansell, S., Topp, M. S., Adriaens, L., Ufkin, M., Kostic, A., Paccaly, A., Gao, B., Trail, P. A., Lowy, I., Brownstein, C. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446804024

• Mutated MYD88 Zygosity and CXCR4 Mutation Status Are Important Determinants of Ibrutinib Response and Progression Free Survival in Waldenstrom's Macroglobulinemia Treon, S. P., Tsakmaklis, N., Meid, K., Yang, G., Chen, J. G., Liu, X., Chen, J., Demos, M., Patterson, C. J., Dubeau, T., Gustine, J., Castillo, J. J., Advani, R. H., Palomba, M., Xu, L., Hunter, Z. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307163

• Contempo: Preliminary Results in First-Line Treatment of Follicular Lymphoma with the Oral Dual PI3K-delta,gamma Inhibitor, Duvelisib, in Combination with Rituximab or Obinutuzumab Casulo, C., Sancho, J., Van Eygen, K., de Vos, S., Mercadal, S., Johnson, R. J., Bouabdallah, K., Holmes, H., Lemmens, J., Gyan, E., Merli, M., Advani, R. H., Steelman, L., Pearlberg, J., Goy, A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307154

• Ibrutinib Combined with Rituximab in Treatment-Naive Patients with Follicular Lymphoma: Arm 1+Arm 2 Results from a Multicenter, Open-Label Phase 2 Study Fowler, N., Nastoupil, L., de Vos, S., Knapp, M., Flinn, I. W., Chen, R. W., Advani, R. H., Bhatia, S., Martin, P., Mena, R., Suzuki, S., Beaupre, D. M., Neuenburg, J. K., Palomba, M. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307142

• Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma Pro, B., Advani, R. H., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M. A., Connors, J. M., Fenton, K., Huebner, D., Pinelli, J., Shustov, A. R. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452308059

• Serum Biomarkers Predict Outcomes in Advanced Hodgkin Lymphoma Independent of International Prognostic Score (IPS) and Treatment: Correlative Analysis from a Large North American Cooperative Group Trial Kanakry, J. A., Hong, F., Martinez-Maza, O., Horning, S. J., Gordon, L. I., Gascoyne, R. D., Gellert, L. L., Lemas, M., Cheson, B., Advani, R. H., Pohlman, B., Kenkre, V. P., Winter, J. N., Stiff, P. J., Tuscano, J., Friedberg, J., Dreosti, L., Fisher, R. I., Laneuville, P., Kahl, B. S., Ambinder, R. F. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452308037

• A Phase 1b, Multi-Center, Open-Label Study of Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-Cell Lymphoma: CC-122-DLBCL-001 Ribrag, V., Chavez, J. C., Kaplan, J. B., Vitolo, U., Chandler, J. C., Santoro, A., Corradini, P., Cassier, P., Flinn, I. W., Advani, R., Sangha, R., Isufi, I., Kenkre, V. P., Hagner, P. R., Trowe, T., Gandhi, A. K., Wu, X., Hege, K., Pourdehnad, M., Kuruvilla, J. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452500040

• Noninvasive Detection of BCL2, BCL6, and MYC Translocations in Diffuse Large B-Cell Lymphoma Kurtz, D. M., Scherer, F., Newman, A. M., Craig, A., Jin, M., Stehr, H., Chabon, J. J., Esfahani, M., Liu, C., Zhou, L., Glover, C., Visser, B. C., Poultsides, G., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Davis, R., Kunder, C. A., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307016

• Absence of Evidence Implicating Hematopoietic Stem Cells As Common Progenitors for DLBCL Mutations Jan, M., Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Liu, C., Zhou, L., Glover, C., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Kunder, C. A., Sanchez-Garcia, I., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307040

• Development and Validation of Biopsy-Free Genotyping for Molecular Subtyping of Diffuse Large B-Cell Lymphoma 58th Annual Meeting and Exposition of the American-Society-of-Hematology Scherer, F., Kurtz, D. M., Newman, A. M., Esfahani, M. S., Craig, A., Stehr, H., Lovejoy, A. F., Chabon, J. J., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Davis, E. R., Gaidano, G., Kunder, C. A., Rossi, D., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803093

• ACR Appropriateness Criteria (R) Recurrent Hodgkin Lymphoma ONCOLOGY-NEW YORK Winkfield, K. M., Advani, R. H., Ballas, L. K., Dabaja, B. S., Dhakal, S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mansur, D. B., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S. M., Terezakis, S. A., Younes, A., Constine, L. S. 2016; 30 (12): 1099-1108

  Abstract

  This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma.

  View details for Web of Science ID 000392195200011

  View details for PubMedID 27987203

• ACR Appropriateness Criteria (R) Hodgkin Lymphoma-Favorable Prognosis Stage I and II AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Dhakal, S., Advani, R., Ballas, L. K., Dabaja, B. S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S. M., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2016; 39 (6): 535-544

  Abstract

  This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy.

  View details for DOI 10.1097/COC.0000000000000331

  View details for PubMedID 27643717

• Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy BLOOD Cheson, B. D., Ansell, S., Schwartz, L., Gordon, L. I., Advani, R., Jacene, H. A., Hoos, A., Barrington, S. F., Armand, P. 2016; 128 (21): 2489-2496

  Abstract

  Uniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudo-progression). Considering this finding as PD could lead to patients being prematurely removed from a treatment from which they actually stand to benefit. This phenomenon has been well described with checkpoint blockade therapy in solid tumors and anecdotally seen in lymphoma as well. To address this issue in the context of lymphoma immunomodulatory therapy, a workshop was convened to provide provisional recommendations to modify current response criteria in patients receiving these and future agents in clinical trials. The term "indeterminate response" was introduced to identify such lesions until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging.

  View details for DOI 10.1182/blood-2016-05-718528

  View details for PubMedID 27574190

• Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leukemia & lymphoma Bartlett, N. L., Smith, M. R., Siddiqi, T., Advani, R. H., O'Connor, O. A., Sharman, J. P., Feldman, T., Savage, K. J., Shustov, A. R., Diefenbach, C. S., Oki, Y., Palanca-Wessels, M. C., Uttarwar, M., Li, M., Yang, J., Jacobsen, E. D. 2016: 1-10

  Abstract

  This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

  View details for PubMedID 27868471

• Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA SCIENCE TRANSLATIONAL MEDICINE Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. F., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C. A., Diehn, M., Alizadeh, A. A. 2016; 8 (364)

  Abstract

  Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

  View details for DOI 10.1126/scitranslmed.aai8545

  View details for PubMedID 27831904

• Classical Hodgkin Lymphoma with Reduced ß2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status. Cancer immunology research Roemer, M. G., Advani, R. H., Redd, R. A., Pinkus, G. S., Natkunam, Y., Ligon, A. H., Connelly, C. F., Pak, C. J., Carey, C. D., Daadi, S. E., Chapuy, B., De Jong, D., Hoppe, R. T., Neuberg, D. S., Shipp, M. A., Rodig, S. J. 2016; 4 (11): 910-916

  Abstract

  In classical Hodgkin lymphoma (cHL), malignant Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple mechanisms, including perturbed antigen presentation and enhanced PD-1 signaling. HRS cell expression of the PD-1 ligands is attributable, in part, to copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) Amplification of PD-L1/PD-L2 is associated with advanced clinical stage and inferior progression-free survival (PFS) following first-line (induction) therapy. The relationships between altered expression of β2-microglobulin (β2M), MHC class I, and MHC class II by HRS cells, PD-L1/PD-L2 amplification, and clinical outcome in cHL are poorly defined. We assessed these variables in diagnostic biopsy specimens from 108 patients with cHL who received uniform treatment and had long-term follow-up and found decreased/absent expression of β2M/MHC class I in 79% (85/108) and decreased/absent expression of MHC class II in 67% (72/108) of cases. Patients with decreased/absent β2M/MHC class I had shorter PFS, independent of PD-L1/PD-L2 amplification and advanced stage. Decreased or absent MHC class II was unrelated to outcome. These results suggest that MHC class I-mediated antigen presentation by HRS cells is an important component of the biological response to standard chemo/radiotherapy. The paucity of β2M/MHC class I expression on HRS cells also prompts speculation regarding alternative mechanisms of action of PD-1 blockade in cHL. Cancer Immunol Res; 4(11); 910-6. ©2016 AACR.

  View details for PubMedID 27737878

• Template for Reporting Results of Biomarker Testing of Specimens From Patients With Diffuse Large B-Cell Lymphoma, Not Otherwise Specified ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Duncavage, E., Advani, R. H., Agosti, S., Foulis, P., Gibson, C., Kang, L., Khoury, J. D., Medeiros, L. J., Ohgami, R. S., O'Malley, D. P., Patel, K. P., Rosenbaum, J. N., Wilson, C. 2016; 140 (11): 1225-1227

  View details for DOI 10.5858/arpa.2015-0418-CP

  View details for PubMedID 27081876

• Template for Reporting Results of Biomarker Testing of Specimens From Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Duncavage, E., Advani, R. H., Agosti, S., Foulis, P., Gibson, C., Kang, L., Khoury, J. D., Medeiros, L. J., Ohgami, R. S., O'Malley, D. P., Patel, K. P., Rosenbaum, J. N., Wilson, C. 2016; 140 (11): 1228-1230

  View details for DOI 10.5858/arpa.2016-0045-CP

  View details for PubMedID 27081879

• Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Yibritumomab tiuxetan: Ten year follow-up of the phase 2 ECOG-ACRIN study E1499. Leukemia Smith, M. R., Hong, F., Li, H., Gordon, L. I., Gascoyne, R. D., Paietta, E. M., Advani, R. H., Forero-Torres, A., Horning, S. J., Kahl, B. S. 2016

  View details for DOI 10.1038/leu.2016.305

  View details for PubMedID 27780968

• BRENTUXIMAB VEDOTIN PLUS BENDAMUSTINE AS A SALVAGE TREATMENT REGIMEN FOR PATIENTS WITH RELAPSED OR REFRACTORY HODGKIN LYMPHOMA LaCasce, A., Bociek, G., Sawas, A., Caimi, P., Agura, E., Matous, J., Ansell, S., Crosswell, H., Islas-Ohlmayer, M., Behler, C., Cheung, E., Forero-Torres, A., Vose, J., O'Connor, O. A., Josephson, N., Advani, R. FERRATA STORTI FOUNDATION. 2016: 45–46

  View details for Web of Science ID 000392549000108

• SEQUENTIAL BRENTUXIMAB VEDOTIN AND ADRIAMYCIN, VINBLASTINE, AND DACARBAZINE FOR OLDER PATIENTS WITH UNTREATED HODGKIN LYMPHOMA: FINDINGS FROM A PHASE II WINDOW STUDY Evens, A. M., Hamlin, P. A., Nabhan, C., Advani, R., Fanale, M., Petrich, A., Smith, S., Bociek, G., Winter, J., Gordon, L. I. FERRATA STORTI FOUNDATION. 2016: 20

  View details for Web of Science ID 000392549000047

• OUTCOMES IN ADOLESCENTS AND YOUNG ADULTS WITH HODGKIN LYMPHOMA TREATED ON US COOPERATIVE GROUP PROTOCOLS: AN ADULT INTERGROUP (E2496) AND CHILDREN'S ONCOLOGY GROUP (COG AHOD0031) COMPARATIVE ANALYSIS Henderson, T. O., Parsons, S. K., Wroblewski, K., Chen, L., Hong, F., Smith, S., McNeer, J., Advani, R., Gascoyne, R. D., Constine, L. S., Horning, S., Bartlett, N. L., Shah, B., Connors, J. M., Leonard, J., Kahl, B. S., Kelly, K., Schwartz, C. L., Friedman, D., Gordon, L. I., Evens, A. M. FERRATA STORTI FOUNDATION. 2016: 34–35

  View details for Web of Science ID 000392549000083

• A PHASE I STUDY WITH AN EXPANSION COHORT OF THE COMBINATION OF IPILIMUMAB AND BRENTUXIMAB VEDOTIN IN PATIENTS WITH RELAPSED/REFRACTORY HODGKIN LYMPHOMA: A TRIAL OF THE ECOG-ACRIN CANCER RESEARCH GROUP (E4412) Diefenbach, C. M., Hong, F., Ambinder, R. F., Cohen, J. B., Robertson, M. J., Fenske, T. S., Advani, R., Kahl, B. S., Ansell, S. FERRATA STORTI FOUNDATION. 2016: 44–45

  View details for Web of Science ID 000392549000106

• Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia. Blood Leblond, V., Kastritis, E., Advani, R., Ansell, S. M., Buske, C., Castillo, J. J., García-Sanz, R., Gertz, M., Kimby, E., Kyriakou, C., Merlini, G., Minnema, M. C., Morel, P., Morra, E., Rummel, M., Wechalekar, A., Patterson, C. J., Treon, S. P., Dimopoulos, M. A. 2016; 128 (10): 1321-1328

  Abstract

  Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM.

  View details for DOI 10.1182/blood-2016-04-711234

  View details for PubMedID 27432877

• NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016. Journal of the National Comprehensive Cancer Network Horwitz, S. M., Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Lee Harris, N., Hernandez-Ilizaliturri, F., Hoppe, R. T., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H., Porcu, P. 2016; 14 (9): 1067-1079

  Abstract

  Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

  View details for PubMedID 27587620

• Non-Hodgkin's Lymphomas, Version 3.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Horwitz, S. M., Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H., Porcu, P. 2016; 14 (9): 1067-1079

  Abstract

  Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

  View details for Web of Science ID 000382903900004

• 2 Gy?×?2 for palliative treatment of mantle cell lymphoma. Leukemia & lymphoma White, E. C., Advani, R., Hoppe, R. T. 2016; 57 (9): 2219-2221

  View details for DOI 10.3109/10428194.2015.1131274

  View details for PubMedID 26763352

• ACR Appropriateness Criteria® Hodgkin Lymphoma-Unfavorable Clinical Stage I and II. American journal of clinical oncology Roberts, K. B., Younes, A., Hodgson, D. C., Advani, R., Dabaja, B. S., Dhakal, S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Shapiro, R., Smith, S. M., Terezakis, S. A., Winkfield, K. M., Constine, L. S. 2016; 39 (4): 384-395

  Abstract

  These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1097/COC.0000000000000294

  View details for PubMedID 27299425

• Ibrutinib in Waldenström macroglobulinemia: latest evidence and clinical experience. Therapeutic advances in hematology Castillo, J. J., Palomba, M. L., Advani, R., Treon, S. P. 2016; 7 (4): 179-186

  Abstract

  Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor, which has recently gained approval by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with symptomatic Waldenström macroglobulinemia (WM). Herein, we review the role of BTK in the pathophysiology of WM, and present the results of the preclinical and clinical studies that led to the initial investigation and later approval of ibrutinib in WM. We also discuss aspects associated with ibrutinib therapy in WM patients, especially focusing on genomic profiling and the impact on response to ibrutinib, and the management of adverse events.

  View details for DOI 10.1177/2040620716654102

  View details for PubMedID 27493708

• Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Blood Matthews, J. M., Bhatt, S., Patricelli, M. P., Nomanbhoy, T. K., Jiang, X., Natkunam, Y., Gentles, A. J., Martinez, E., Zhu, D., Chapman, J. R., Cortizas, E., Shyam, R., Chinichian, S., Advani, R., Tan, L., Zhang, J., Choi, H. G., Tibshirani, R., Buhrlage, S. J., Gratzinger, D., Verdun, R., Gray, N. S., Lossos, I. S. 2016; 128 (2): 239-248

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), yet 40-50% of patients will eventually succumb to their disease demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNA's that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that Germinal Center Kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Since the majority of DLBCL tumors (~80%) exhibit activation of GCK, this therapy may be applicable to most patients.

  View details for DOI 10.1182/blood-2016-02-696856

  View details for PubMedID 27151888

• Diffuse Large B-Cell Lymphoma: Prospective Multicenter Comparison of Early Interim FLT PET/CT versus FDG PET/CT with IHP, EORTC, Deauville, and PERCIST Criteria for Early Therapeutic Monitoring RADIOLOGY Minamimoto, R., Fayad, L., Advani, R., Vose, J., Macapinlac, H., Meza, J., Hankins, J., Mottaghy, F., Juweid, M., Quon, A. 2016; 280 (1): 220-229

  Abstract

  Purpose To compare the performance characteristics of interim fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (after two cycles of chemotherapy) by using the most prominent standardized interpretive criteria (including International Harmonization Project [IHP] criteria, European Organization for Research and Treatment of Cancer [EORTC] criteria, and PET Response Criteria in Solid Tumors (PERCIST) versus those of interim (18)F fluorothymidine (FLT) PET/CT and simple visual interpretation. Materials and Methods This HIPAA-compliant prospective study was approved by the institutional review boards, and written informed consent was obtained. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) underwent both FLT and FDG PET/CT 18-24 days after two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. For FDG PET/CT interpretation, IHP criteria, EORTC criteria, PERCIST, Deauville criteria, standardized uptake value, total lesion glycolysis, and metabolic tumor volume were used. FLT PET/CT images were interpreted with visual assessment by two reviewers in consensus. The interim (after cycle 2) FDG and FLT PET/CT studies were then compared with the end-of-treatment FDG PET/CT studies to determine which interim examination and/or criteria best predicted the result after six cycles of chemotherapy. Results From November 2011 to May 2014, there were 60 potential patients for inclusion, of whom 46 patients (24 men [mean age, 60.9 years ± 13.7; range, 28-78 years] and 22 women [mean age, 57.2 years ± 13.4; range, 25-76 years]) fulfilled the criteria. Thirty-four patients had complete response, and 12 had residual disease at the end of treatment. FLT PET/CT had a significantly higher positive predictive value (PPV) (91%) in predicting residual disease than did any FDG PET/CT interpretation method (42%-46%). No difference in negative predictive value (NPV) was found between FLT PET/CT (94%) and FDG PET/CT (82%-95%), regardless of the interpretive criteria used. FLT PET/CT showed statistically higher (P < .001-.008) or similar NPVs than did FDG PET/CT. Conclusion Early interim FLT PET/CT had a significantly higher PPV than standardized FDG PET/CT-based interpretation for therapeutic response assessment in DLBCL. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2015150689

  View details for PubMedID 26854705

• Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma. Clinical advances in hematology & oncology : H&O Varma, G., Johnson, T. P., Advani, R. H. 2016; 14 (7): 543-554

  Abstract

  The development of Bruton's tyrosine kinase (BTK) inhibitors and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Although ibrutinib is the only BTK inhibitor that has been approved by the US Food and Drug Administration, several others are under investigation. Ibrutinib is currently approved for use in relapsed/refractory CLL, CLL with 17p deletion (del[17p]), relapsed or refractory mantle cell lymphoma, and Waldenström macroglobulinemia. Although it is clear that ibrutinib has altered treatment paradigms and outcomes in these diseases, several questions remain regarding (1) its role in frontline vs salvage therapy; (2) its use as a single agent vs in combination with biologic agents, other small molecules, or traditional chemoimmunotherapy; (3) the optimal duration of treatment; and (4) the treatment of patients who cannot tolerate or have disease resistant to ibrutinib. Because sparse clinical data are available on other BTK inhibitors, it is unclear at present whether their clinical efficacy and toxicity will differ from those of ibrutinib.

  View details for PubMedID 27379948

• BIOMARKERS IN RELAPSED/REFRACTORY DLBCL AND FL PATIENTS TREATED WITH POLATUZUMAB VEDOTIN: RESULTS FROM THE PHASE II CLINICAL TRIAL (ROMULUS) Penuel, E., Mundt, K., Bourgon, R., Sumiyoshi, T., Flinn, I., Press, O., Patel, M., Advani, R., Venstrom, J. M., Chu, Y. W., Hirata, J. FERRATA STORTI FOUNDATION. 2016: 578

  View details for Web of Science ID 000379484602185

• Noninvasive molecular subtyping and risk stratification of DLBCL. Scherer, F., Kurtz, D., Newman, A. M., Stehr, H., Craig, A. M., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C., Zhou, L., Glover, C., Advani, R. H., Maeda, L., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.7554

  View details for Web of Science ID 000404711505067

• Subsequent primary malignancies (SPMs) after diffuse large B-cell lymphoma (DLBCL) in the modern treatment era. Keegan, T. M., Clarke, C. A., Rosenberg, A., Advani, R. H., Jonas, B., Flowers, C., Tao, L. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.7543

  View details for Web of Science ID 000404711505056

• A first in human experience of the anti-CD37 antibody-drug conjugate AGS67E in lymphoid malignancies. Sawas, A., Savage, K. J., Perez, R. P., Advani, R. H., Melhem-Bertrandt, A., Lackey, J., Trave, F., Anand, B., Huang, Y., Vincent, M., Reyno, L. M., O'Connor, O. A. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.7549

  View details for Web of Science ID 000404711505062

• The 2016 revision of the World Health Organization classification of lymphoid neoplasms BLOOD Swerdlow, S. H., Campo, E., Pileri, S. A., Harris, N. L., Stein, H., Siebert, R., Advani, R., Ghielmini, M., Salles, G. A., Zelenetz, A. D., Jaffe, E. S. 2016; 127 (20): 2375-2390

  Abstract

  A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.

  View details for DOI 10.1182/blood-2016-01-643569

  View details for PubMedID 26980727

• Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Lynch, R. C., Advani, R. H. 2016: e376–e385

  Abstract

  Although patients with advanced-stage classic Hodgkin lymphoma have excellent outcomes with contemporary therapy, the outcomes of patients with refractory disease is suboptimal. Identification of these high-risk patients at diagnosis is challenging as the differences in outcomes using clinical criteria are less marked using current modern therapy. Data suggest that an interim PET-CT may be a powerful tool in risk-stratifying patients. Retrospective studies show that a negative interim PET-CT after two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is predictive of favorable outcome independent of IPS score. Currently, there are several ongoing trials that aim to determine whether early-response assessment can be used to select patients who might benefit from modifications of subsequent therapy, either by intensifying or abbreviating regimens and/or omitting radiotherapy with promising early results. Longer follow-up is required to assess whether this strategy impacts overall survival (OS). Herein, we review the results of recent trials using interim PET-CT-based adaptive design in the treatment of advanced HL.

  View details for DOI 10.1200/EDBK_159036

  View details for PubMedID 30372281

• Prognostic role of baseline 18F-FDG PET/CT in DLBCL patients Baratto, L., Wu, F., Minamimoto, R., Sabile, J., Advani, R., Mittra, E. SOC NUCLEAR MEDICINE INC. 2016

  View details for Web of Science ID 000442211002266

• The role of interim 18F-FDG PET/CT in DLBCL patients: SUV max, SUV mean and SUV peak as predictive metabolic parameters of prognosis Baratto, L., Wu, F., Minamimoto, R., Sabile, J., Advani, R., Mittra, E. SOC NUCLEAR MEDICINE INC. 2016

  View details for Web of Science ID 000442211002273

• Prognostic value of LUGANO, EORTC, PERCIST and IHP criteria in patients with diffuse large B cell lymphoma based on 18F-FDG PET/CT Wu, F., Baratto, L., Minamimoto, R., Advani, R., Sabile, J., Mittra, E. SOC NUCLEAR MEDICINE INC. 2016

  View details for Web of Science ID 000442211002429

• Speeding up PET/MR for cancer staging of children and young adults. European radiology Aghighi, M., Pisani, L. J., Sun, Z., Klenk, C., Madnawat, H., Fineman, S. L., Advani, R., von Eyben, R., Owen, D., Quon, A., Moseley, M., Daldrup-Link, H. E. 2016: -?

  Abstract

  Combining (18)F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared (18)F-FDG PET/STIR with accelerated (18)F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults.Thirty-three children and young adults (17.5 ± 5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a (18)F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. (18)F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively.Comparing (18)F-FDG PET/FSPGR to (18)F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001).F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to (18)F-FDG PET/STIR, but could be acquired with shorter acquisition time.• Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • (18) F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to (18) F-FDG PET/STIR.

  View details for PubMedID 27048532

• Breast Imaging in Women Previously Irradiated for Hodgkin Lymphoma. American journal of clinical oncology Horst, K. C., Fero, K. E., Hancock, S. L., Advani, R. H., Ikeda, D. M., Daniel, B., Rosenberg, S. A., Donaldson, S. S., Hoppe, R. T. 2016; 39 (2): 114-119

  Abstract

  Women treated with mantle irradiation for Hodgkin lymphoma (HL) are at an increased risk of developing breast cancer (BC). Current guidelines recommend screening breast magnetic resonance imaging (MRI) as an adjunct to mammography (M) in these patients. There are limited data, however, as to the impact of breast MRI on cancer detection rates. The aim of the current study is to evaluate the use of breast MRI in survivors of HL treated and followed at a single institution.We retrospectively reviewed 980 female patients treated with mantle irradiation for HL between 1961 and 2008. Records were reviewed to determine age at radiotherapy treatment, radiotherapy dose, breast imaging (including M and breast MRI), biopsy results if applicable, and incidence of BC.A total of 118 patients had breast imaging performed at our institution. Median age at HL diagnosis was 28 years (range, 10 to 69 y). Median radiotherapy dose was 36 Gy (range, 20 to 45 Gy). Seventy-nine patients (67%) underwent M screening only, 1 (1%) breast MRI only, and 38 (32%) both M and breast MRI. Of these 38, 19 (50%) underwent 54 screening MRI studies (range per patient=1 to 8), 13 (34%) underwent preoperative MRI for workup of BC, and 6 (16%) initiated screening MRI of the contralateral breast only after diagnosed with BC. Fifty-nine biopsies were performed: 47 were prompted by suspicious M findings only, 10 by palpable findings on physical examination (PE), and 2 by suspicious breast MRI findings. Of the 47 biopsies prompted by M, 24 revealed malignant disease, whereas 23 proved to be benign. All 10 biopsies performed by palpation were malignant. Both biopsies prompted by MRI findings were benign. With M, there were 34 true-positive findings in 32 patients, 23 false-positive findings, and 1 false-negative finding. With screening MRI, there were 2 false-positive findings, 1 false-negative finding, and no true-positive findings.The role of screening breast MRI in women previously irradiated for HL is evolving. Further education of patients and physicians is important to increase awareness of more sensitive BC screening modalities in this high-risk population. Future studies are necessary to determine the appropriate integration of screening breast MRI into the ongoing follow-up of these women.

  View details for DOI 10.1097/COC.0000000000000025

  View details for PubMedID 24390271

• Postibrutinib outcomes in patients with mantle cell lymphoma BLOOD Martin, P., Maddocks, K., Leonard, J. P., Ruan, J., Goy, A., Wagner-Johnston, N., Rule, S., Advani, R., Iberri, D., Phillips, T., Spurgeon, S., Kozin, E., Noto, K., Chen, Z., Jurczak, W., Auer, R., Chmielowska, E., Stilgenbauer, S., Bloehdorn, J., Portell, C., Williams, M. E., Dreyling, M., Barr, P. M., Chen-Kiang, S., DiLiberto, M., Furman, R. R., Blum, K. A. 2016; 127 (12): 1559-1563

  Abstract

  Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients that experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL that experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological, and radiological data, and therapies used pre and post ibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range 0-10). The MIPI scores at start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23%, respectively. Of patients with available data prior to ibrutinib and post-ibrutinib, 34/47 and 11/12 had a Ki67>30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% CI 1.6-4.9 months). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% C.I. 3.7 to 10.4 months). Multivariate Cox regression analysis of MIPI prior to post-ibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment following ibrutinib.

  View details for DOI 10.1182/blood-2015-10-673145

  View details for PubMedID 26764355

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy LEUKEMIA & LYMPHOMA Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for Web of Science ID 000372499800016

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy. Leukemia & lymphoma Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for PubMedID 26159046

• Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia BRITISH JOURNAL OF HAEMATOLOGY Xu, L., Hunter, Z. R., Tsakmaklis, N., Cao, Y., Yang, G., Chen, J., Liu, X., Kanan, S., Castillo, J. J., Tai, Y., Zehnder, J. L., Brown, J. R., Carrasco, R. D., Advani, R., Sabile, J. M., Argyropoulos, K., Palomba, M. L., Morra, E., Trojani, A., Greco, A., Tedeschi, A., Varettoni, M., Arcaini, L., Munshi, N. M., Anderson, K. C., Treon, S. P. 2016; 172 (5): 735-744

  Abstract

  CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

  View details for DOI 10.1111/bjh.13897

  View details for PubMedID 26659815

• Diffuse Large B-Cell Lymphoma Version 1.2016. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Lee Harris, N., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2016; 14 (2): 196-231

  Abstract

  Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

  View details for PubMedID 26850490

• Diffuse Large B-Cell Lymphoma Version 1.2016 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2016; 14 (2): 196-231

  Abstract

  Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

  View details for Web of Science ID 000369634300011

• Ibrutinib-associated rash: a single-centre experience of clinicopathological features and management. British journal of haematology 2016

  View details for PubMedID 27539794

• Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting Lynch, R. C., Advani, R. H. 2016; 35: e376-85

  Abstract

  Although patients with advanced-stage classic Hodgkin lymphoma have excellent outcomes with contemporary therapy, the outcomes of patients with refractory disease is suboptimal. Identification of these high-risk patients at diagnosis is challenging as the differences in outcomes using clinical criteria are less marked using current modern therapy. Data suggest that an interim PET-CT may be a powerful tool in risk-stratifying patients. Retrospective studies show that a negative interim PET-CT after two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is predictive of favorable outcome independent of IPS score. Currently, there are several ongoing trials that aim to determine whether early-response assessment can be used to select patients who might benefit from modifications of subsequent therapy, either by intensifying or abbreviating regimens and/or omitting radiotherapy with promising early results. Longer follow-up is required to assess whether this strategy impacts overall survival (OS). Herein, we review the results of recent trials using interim PET-CT-based adaptive design in the treatment of advanced HL.

  View details for DOI 10.14694/EDBK_159036

  View details for PubMedID 27249744

• The Clonal Architecture of CXCR4mutations in Waldenstrom's Macroglobulinemia Shows Highly Variable Subclonal Distribution, and Multiple Mutations within Individual Patients Indicative of Targeted Genomic Instability Xu, L., Hunter, Z., Tsakmaklis, N., Cao, Y., Yang, G., Chen, J., Liu, X., Kanan, S., Castillo, J. J., Tai, Y., Zehnder, J. L., Brown, J. R., Carrasco, R. D., Advani, R. H., Argyropoulos, K. V., Palomba, M., Morra, E., Trojani, A., Greco, A., Tedeschi, A., Varettoni, M., Arcaini, L., Munshi, N. C., Anderson, K. C., Treon, S. P. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019004286

• PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome Roemer, M. M., Advani, R. H., Ligon, A. H., Natkunam, Y., Redd, R. A., Homer, H., Connelly, C., Sun, H. H., Daadi, S. E., Chapuy, B., de Jong, D., Hoppe, R. T., Neuberg, D. S., Rodig, S. J., Shipp, M. A. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019000240

• Ibrutinib-Associated Rash: Single-Center Experience of Clinicopathologic Features and Management Iberri, D. J., Kwong, B., Stevens, L., Coutre, S. E., Kim, J., Sabile, J., Advani, R. H. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368021803163

• Outcomes in Adolescents and Young Adults (AYA) with Hodgkin Lymphoma (HL) Treated on US Cooperative Group Protocols: An Adult Intergroup (E2496) and Children's Oncology Group (COG AHOD0031) Comparative Analysis Henderson, T. O., Parsons, S. K., Wroblewski, K., Chen, L., Hong, F., Smith, S. M., McNeer, J., Advani, R., Cascoynee, R. D., Constine, L., Horning, S. J., Bartlett, N. L., Shah, B. D., Connors, J. M., Leonard, J. P., Kahl, B. S., Kelly, K. M., Schwartz, C., Friedman, D. L., Gordon, L. I., Evens, A. M. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368020102148

• Initial Therapy for Mantle Cell Lymphoma with Abbreviated R-CHOP Followed By Y-90-Ibritumomab Tiuxetan: Ten Year Follow-up of the Phase 2 ECOG-ACRIN Study E1499 Smith, M. R., Li, H., Hong, F., Gordon, L. I., Gascoyne, R. D., Paietta, E., Advani, R. H., Forrero-Torres, A., Horning, S. J., Kahl, B. S. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368020102214

• Long-Term Follow-up and Analysis of Dose Groups with Ibrutinib in Relapsed Follicular Lymphoma Fowler, N., Boyd, T. E., Sharman, J. P., Smith, S. M., Clow, F., Chu, A. D., Advani, R. H. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368020102218

• A Phase 1 Study of the Anti-CD37 Antibody-Drug Conjugate AGS67E in Advanced Lymphoid Malignancies. Interim Results Sawas, A., Savage, K. J., Perez, R., Advani, R. H., Butturini, A., Lackey, J., Trave, F., Anand, B., Huang, Y., Reyno, L., O'Connor, O. A. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368021800233

• Brentuximab Vedotin Plus Bendamustine: A Highly Active Salvage Treatment Regimen for Patients with Relapsed or Refractory Hodgkin Lymphoma LaCasce, A. S., Bociek, G., Sawas, A., Caimi, P. F., Agura, E., Matous, J., Ansell, S., Crosswell, H., Islas-Ohlmayer, M., Behler, C., Cheung, E., Forero-Torres, A., Vose, J., O'Connor, O. A., Josephson, N., Advani, R. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368021800239

• A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refactory B-Lineage Non-Hodgkin Lymphoma Moskowitz, C. H., Fanale, M. A., Shah, B. D., Advani, R. H., Chen, R., Kim, S., Kostic, A., Liu, T., Peng, J., Forero-Torres, A. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019000246

• Ibrutinib Plus Rituximab in Treatment-Naive Patients with Follicular Lymphoma: Results from a Multicenter, Phase 2 Study Fowler, N., Nastoupil, L., de Vos, S., Knapp, M., Flinn, I. W., Chen, R., Advani, R. H., Bhatia, S., Martin, P., Mena, R., Suzuki, S., Beaupre, D. M., Neuenburg, J. K., Palomba, M. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019001216

• Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412) Diefenbach, C. S., Hong, F., Cohen, J. B., Robertson, M. J., Ambinder, R. F., Fenske, T. S., Advani, R. H., Kahl, B. S., Ansell, S. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019002022

• Brentuximab Vedotin with RCHOP As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL): Results from an Ongoing Phase 2 Study Yasenchak, C. A., Halwani, A., Advani, R., Ansell, S., Budde, L., Burke, J. M., Farber, C. M., Holkova, B., Fayad, L. E., Kolibaba, K. S., Knapp, M., Li, M., Manley, T. J., Patel-Donnelly, D., Seetharam, M., Yimer, H. A., Bartlett, N. L. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019002251

• Phase II Study of Rituximab Given in Conjunction with Standard Chemotherapy in Primary Central Nervous System Lymphoma (PCNSL)[E1F05] Swinnen, L. J., O'Neill, A., Imus, P. H., Gujar, S., Schiff, D., Kleinberg, L., Advani, R., Dunbar, E., Moore, D. F., Grossman, S. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019005008

• Frontline Treatment of CD30+Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up Horwitz, S. M., Shustov, A. R., Forero-Torres, A., Bartlett, N. L., Advani, R., Pro, B., Chen, R., Davies, A. J., Illidge, T., Huebner, D., Kennedy, D. A., Fanale, M. A. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019005015

• Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia Thomas, S. K., Harb, W. A., Beck, J., Nashat, G., Palomba, M., Ansell, S. M., Eradat, H., Libby, E. N., Advani, R. H., Hajdenberg, J., Heffner, L. T., Hoffman, J., Vesole, D. H., Simov, L., Wyant, N., Brevard, J., O'Leary, J., Agrawal, S. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019005018

• Phase I/II Clinical Trial of CpG-Activated Whole Cell Vaccine in Mantle Cell Lymphoma (MCL): Results in Safety and Efficacy from Planned Interim Analysis Chu, M. P., Brody, J., Kohrt, H. E., Frank, M. J., Khodadoust, M., Reddy, S., Advani, R. H., Gupta, N. K., Laport, G., Maeda, L. S., Meyer, E., Miklos, D. B., Negrin, R., Rezvani, A. R., Weng, W., Sheehan, K., Faham, M., Czerwinski, D. K., Okada, A., Levy, R. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019005014

• ACR Appropriateness Criteria® Diffuse Large B-Cell Lymphoma. American journal of clinical oncology Dabaja, B. S., Advani, R., Hodgson, D. C., Dhakal, S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S. M., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2015; 38 (6): 610-620

  Abstract

  The management of diffuse large B-cell lymphoma depends on the initial diagnosis including molecular and immunophenotypic characteristics, Ann Arbor staging, and International Prognostic Index (IPI score). Treatment approaches with different chemotherapy regimens used is discussed in detail. The role of radiation as a consolidation is discussed including: (1) the prerituximab randomized trials that challenged the role of radiation, (2) recent prospective studies (UNFOLDER/RICOVER-60), and (3) retrospective studies; the last 2 showed a potential benefit of radiation both for early and advanced stage. The document also discusses the role of positron emission tomography/computed tomography for predicting outcome and potentially guiding therapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1097/COC.0000000000000215

  View details for PubMedID 26583344

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  Abstract

  In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Long-term safety and efficacy of single-agent lbrutinib in patients with relapsed or refractory mantle cell lymphoma: Updated results of an international, multicenter, open-label phase 2 study Dreyling, M., Wang, M. L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Zhang, L., Baher, L., Cheng, M., Beaupre, D. M., Blum, K. A. KARGER. 2015: 18–19

  View details for Web of Science ID 000364268800038

• Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease-the Role of Functional Imaging. Current treatment options in oncology Iberri, D. J., Hoppe, R. T., Advani, R. H. 2015; 16 (9): 360-?

  View details for DOI 10.1007/s11864-015-0360-6

  View details for PubMedID 26187795

• Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-cell malignancies. Poggesi, I., Sardu, M., Marostica, E., Sukbuntherng, J., Chang, B. Y., de Jong, J., de Trixhe, X., Vermeulen, A., De Nicolao, G., O'Brien, S., Byrd, J. C., Advani, R. H., James, D., Deraedt, W., Beaupre, D., Wang, M. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1557-3265.HEMMAL14-B19

  View details for Web of Science ID 000361386200055

• Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: Characteristics, outcomes, and prognostication among a large multicenter cohort AMERICAN JOURNAL OF HEMATOLOGY Evens, A. M., Kanakry, J. A., Sehn, L. H., Kritharis, A., Feldman, T., Kroll, A., Gascoyne, R. D., Abramson, J. S., Petrich, A. M., Hernandez-Ilizaliturri, F. J., Al-Mansour, Z., Adeimy, C., Hemminger, J., Bartlett, N. L., Mato, A., Caimi, P. F., Advani, R. H., Klein, A. K., Nabhan, C., Smith, S. M., Fabregas, J. C., Lossos, I. S., Press, O. W., Fenske, T. S., Friedberg, J. W., Vose, J. M., Blum, K. A. 2015; 90 (9): 778-783

  Abstract

  Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone-rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/-R had markedly inferior 2-year PFS (22% versus 52%, P = 0.03) compared with DLBCL-directed therapy (CHOP+/-R and DA-EPOCH-R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03-3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18-0.69; P = 0.002). Collectively, GZL is a heterogeneous and likely more common entity and often with nonmediastinal presentation, whereas outcomes seem superior when treated with a rituximab-based, DLBCL-specific regimen. Am. J. Hematol. 90:778-783, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajh.24082

  View details for Web of Science ID 000360218000019

• Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20(+) lymphoid malignancies BRITISH JOURNAL OF HAEMATOLOGY Roberts, A. W., Advani, R. H., Kahl, B. S., Persky, D., Sweetenham, J. W., Carney, D. A., Yang, J., Busman, T. B., Enschede, S. H., Humerickhouse, R. A., Seymour, J. F. 2015; 170 (5): 669-678

  Abstract

  The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19(+) counts were severely reduced, while CD3(+) cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.

  View details for DOI 10.1111/bjh.13487

  View details for PubMedID 25942994

• Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. American journal of hematology Evens, A. M., Kanakry, J. A., Sehn, L. H., Kritharis, A., Feldman, T., Kroll, A., Gascoyne, R. D., Abramson, J. S., Petrich, A. M., Hernandez-Ilizaliturri, F. J., Al-Mansour, Z., Adeimy, C., Hemminger, J., Bartlett, N. L., Mato, A., Caimi, P. F., Advani, R. H., Klein, A. K., Nabhan, C., Smith, S. M., Fabregas, J. C., Lossos, I. S., Press, O. W., Fenske, T. S., Friedberg, J. W., Vose, J. M., Blum, K. A. 2015; 90 (9): 778-783

  Abstract

  Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone-rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/-R had markedly inferior 2-year PFS (22% versus 52%, P = 0.03) compared with DLBCL-directed therapy (CHOP+/-R and DA-EPOCH-R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03-3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18-0.69; P = 0.002). Collectively, GZL is a heterogeneous and likely more common entity and often with nonmediastinal presentation, whereas outcomes seem superior when treated with a rituximab-based, DLBCL-specific regimen. Am. J. Hematol. 90:778-783, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajh.24082

  View details for PubMedID 26044261

• A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402 BRITISH JOURNAL OF HAEMATOLOGY Witzig, T. E., Hong, F., Micallef, I. N., Gascoyne, R. D., Dogan, A., Wagner, H., Kahl, B. S., Advani, R. H., Horning, S. J. 2015; 170 (5): 679-686

  Abstract

  Patients with early stage diffuse large B-cell lymphoma (DLBCL) receive RCHOP (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) alone or with involved field radiotherapy (IFRT). Anti-CD20 radioimmunotherapy (RIT) delivers radiation to microscopic sites outside of known disease. This phase II study aimed to achieve a functional complete response (CR) rate of ≥75% to RCHOP and (90) Yttrium-ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4-6 cycles of RCHOP followed by RIT [14·8 MBq/kg (0·4 mCi/kg)]; patients with positron emission tomographypositive sites of disease after RCHOP/RIT received 30 Gy IFRT. Of the 62 patients enrolled; 53 were eligible. 42% (22/53) had stage I/IE; 58% (31/53) stage II/IIE. After RCHOP, 79% (42/53) were in CR/unconfirmed CR. Forty-eight patients proceeded to RIT. One partial responder after RIT received IFRT and achieved a CR. The best response after RCHOP + RIT in all 53 patients was a functional CR rate of 89% (47/53; 95% confidence interval: 77-96%). With a median follow-up of 5·9 years, 7 (13%) patients have progressed and 4 (8%) have died (2 with DLBCL). At 5 years, 78% of patients remain in remission and 94% are alive. Chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients. Eighty-nine percent of patients achieved functional CR without the requirement of IFRT. This regimen is worthy of further study for early stage DLBCL in a phase III trial.

  View details for DOI 10.1111/bjh.13493

  View details for PubMedID 25974212

• Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results BLOOD Wang, M. L., Blum, K. A., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreyling, M., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Zhang, L., Baher, L., Cheng, M., Lee, D., Beaupre, D. M., Rule, S. 2015; 126 (6): 739-745

  Abstract

  Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.

  View details for DOI 10.1182/blood-2015-03-635326

  View details for Web of Science ID 000360519600009

  View details for PubMedCentralID PMC4528064

• Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood Wang, M. L., Blum, K. A., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreyling, M., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Zhang, L., Baher, L., Cheng, M., Lee, D., Beaupre, D. M., Rule, S. 2015; 126 (6): 739-45

  Abstract

  Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.

  View details for DOI 10.1182/blood-2015-03-635326

  View details for PubMedID 26059948

  View details for PubMedCentralID PMC4528064

• Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma NATURE MEDICINE Wilson, W. H., Young, R. M., Schmitz, R., Yang, Y., Pittaluga, S., Wright, G., Lih, C., Williams, P. M., Shaffer, A. L., Gerecitano, J., de Vos, S., Goy, A., Kenkre, V. P., Barr, P. M., Blum, K. A., Shustov, A., Advani, R., Fowler, N. H., Vose, J. M., Elstrom, R. L., Habermann, T. M., Barrientos, J. C., McGreivy, J., Fardis, M., Chang, B. Y., Clow, F., Munneke, B., Moussa, D., Beaupre, D. M., Staudt, L. M. 2015; 21 (8): 922-926

  Abstract

  The two major subtypes of diffuse large B cell lymphoma (DLBCL)-activated B cell-like (ABC) and germinal center B cell-like (GCB)-arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.

  View details for DOI 10.1038/nm.3884

  View details for PubMedID 26193343

• In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs MAYO CLINIC PROCEEDINGS Tefferi, A., Rajkumar, S., Gertz, M. A., Kyle, R. A., Kantarjian, H., Allison, J., Bast, R. C., Cortes, J., Fidler, I. J., Freireich, E., Gutterman, J., Hong, W., Hortobagyi, G. N., Mendelsohn, J., Strong, L. C., Ueno, N. T., LeMaistre, C. A., Baker, L. H., Lawrence, T. S., Abkowitz, J. L., Deeg, H., Estey, E., Lyman, G. H., Adamson, J. W., Advani, R., Coutre, S., Greenberg, P., Link, M. P., Rosenberg, S. A., Antman, K. H., Bennett, J. M., Benz, E. J., Canellos, G., Daley, G. Q., DeAngelo, D. J., Fuchs, C., Handin, R. I., Kantoff, P. W., Steensma, D. P., Stone, R., Winer, E. P., Berliner, N., Handin, R. I., Bertino, J., Bhatia, R., Bhatia, S., Erba, H. P., Bhojwani, D., Blanke, C. D., Bloomfield, C. D., Byrd, J. C., Pollock, R., Bosserman, L., Forman, S., Broxmeyer, H. E., Einhorn, L. H., Cabanillas, F., Chabner, B. A., Colon-Otero, G., Chanan-Khan, A., Foran, J., Cheson, B., Clarkson, B., Giralt, S., Hudis, C., Levine, R., Tallman, M. S., Younes, A., Zelenetz, A. D., Cohn, S. L., Golomb, H., Hellman, S., Larson, R. A., Stock, W., Cristofanilli, M., Curran, W. J., Khuri, F. R., Lonial, S., Daley, G. Q., Deeg, H., Lyman, G. H., Press, O., Radich, J., Sandmaier, B. M., Stone, R., Esteva, F. J., George, J. N., Hoff, P., Hoffman, R., Horowitz, M., Issa, J., Johnson, B., Kaushansky, K., Khayat, D., Kipps, T. J., Lippman, S. M., Kripke, M., Markman, M., Neropol, N. J., Messinger, Y., Mulvey, T. M., O'Brien, S., Van Etten, R. A., Perez-Soler, R., Prchal, J., Rai, K., Rowe, J. M., Rugo, H., Runowicz, C. D., Saven, A., Silver, R. T., Schafer, A. I., Schiffer, C., Sekeres, M. A., Siu, L. L., Stewart, F., Thompson, M., Vose, J. M., Wiernik, P. H. 2015; 90 (8): 996–1000

  View details for DOI 10.1016/j.mayocp.2015.06.001

  View details for Web of Science ID 000359138000005

  View details for PubMedID 26211600

  View details for PubMedCentralID PMC5365030

• Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia Pfeifer, M., Zheng, B., Erdmann, T., Koeppen, H., McCord, R., Grau, M., STAIGER, A., Chai, A., Sandmann, T., MADLE, H., Dörken, B., Chu, Y., Chen, A. I., LEBOVIC, D., Salles, G. A., Czuczman, M. S., Palanca-Wessels, M. C., Press, O. W., Advani, R., Morschhauser, F., Cheson, B. D., Lenz, P., Ott, G., Polson, A. G., Mundt, K. E., Lenz, G. 2015; 29 (7): 1578-1586

  Abstract

  Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.

  View details for DOI 10.1038/leu.2015.48

  View details for PubMedID 25708834

• Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes LEUKEMIA Pfeifer, M., Zheng, B., Erdmann, T., Koeppen, H., McCord, R., Grau, M., STAIGER, A., Chai, A., Sandmann, T., MADLE, H., Doerken, B., Chu, Y., Chen, A. I., LEBOVIC, D., Salles, G. A., Czuczman, M. S., Palanca-Wessels, M. C., Press, O. W., Advani, R., Morschhauser, F., Cheson, B. D., Lenz, P., Ott, G., Polson, A. G., Mundt, K. E., Lenz, G. 2015; 29 (7): 1578-1586

  Abstract

  Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.

  View details for DOI 10.1038/leu.2015.48

  View details for Web of Science ID 000357623100018

• Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood Kurtz, D. M., Green, M. R., Bratman, S. V., Scherer, F., Liu, C. L., Kunder, C. A., Takahashi, K., Glover, C., Keane, C., Kihira, S., Visser, B., Callahan, J., Kong, K. A., Faham, M., Corbelli, K. S., Miklos, D., Advani, R. H., Levy, R., Hicks, R. J., Hertzberg, M., Ohgami, R. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. 2015; 125 (24): 3679-3687

  Abstract

  Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.

  View details for DOI 10.1182/blood-2015-03-635169

  View details for PubMedID 25887775

• Management of nodular lymphocyte predominant Hodgkin lymphoma HEMATOLOGICAL ONCOLOGY Advani, R. H., Hoppe, R. T. 2015; 33: 90-95

  View details for DOI 10.1002/hon.2226

  View details for Web of Science ID 000356094300017

  View details for PubMedID 26062064

• INTERNATIONAL EXTRANODAL NK/T-CELL LYMPHOMA PROJECT: PROGNOSTIC FACTORS IN THE ERA OF NONANTHRACYCLINE-BASED TREATMENT Kim, S. J., Park, Y., Chang, M. H., Oh, S. Y., Kwak, J. Y., Yang, D. H., Kim, J. S., Eom, H. S., Won, J. H., Won, Y. W., Do, Y. R., Mun, Y. C., Suh, C., Lee, S. I., Jo, J. C., Lee, S. R., Shin, D. Y., Shin, H. J., Sohn, B. S., d'Amore, F., Chang, K. M., Chng, W. J., Tan, D., Lim, S. T., Chuang, S. S., Chen, T. Y., Relander, T., Jaccard, A., Koji, I., Maeda, Y., Murayama, T., Suzuki, R., Schmitz, N., Kwong, Y. L., Ishida, F., Uike, N., Yasuhiro, O., Advani, R., Kim, K., Jung, S. H., Kim, W. S. FERRATA STORTI FOUNDATION. 2015: 5

  View details for Web of Science ID 000361204901010

• IBRUTINIB IN PREVIOUSLY TREATED PATIENTS WITH WALDENSTROM'S MACROGLOBULINEMIA IS HIGHLY ACTIVE, PRODUCES DURABLE RESPONSES, AND IS IMPACTED BY MYD88 AND CXCR4 MUTATION STATUS Treon, S., Tripsas, C., Meid, K., Warren, D., Varma, G., Green, R., Argyropoulos, K., Yang, G., Cao, Y., Xu, L., Patterson, C., Rodig, S., Zehnder, J., Aster, J., Harris, N. L., Kanan, S., Ghobrial, I., Laubach, J., Hunter, Z., Salman, Z., Cheng, M., Li, J., Clow, F., Graef, T., Castillo, J., Palomba, M. L., Advani, R. FERRATA STORTI FOUNDATION. 2015: 311

  View details for Web of Science ID 000361204902289

• TWO DOSES OF POLATUZUMAB VEDOTIN (POV, ANTI-CD79B ANTI-BODY-DRUG CONJUGATE) PLUS RITUXIMAB (R) IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) FOLLICULAR LYMPHOMA (FL): DURABLE RESPONSES AT LOWER DOSE LEVEL Sharman, J., Flinn, I., Advani, R., Diefenbach, C., Kolibaba, K., Press, O., Sehn, L., Chen, A., Salles, G., Tilly, H., Cheson, B., Assouline, S., Dreyling, M., Hagenbeek, A., Zinzani, P. L., Jones, C., Jones, S., Chu, W., Hirata, J., Wenger, M., Morschhauser, F. FERRATA STORTI FOUNDATION. 2015: 272

  View details for Web of Science ID 000361204902192

• Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study LANCET ONCOLOGY Palanca-Wessels, M. C., Czuczman, M., Salles, G., Assouline, S., Sehn, L. H., Flinn, I., Patel, M. R., Sangha, R., Hagenbeek, A., Advani, R., Tilly, H., Casasnovas, O., Press, O. W., Yalamanchili, S., Kahn, R., Dere, R. C., Lu, D., Jones, S., Jones, C., Chu, Y., Morschhauser, F. 2015; 16 (6): 704-715

  Abstract

  Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL).In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549.Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL.Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL.Genentech.

  View details for DOI 10.1016/S1470-2045(15)70128-2

  View details for Web of Science ID 000355246600055

  View details for PubMedID 25925619

• First-in-human study assessing safety and tolerability of REGN1979, a novel CD20xCD3 bispecific antibody, in patients with CD20+B-cell malignancies previously treated with anti-CD20 therapy. Brownstein, C. M., Adriaens, L., Bannerji, R., Chavez, J. C., Levy, R., Ansell, S., Advani, R. H., Patel, S., Kostic, A., Trail, P., Lowy, I., Kohrt, H. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036904705

• Phase I/II study of intratumoral injection of SD-101, an immunostimulatory CpG, and intratumoral injection of ipillumumab, an anti-CTLA-4 monoclonal antibody, in combination with local radiation in low-grade B-cell lymphomas. Khodadoust, M., Chu, M., Czerwinski, D., McDonald, K., Long, S., Kohrt, H., Hoppe, R. T., Advani, R. H., Lowsky, R., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036904866

• Updated results of a phase II trial of brentuximab vedotin combined with R-CHOP in frontline treatment of patients (pts) with high-intermediate/high-risk diffuse large B-cell lymphoma (DLBCL). Bartlett, N. L., Farber, C. M., Yasenchak, C. A., Ansell, S., Advani, R. H., Knapp, M. H., Fayad, L., Kolibaba, K. S., Patel-Donnelly, D., Seetharam, M., Yimer, H., Manley, T., Burke, J. M., Holkova, B., Budde, L., Halwani, A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901819

• Two doses of polatuzumab vedotin (PoV, anti-CD79b antibody-drug conjugate) in patients (pts) with relapsed/refractory (RR) follicular lymphoma (FL): Durable responses at lower dose level. Advani, R. H., Flinn, I., Sharman, J., Diefenbach, C., Kolibaba, K. S., Press, O. W., Sehn, L., Chen, A. I., Salles, G. A., Tilly, H., Cheson, B. D., Assouline, S. E., Dreyling, M. H., Hagenbeek, A., Zinzani, P., Jones, C., Chu, Y., Hirata, J., Wenger, M., Morschhauser, F. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901816

• CD30+expression in Peripheral T-cell lymphomas (PTCLs): A subset analysis from the international, prospective T-Cell Project Federico, M., Bellei, M., Luminari, S., Horwitz, S. M., Montoto, S., Zucca, E., Pileri, S. A., Ko, Y., Zinzani, P., Connors, J. M., Foss, F. M., Polliack, A., Cabrera, M., Kim, W., Spina, M., De Souza, C., Varela, S., Dlouhy, I., Advani, R. H., Vose, J., T-Cell Project AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901864

• A phase I study with an expansion cohort of the combination of ipilimumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: A trial of the ECOG-ACRIN Cancer Research Group (E4412). Diefenbach, C., Li, H., Kahl, B. S., Robertson, M. J., Cohen, J., Advani, R. H., Ambinder, R., Fenske, T. S., Ansell, S. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036904864

• Pre-treatment circulating tumor DNA as a biomarker for disease burden in diffuse large B cell lymphoma (DLBCL) Scherer, F., Kurtz, D., Green, M., Newman, A. M., Klass, D. M., Zhou, L., Krishnan, R., Liu, C., Glover, C., Ohgami, R. S., Hicks, R. J., Keane, C., Kong, K. A., Faham, M., Hertzberg, M. S., Gandhi, M. K., Advani, R. H., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901851

• Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era. International journal of radiation oncology, biology, physics Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Xu, G., Quon, A., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 99-106

  Abstract

  The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL.A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013.One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/- rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse.A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as posttreatment surveillance is not associated with a survival advantage. LDH is not a sensitive marker for relapse. Our results argue for limiting the use of posttreatment surveillance in patients with limited-stage DLBCL.

  View details for DOI 10.1016/j.ijrobp.2015.01.039

  View details for PubMedID 25863757

• Prospective multicenter comparison of early interim F-18-FLT PET/CT versus F-18-FDG PET/CT Minamimoto, R., Fayad, L., Advani, R., Vose, J., Macapinlac, H., Meza, J., Hankins, J., Mottaghy, F., Juweid, M., Quon, A. SOC NUCLEAR MEDICINE INC. 2015

  View details for Web of Science ID 000358738802324

• IBRUTINIB FOR THE TREATMENT OF MANTLE CELL LYMPHOMA (MCL): EVALUATING THE CORRELATION BETWEEN PATIENT-REPORTED OUTCOMES AND DURABILITY OF RESPONSE IN A PHASE 2 STUDY Rule, S., Goy, A., Martin, P., Ramchandren, R., Alexeeva, J., Popat, R., Avivi, Advani, R., Le Gouill, S., Horowitz, N., Yuan, Z., Kranenburg, B., Zhuang, S. H., Deraedt, W., Rizo, A., Wildgust, M., Wang, M. ELSEVIER SCIENCE INC. 2015: A300–A301

  View details for DOI 10.1016/j.jval.2015.03.1750

  View details for Web of Science ID 000354498505103

• Hodgkin Lymphoma, Version 2.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Benitez, C. M., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Khan, N., Maloney, D. G., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Poppe, M., Rabinovitch, R., Seropian, S., Tsien, C., Winter, J. N., Yahalom, J., Burns, J. L., Sundar, H. 2015; 13 (5): 554-586

  Abstract

  Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment.

  View details for Web of Science ID 000354283800008

  View details for PubMedID 25964641

  View details for PubMedCentralID PMC4898052

• Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma in the Modern Era INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS King, M. T., Donaldson, S. S., Link, M. P., Natkunam, Y., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 67-75

  Abstract

  To analyze treatment outcomes for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) at a single institution.Patients with newly diagnosed NLPHL between 1996 and 2013 were reviewed retrospectively. Patients treated before 1996 were excluded because the majority received extended field radiation therapy (RT) alone.Fifty-five patients (22 ≤ 21 years old) were identified. The median follow-up time was 6.8 years. Among 37 patients with limited-stage (I-II) disease, treatments included involved field RT at a median dose of 36 Gy (n=9), rituximab monotherapy (n=9), observation (n=3), and response-adaptive therapy (n=16), in which the RT dose was reduced from 25.5 Gy to 15 Gy or was eliminated based on interim imaging after chemotherapy. The 5-year progression-free survival (PFS) was 76.4% (95% confidence interval [CI], 63.1-92.4). Nine patients experienced progression, including 5 receiving rituximab, 2 undergoing observation, and 2 receiving response-adaptive therapy. Rituximab was associated with an inferior PFS compared with RT alone (P=.02). The difference in PFS between response-adaptive therapy and RT alone was not statistically significant (P=.39). Among 18 patients with advanced-stage (III-IV) disease, treatments included chemotherapy alone (n=3), combined modality therapy (CMT) (n=2), response-adaptive therapy (n=2), rituximab (n=7), and observation (n=4). The 5-year PFS was 29.9% (CI, 13.3-67.4). Twelve patients experienced progression, including 1 receiving chemotherapy, 1 receiving CMT, 6 receiving rituximab, and 4 undergoing observation. There was no significant PFS difference between rituximab and non-rituximab therapies (P=.19) within the caveat of small sample sizes. In the entire cohort, 9 patients (3 with limited disease, 6 with advanced disease) experienced large cell transformation (LCT). Seven patients died; of those, 5 died with LCT.For limited disease, response-adaptive therapy demonstrated comparable outcomes with RT alone. Rituximab monotherapy resulted in inferior outcomes for limited disease and a high relapse rate for advanced disease.

  View details for DOI 10.1016/j.ijrobp.2015.02.001

  View details for Web of Science ID 000353988200011

  View details for PubMedID 25863755

• Single-agent ibrutinib for the treatment of mantle cell lymphoma (MCL): evaluating the link between durable response and quality of life (QoL) in the SPARK study Rule, S., Goy, A., Martin, P., Ramchandren, R., Alexeeva, J., Popat, R., Avivi, I., Advani, R., Le Gouill, S., Horowitz, N., Yuan, Z., Kranenburg, B., Zhuang, S. H., Deraedt, W., Rizo, A., Wildgust, W., Wang, M. WILEY-BLACKWELL. 2015: 59

  View details for Web of Science ID 000353231200142

• A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma BRITISH JOURNAL OF HAEMATOLOGY Foss, F., Advani, R., Duvic, M., Hymes, K. B., Intragumtornchai, T., Lekhakula, A., Shpilberg, O., Lerner, A., Belt, R. J., Jacobsen, E. D., Laurent, G., Ben-Yehuda, D., Beylot-Barry, M., Hillen, U., Knoblauch, P., Bhat, G., Chawla, S., Allen, L. F., Pohlman, B. 2015; 168 (6): 811-819

  Abstract

  Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m(2) intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1-9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0-4) and four prior systemic therapies (range 1-9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.

  View details for DOI 10.1111/bjh.13222

  View details for Web of Science ID 000351043400005

  View details for PubMedID 25404094

• Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Saad, A. A., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Wilson, L., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2015; 13 (3): 326-362

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

  View details for PubMedID 25736010

• Anxiety and Health-Related Quality of Life Among Patients With Low-Tumor Burden Non-Hodgkin Lymphoma Randomly Assigned to Two Different Rituximab Dosing Regimens: Results From ECOG Trial E4402 (RESORT) JOURNAL OF CLINICAL ONCOLOGY Wagner, L. I., Zhao, F., Hong, F., Williams, M. E., Gascoyne, R. D., Krauss, J. C., Advani, R. H., Go, R. S., Habermann, T. M., Leach, J. W., O'Connor, B., Schuster, S. J., Cella, D., Horning, S. J., Kahl, B. S. 2015; 33 (7)

  Abstract

  The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style.Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style.Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment.Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL.

  View details for DOI 10.1200/JCO.2014.57.6801

  View details for Web of Science ID 000352524200014

  View details for PubMedID 25605841

  View details for PubMedCentralID PMC4334777

• Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT). Journal of clinical oncology Wagner, L. I., Zhao, F., Hong, F., Williams, M. E., Gascoyne, R. D., Krauss, J. C., Advani, R. H., Go, R. S., Habermann, T. M., Leach, J. W., O'Connor, B., Schuster, S. J., Cella, D., Horning, S. J., Kahl, B. S. 2015; 33 (7): 740-748

  Abstract

  The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style.Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style.Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment.Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL.

  View details for DOI 10.1200/JCO.2014.57.6801

  View details for PubMedID 25605841

• Allogeneic transplant following brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma LEUKEMIA & LYMPHOMA Illidge, T., Bouabdallah, R., Chen, R., Gopal, A. K., Moskowitz, C. H., Ramchandren, R., Shustov, A. R., Tilly, H., Trippett, T. M., Gibb, A., Grove, L. E., Advani, R. 2015; 56 (3): 703-710

  Abstract

  Brentuximab vedotin is an antibody drug conjugate that induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Fifteen of 160 patients who participated in two pivotal phase 2 studies received a consolidative allogeneic stem cell transplant (allo-SCT) following brentuximab vedotin treatment. This case series describes their experience. The studies were approved by Institutional Review Boards prior to patient enrollment. Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks for up to 16 cycles. The estimated 2-year progression-free survival (PFS) rate was 66%, and the median PFS has not yet been reached. Eleven of the 15 patients were alive and the estimated 2-year survival rate was 80%. The safety of brentuximab vedotin treatment in this series was consistent with the known safety profile in this setting. Brentuximab vedotin is a compelling option for reducing tumor burden to facilitate a consolidative allo-SCT.

  View details for DOI 10.3109/10428194.2014.930852

  View details for Web of Science ID 000351144500025

  View details for PubMedID 24913507

• Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Saad, A. A., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Wilson, L., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2015; 13 (3): 326-362

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

  View details for PubMedID 25736010

• Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression BLOOD Jacobsen, E. D., Sharman, J. P., Oki, Y., Advani, R. H., Winter, J. N., Bello, C. M., Spitzer, G., Palanca-Wessels, M. C., Kennedy, D. A., Levine, P., Yang, J., Bartlett, N. L. 2015; 125 (9): 1394-1402

  Abstract

  Several non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), variably express CD30. This phase 2, open-label study evaluated the efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30(+) NHL. This planned subset analysis of B-cell NHLs includes 49 patients with DLBCL and 19 with other B-cell NHLs. Objective response rate was 44% for DLBCL, including 8 (17%) complete remissions (CRs) with a median duration of 16.6 months thus far (range, 2.7 to 22.7+ months). There was no statistical correlation between response and level of CD30 expression; however, all responding patients had quantifiable CD30 by computer-assisted assessment of immunohistochemistry. DLBCL patients were generally refractory to first-line (76%) and most recent therapies (82%), and 44% of these refractory patients responded (15% CRs). Patients with other B-cell lymphomas also responded: 1 CR, 2 partial responses (PRs) of 6 with gray zone, 1 CR of 6 with primary mediastinal B-cell, and 1 CR of 3 with posttransplant lymphoproliferative disorder. Adverse events were consistent with known toxicities. The combination of brentuximab vedotin with rituximab was generally well tolerated and had activity similar to brentuximab vedotin alone. Overall, significant activity with brentuximab vedotin was observed in relapsed/refractory DLBCL, and responses occurred across a range of CD30 expression. This study was registered at www.clinicaltrials.gov as #NCT01421667.

  View details for DOI 10.1182/blood-2014-09-598763

  View details for PubMedID 25573987

• Improved outcomes after autologous bone marrow transplantation for children with relapsed or refractory hodgkin lymphoma: twenty years experience at a single institution. Biology of blood and marrow transplantation Garfin, P. M., Link, M. P., Donaldson, S. S., Advani, R. H., Luna-Fineman, S., Kharbanda, S., Porteus, M., Weinberg, K. I., Agarwal-Hashmi, R. 2015; 21 (2): 326-334

  Abstract

  The purpose of this study is to evaluate the survival of pediatric patients undergoing autologous bone marrow transplantation (auBMT) for relapsed or refractory Hodgkin lymphoma (rrHL) and to identify factors that might contribute to their outcome. We reviewed the records and clinical course of 89 consecutive rrHL patients ≤ 21 years old who underwent auBMT at Stanford Hospitals and Clinics and the Lucile Packard Children's Hospital, Stanford between 1989 and 2012. We investigated, by multiple analyses, patient, disease, and treatment characteristics associated with outcome. Endpoints were 5-year overall and event-free survival. Our findings include that cyclophosphamide, carmustine, and etoposide (CBV) as a conditioning regimen for auBMT is effective for most patients ≤ 21 years old with rrHL (5-year overall survival, 71%). Transplantation after the year 2001 was associated with significantly improved overall survival compared with our earlier experience (80% compared with 65%). Patients with multiply relapsed disease or with disease not responsive to initial therapy fared less well compared with those with response to initial therapy or after first relapse. Administration of post-auBMT consolidative radiotherapy (cRT) also appears to contribute to improved survival. We are able to conclude that high-dose chemotherapy with CBV followed by auBMT is effective for the treatment of rrHL in children and adolescents. Survival for patients who undergo auBMT for rrHL has improved significantly. This improvement may be because of patient selection and improvements in utilization of radiotherapy rather than improvements in chemotherapy. Further investigation is needed to describe the role of auBMT across the entire spectrum of patients with rrHL and to identify the most appropriate preparative regimen with or without cRT therapy in the treatment of rrHL in young patients.

  View details for DOI 10.1016/j.bbmt.2014.10.020

  View details for PubMedID 25445024

• Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Marostica, E., Sukbuntherng, J., Loury, D., de Jong, J., de Trixhe, X. W., Vermeulen, A., De Nicolao, G., O'Brien, S., Byrd, J. C., Advani, R., McGreivy, J., Poggesi, I. 2015; 75 (1): 111-121

  Abstract

  Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.

  View details for DOI 10.1007/s00280-014-2617-3

  View details for Web of Science ID 000347153200012

  View details for PubMedID 25381051

• Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leukemia & lymphoma Fayad, L., Ansell, S. M., Advani, R., Coiffier, B., Stuart, R., Bartlett, N. L., Forero-Torres, A., Kuliczkowski, K., Belada, D., Ng, E., Drachman, J. G. 2015; 56 (9): 2569-2578

  Abstract

  Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved dacetuzumab antitumor activity in combination with rituximab, ± chemotherapy. We designed a phase 2b, double-blind, placebo-controlled trial to compare rituximab, ifosfamide, carboplatin and etoposide (R-ICE) + dacetuzumab with R-ICE + placebo in patients with DLBCL who relapsed after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (ClinicalTrials.gov #NCT00529503). The primary endpoint was complete response (CR); additional endpoints included failure-free survival and overall survival (OS). Overall, 151 patients were randomized (75 dacetuzumab, 76 placebo). No notable differences between arms in demographics or subsequent treatment parameters were observed. Cytopenias, cough and infection were more frequent with dacetuzumab. Futility analysis failed to demonstrate higher CR rates with dacetuzumab (36% dacetuzumab, 42% placebo); consequently, enrollment was stopped. Unplanned post hoc analysis showed that patients who underwent subsequent autologous stem cell transplant experienced improvement in OS (hazard ratio = 0.195, p = 0.004), which may be explained by potential immunomodulatory effects of dacetuzumab on antigen-presenting cells.

  View details for DOI 10.3109/10428194.2015.1007504

  View details for PubMedID 25651427

• Single-Agent Ibrutinib Demonstrates Safety and Durability of Response at 2 Years Follow-up in Patients with Relapsed or Refractory Mantle Cell Lymphoma: Updated Results of an International, Multicenter, Open-Label Phase 2 Study Wang, M., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreylingls, M., Jedrzejczak, W., Johnson, P. W., Spurgeon, S. E., Zhang, L., Baher, L., Cheng, M., Beaupre, D. M., Blum, K. A. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242705013

• Gray Zone Lymphoma (GZL) with Features Intermediate Between Classical Hodgkin Lymphoma (cHL) and Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of Tumor Immunophenotype (IP) and Critical Examination of Therapy with Associated Impact on Outcome Kritharis, A., Kanakry, J. A., Sehn, L. H., Feldman, T., Kroll, A., Gascoyne, R. D., Petrich, A. M., Abramson, J. S., Hernandez-Ilizaliturri, F., Al-Mansour, Z., Adeimy, C., Hemminger, J., Bartlett, N. L., Mato, A. R., Caimi, P., Advani, R., Klein, A. K., Lossos, I. S., Press, O. W., Smith, S. M., Fabregas, J. C., Nabhan, C., Fenske, T. S., Friedberg, J. W., Vose, J. M., Blum, K. A., Evens, A. M. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243505124

• Brentuximab Vedotin Monotherapy in DLBCL Patients with Undetectable CD30: Preliminary Results from a Phase 2 Study Bartlett, N. L., Smith, M. R., Advani, R., Feldman, T., Savage, K. J., Palanca-Wessels, M., Siddiqi, T. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233800109

• Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma Moskowitz, C. H., Forero-Torres, A., Shah, B. D., Advani, R., Hamlin, P., Kim, S., Kostic, A., Sandalic, L., Zhao, B., Fanale, M. A. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233803206

• Patient Characteristics and Initial Treatment Patterns in the United States for the Most Common Subtypes of Peripheral T-Cell Lymphoma (PTCL) Pinter-Brown, L., Foss, F. M., Carson, K. R., Horwitz, S. M., Rosen, S. T., Pro, B., Federico, M., Gisselbrecht, C., Hsi, E. D., Shustov, A. R., Advani, R., Feldman, T., Lechowicz, M., Smith, S., Tulpule, A., Greer, J. P., Kahl, B. S., Leach, J., Morganstein, N., Casulo, C., Park, S. I. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243501060

• Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma Pro, B., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandern, R., Fanale, M. A., Connors, J. M., Wang, Y., Huebner, D., Kennedy, D. A., Shustov, A. R. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243503193

• Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma Morschhauser, F., Flinn, I., Advani, R. H., Diefenbach, C. S., Kolibaba, K., Press, O. W., Sehn, L. H., Chen, A. I., Salles, G., Tilly, H., Cheson, B. D., Assouline, S., Dreyling, M., Hagenbeek, A., Zinzani, P., Yalamanchili, S., Lu, D., Jones, C., Jones, S., Chu, Y., Sharman, J. P. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243504136

• Brentuximab Vedotin in Combination with RCHOP As Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study Yasenchak, C. A., Farber, C. M., Budde, L., Ansell, S. M., Advani, R., Holkova, B., Halwani, A., Knapp, M., Fayad, L., Kolibaba, K. S., Patel-Donnelly, D., Seetharam, M., Manley, T. J., Bartlett, N. L. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242703137

• Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma who are Relapsed or Refractory after Frontline Therapy LaCasce, A., Bociek, R., Matous, J., Sawas, A., Caimi, P., Ansell, S. M., Islas-Ohlmayer, M., Cheung, E., Agura, E., Behler, C., Crosswell, H., Vose, J. M., Josephson, N., Advani, R. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242708087

• Dose-Escalated, Intratumoral TLR9 Agonist and Low-Dose Radiation Induce Abscopal Effects in Follicular Lymphoma Kohrt, H. E., Chu, J., Brody, J., Czerwinski, D. K., Chester, C., Sadaram, M., Advani, R., Kim, Y. H., Hoppe, R. T., Knox, S. J., Wapnir, I., Tibshirani, R. J., Levy, R. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233804172

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides or Sezary Syndrome: Final Results Show Significant Clinical Activity and Suggest Correlation with CD30 Expression Kim, Y. H., Tavallaee, M., Rozati, S., Sundram, U., Salva, K., Wood, G. S., Li, S., Krathen, M., Nagpal, S., Reddy, S., Armstrong, R., Hoppe, R. T., Pulitzer, M., Advani, R. H., Horwitz, S. M. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233802083

• Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy Wang, M., Goy, A., Martin, P., Ramchandren, R., Alexeeva, J., Popat, R., Avivi, I., Advani, R., Le Gouill, S., Horowitz, N., Yuan, Z., Kranenburg, B., Rizo, A., Zhuang, S., Deraedt, W., Rule, S. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233808157

• ACR Appropriateness Criteria Follow-up of Hodgkin Lymphoma JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Ha, C. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Dhakal, S., Flowers, C. R., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2014; 11 (11): 1026-1033

  Abstract

  The main objectives of follow-up studies after completion of treatment for Hodgkin lymphoma are detection of recurrence for salvage therapy and monitoring for sequelae of treatment. The focus of the follow-up shifts, with time after treatment, from detection of recurrence to long-term sequelae. A majority of recurrence is detected by history and physical examination. The yield for routine imaging studies and blood tests is low. Although routine surveillance CT scan can detect recurrence not detected by history and physical examination, its benefit in ultimate survival and cost-effectiveness is not well defined. Although PET scan is a useful tool in assessing response to treatment, its routine use for follow-up is not recommended. Long-term sequelae of treatment include secondary malignancy, cardiovascular disease, pneumonitis, reproductive dysfunction, and hypothyroidism. Follow-up strategies for these sequelae need to be individualized, as their risks in general depend on the dose and volume of radiation to these organs, chemotherapy, age at treatment, and predisposing factors for each sequela. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is either lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1016/j.jacr.2014.07.038

  View details for Web of Science ID 000344834800008

• ACR appropriateness criteria follow-up of Hodgkin lymphoma. Journal of the American College of Radiology Ha, C. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Dhakal, S., Flowers, C. R., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2014; 11 (11): 1026-1033 e3

  Abstract

  The main objectives of follow-up studies after completion of treatment for Hodgkin lymphoma are detection of recurrence for salvage therapy and monitoring for sequelae of treatment. The focus of the follow-up shifts, with time after treatment, from detection of recurrence to long-term sequelae. A majority of recurrence is detected by history and physical examination. The yield for routine imaging studies and blood tests is low. Although routine surveillance CT scan can detect recurrence not detected by history and physical examination, its benefit in ultimate survival and cost-effectiveness is not well defined. Although PET scan is a useful tool in assessing response to treatment, its routine use for follow-up is not recommended. Long-term sequelae of treatment include secondary malignancy, cardiovascular disease, pneumonitis, reproductive dysfunction, and hypothyroidism. Follow-up strategies for these sequelae need to be individualized, as their risks in general depend on the dose and volume of radiation to these organs, chemotherapy, age at treatment, and predisposing factors for each sequela. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is either lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1016/j.jacr.2014.07.038

  View details for PubMedID 25278496

• Brentuximab Vedotin in the Front-Line Treatment of Patients With CD30(+) Peripheral T-Cell Lymphomas: Results of a Phase I Study JOURNAL OF CLINICAL ONCOLOGY Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Huebner, D., Kennedy, D. A., Shustov, A. R. 2014; 32 (28): 3137-?

  Abstract

  Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL.Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches.After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).Brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30(+) PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152).

  View details for DOI 10.1200/JCO.2013.54.2456

  View details for Web of Science ID 000342671000009

  View details for PubMedCentralID PMC4171358

• Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies Marostica, E., Sukbuntherng, J., Loury, D., Jong, J. D., de Trixhie, X., Vermeulen, A., de Nicolao, G., O'Brien, S., Byrd, J. C., Advani, R., McGreivy, J., Poggesi, I. AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1538-7445.AM2014-4634

  View details for Web of Science ID 000349910203108

• Updated phase 2 safety analysis of prevalence of infection, diarrhea, and bleeding with ibrutinib over time in previously treated mantle cell lymphoma Stilgenbauer, S., Rule, S., Wang, M. L., Martin, P., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J., Williams, M., Barrientos, J. C., Chmielowska, E., Radford, J., Truong, V., Chang, M., Beaupre, D. M., Goy, A., Blum, K. A. KARGER. 2014: 34–35

  View details for Web of Science ID 000343816900074

• Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. Journal of clinical oncology Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Huebner, D., Kennedy, D. A., Shustov, A. R. 2014; 32 (28): 3137-3143

  Abstract

  Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL.Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches.After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).Brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30(+) PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152).

  View details for DOI 10.1200/JCO.2013.54.2456

  View details for PubMedID 25135998

• Non-Hodgkin's Lymphomas, Version 4.2014. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Saad, A. A., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2014; 12 (9): 1282-1303

  Abstract

  Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

  View details for PubMedID 25190696

• Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL): Management in the Modern Era King, M., Donaldson, S., Link, M., Advani, R., Hoppe, R. ELSEVIER SCIENCE INC. 2014: S67–S68

  View details for DOI 10.1016/j.ijrobp.2014.05.226

  View details for Web of Science ID 000342331400155

• BRENTUXIMAB VEDOTIN IN COMBINATION WITH CHP IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED CD30+PERIPHERAL T-CELL LYMPHOMAS (PTCL): 2-YEAR FOLLOW-UP Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Huebner, D., Kennedy, D. A., Shustov, A. R. OXFORD UNIV PRESS. 2014

  View details for DOI 10.1093/annonc/mdu339.1

  View details for Web of Science ID 000346901000272

• Prognostic Factors, Treatment, and Outcomes of Limited-Stage Diffuse Large B-Cell Lymphoma (DLBCL) in the Rituximab (R) Era Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Advani, R. H., Hoppe, R. T. ELSEVIER SCIENCE INC. 2014: S677–S678

  View details for DOI 10.1016/j.ijrobp.2014.05.1993

  View details for Web of Science ID 000342331402400

• Treatment recommendations for patients with Waldenstrom macroglobulinemia (WM) and related disorders: IWWM-7 consensus BLOOD Dimopoulos, M. A., Kastritis, E., Owen, R. G., Kyle, R. A., Landgren, O., Morra, E., Leleu, X., Garcia-Sanz, R., Munshi, N., Anderson, K. C., Terpos, E., Ghobrial, I. M., Morel, P., Maloney, D., Rummel, M., Leblond, V., Advani, R. H., Gertz, M. A., Kyriakou, C., Thomas, S. K., Barlogie, B., Gregory, S. A., Kimby, E., Merlini, G., Treon, S. P. 2014; 124 (9): 1404-1411

  Abstract

  Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

  View details for DOI 10.1182/blood-2014-03-565135

  View details for Web of Science ID 000342762100012

  View details for PubMedID 25027391

  View details for PubMedCentralID PMC4148763

• Bruton's tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib. Therapeutic advances in hematology Aalipour, A., Advani, R. H. 2014; 5 (4): 121-133

  Abstract

  Aberrant signaling of the B-cell receptor pathway has been linked to the development and maintenance of B-cell malignancies. Bruton's tyrosine kinase (BTK), a protein early in this pathway, has emerged as a new therapeutic target in a variety of such malignancies. Ibrutinib, the most clinically advanced small molecule inhibitor of BTK, has demonstrated impressive tolerability and activity in a range of B-cell lymphomas which led to its recent approval for relapsed mantle cell lymphoma and chronic lymphocytic leukemia. This review focuses on the preclinical and clinical development of ibrutinib and discusses its therapeutic potential.

  View details for DOI 10.1177/2040620714539906

  View details for PubMedID 25360238

• ACR appropriateness Criteria® pediatric Hodgkin lymphoma. Pediatric blood & cancer Terezakis, S. A., Metzger, M. L., Hodgson, D. C., Schwartz, C. L., Advani, R., Flowers, C. R., Hoppe, B. S., Ng, A., Roberts, K. B., Shapiro, R., Wilder, R. B., Yunes, M. J., Constine, L. S. 2014; 61 (7): 1305-1312

  Abstract

  Pediatric Hodgkin lymphoma is a highly curable malignancy and potential long-term effects of therapy need to be considered in optimizing clinical care. An expert panel was convened to reach consensus on the most appropriate approach to evaluation and treatment of pediatric Hodgkin lymphoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Four clinical variants were developed to assess common clinical scenarios and render recommendations for evaluation and treatment approaches to pediatric Hodgkin lymphoma. We provide a summary of the literature as well as numerical ratings with commentary. By combining available data in published literature and expert medical opinion, we present a consensus to the approach for management of pediatric Hodgkin lymphoma.

  View details for DOI 10.1002/pbc.24983

  View details for PubMedID 24616347

• A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors JOURNAL OF HEMATOLOGY & ONCOLOGY de Vos, S., Forero-Torres, A., Ansell, S. M., Kahl, B., Cheson, B. D., Bartlett, N. L., Furman, R. R., Winter, J. N., Kaplan, H., Timmerman, J., Whiting, N. C., Drachman, J. G., Advani, R. 2014; 7

  Abstract

  Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies.Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity.Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development.ClinicalTrials.gov identifier NCT00435916.

  View details for DOI 10.1186/1756-8722-7-44

  View details for Web of Science ID 000338587000001

  View details for PubMedCentralID PMC4065310

• Non-Hodgkin's lymphomas, version 2.2014. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2014; 12 (6): 916-946

  Abstract

  Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.

  View details for PubMedID 24925202

• PRELIMINARY RESULTS OF A PHASE II RANDOMIZED STUDY (ROMULUS) OF POLATUZUMAB VEDOTIN OR PINATUZUMAB VEDOTIN PLUS RITUXIMAB IN PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA (NHL) Morschhauser, F., Flinn, I., Advani, R., Sehn, L., Kolibaba, K., Press, O., Salles, G., Diefenbach, C., Tilly, H., Assouline, S., Chen, A., Dreyling, M., Hagenbeek, A., Zinzani, P. L., Cheson, B. D., Yalamanchili, S., Lu, D., Chai, A., Chu, Y. W., Sharman, J. FERRATA STORTI FOUNDATION. 2014: 525

  View details for Web of Science ID 000342830902333

• PHASE 2 STUDY OF IBRUTINIB IN RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA: UPDATED SAFETY ANALYSIS ON PREVALENCE OF INFECTION, DIARRHEA, AND BLEEDING OVER TIME Rule, S., Wang, M. L., Martin, P., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J., Williams, M., Barrientos, J. C., Chmielowska, E., Radford, J. A., Stilgenbauer, S., Truong, V., Chang, M., Beaupre, D. M., Goy, A., Blum, K. A. FERRATA STORTI FOUNDATION. 2014: 150

  View details for Web of Science ID 000342830900361

• Non-Hodgkin's Lymphomas, Version 2.2014. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2014; 12 (6): 916-946

  View details for PubMedID 24925202

• Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Morschhauser, F., Flinn, I., Advani, R. H., Sehn, L., Kolibaba, K. S., Press, O. W., Salles, G. A., Diefenbach, C., Tilly, H., Assouline, S. E., Chen, A., Dreyling, M. H., Hagenbeek, A., Zinzani, P., Cheson, B. D., Yalamanchili, S., Lu, D., Chai, A., Chu, Y., Sharman, J. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204199

• Value of surveillance studies for patients (pts) with stage I-II diffuse large B-cell lymphoma (DLBCL) in the rituximab (R) era. Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Advani, R. H., Hoppe, R. T. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204223

• Interim analysis of a phase 1, open-label, dose-escalation study of SGN-CD19A in patients with relapsed or refractory B-lineage non-Hodgkin lymphoma (NHL). Forero-Torres, A., Moskowitz, C., Advani, R. H., Shah, B. D., Kostic, A., Albertson, T. M., Sandalic, L., Zhao, B., Fanale, M. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.8505

  View details for Web of Science ID 000358613204186

• Noninvasive monitoring of cellular versus acellular tumor DNA from immunoglobulin genes for DLBCL. Kurtz, D., Green, M. R., Bratman, S., Liu, C., Glover, C., Keane, C., Kong, K., Faham, M., Miklos, D., Advani, R. H., Levy, R., Hertzberg, M. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204185

• Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin BLOOD Horwitz, S. M., Advani, R. H., Bartlett, N. L., Jacobsen, E. D., Sharman, J. P., O'Connor, O. A., Siddiqi, T., Kennedy, D. A., Oki, Y. 2014; 123 (20): 3095-3100

  Abstract

  This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30(+) non-Hodgkin lymphomas. The primary end point was objective response rate (ORR). Key secondary end points included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until progression or unacceptable toxicity. This planned subset analysis included patients with peripheral T-cell lymphomas (PTCLs; n = 35), specifically angioimmunoblastic T-cell lymphoma (AITL; n = 13) and PTCL not otherwise specified (n = 22). Median age was 64 years; 63% were refractory to most recent therapy. Of 34 evaluable patients, ORR was 41% (8 complete remissions [CRs], 6 partial remissions [PRs]), and ORR was 54% in AITL (5 CRs, 2 PRs) with median PFS of 6.7 months thus far. No correlation between CD30 expression per central review and response was observed. Safety data were consistent with the known profile of brentuximab vedotin, and included at least grade 3 events of neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each). In summary, brentuximab vedotin showed antitumor activity in patients with relapsed PTCL particularly AITL. This trial was registered at www.clinicaltrials.gov as #NCT01421667.

  View details for DOI 10.1182/blood-2013-12-542142

  View details for PubMedID 24652992

• A multicentre study of primary breast diffuse large B-cell lymphoma in the rituximab era BRITISH JOURNAL OF HAEMATOLOGY Hosein, P. J., Maragulia, J. C., Salzberg, M. P., Press, O. W., Habermann, T. M., Vose, J. M., Bast, M., Advani, R. H., Tibshirani, R., Evens, A. M., Islam, N., Leonard, J. P., Martin, P., Zelenetz, A. D., Lossos, I. S. 2014; 165 (3): 358-363

  Abstract

  Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.

  View details for DOI 10.1111/bjh.12753

  View details for Web of Science ID 000334031000011

  View details for PubMedID 24467658

  View details for PubMedCentralID PMC3990235

• Multicenter study for comparison of FLT and FDG PET/CT for early interim therapy monitoring of diffuse large B-cell lymphoma Minamimoto, R., Vose, J., Advani, R., Fayad, L., Macapinlac, H., Meza, J., Hankins, J., Mottaghy, F., Juweid, M., Quon, A. SOC NUCLEAR MEDICINE INC. 2014

  View details for Web of Science ID 000361438101089

• Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404). Leukemia & lymphoma Ganjoo, K., Hong, F., Horning, S. J., Gascoyne, R. D., Natkunam, Y., Swinnen, L. J., Habermann, T. M., Kahl, B. S., Advani, R. H. 2014; 55 (4): 768-772

  Abstract

  Peripheral T-cell lymphoma (PTCL) and natural killer (NK) cell lymphoma have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab (A), was studied in combination with standard cyclosphosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients. Patients were treated with 6-8 cycles of ACHOP followed by eight doses of maintenance A (15 mg/kg every 21 days). Forty-six patients were enrolled on this phase 2 study from July 2006 through March 2009. Forty-four patients were evaluable for toxicity and 39 were evaluable for response, progression and survival. A total of 324 cycles (range: 2-16, median 7) were administered to 39 evaluable patients and only nine completed all planned treatment. The overall response rate was 90% with 19 (49%) complete response/complete response unconfirmed (CR/CRu) and 16 (41%) a partial response (PR). The 1-year progression-free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, two while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n = 8), anemia (n = 3), thrombocytopenia (n = 5), congestive heart failure (n = 4), venous thrombosis (n = 3), gastrointestinal hemorrhage/perforation (n = 2), infection (n = 8) and fatigue (n = 6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.

  View details for DOI 10.3109/10428194.2013.816700

  View details for PubMedID 23786456

• Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology Horst, K. C., Hancock, S. L., Ognibene, G., Chen, C., Advani, R. H., Rosenberg, S. A., Donaldson, S. S., Hoppe, R. T. 2014; 25 (4): 848–51

  Abstract

  BACKGROUND: The purpose of the study was to determine whether breast cancers (BCs) that develop in women previously irradiated for Hodgkin lymphoma (HL) are biologically similar to sporadic BC.MATERIALS AND METHODS: We retrospectively reviewed the charts of patients who developed BC after radiotherapy (RT) for HL. Tumors were classified as ductal carcinoma in situ (DCIS) or invasive carcinoma. Invasive carcinomas were further characterized according to the subtype: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. BCs after HL were compared with four age-matched sporadic, non-breast cancer (BRCA) I or II mutated BCs.RESULTS: One hundred forty-seven HL patients who were treated with RT between 1966 and 1999 and subsequently developed BCs were identified. Of these, 65 patients with 71 BCs had complete pathologic information. The median age at HL diagnosis was 23 (range, 10-48). The median age at BC diagnosis was 44 (range, 28-66). The median time to developing BC was 20 years. Twenty cancers (28%) were DCIS and 51 (72%) were invasive. Of the 51 invasive cancers, 24 (47%) were HR+/HER2-, 2 (4%) were HR+/HER2+, 5 (10%) were HR-/HER2+, and 20 (39%) were HR-/HER2-. There were no differences in BC histologic subtype according to the age at which patients were exposed to RT, the use of chemotherapy for HL treatment, or the time from RT exposure to the development of BC. In a 4 : 1 age-matched comparison to sporadic BCs, BCs after HL were more likely to be HR-/HER2- (39% versus 14%) and less likely to be HR+/HER2- (47% versus 61%) or HR+/HER2+ (4% versus 14%) (P = 0.0003).CONCLUSION(S): BCs arising in previously irradiated breast tissue were more likely to be triple negative compared with age-matched sporadic invasive cancers and less likely to be HR positive. Further studies will be important to determine the molecular pathways of carcinogenesis in breast tissue that is exposed to RT.

  View details for DOI 10.1093/annonc/mdu017

  View details for PubMedID 32018915

• Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma. Annals of oncology Horst, K. C., Hancock, S. L., OGNIBENE, G., Chen, C., Advani, R. H., Rosenberg, S. A., Donaldson, S. S., Hoppe, R. T. 2014; 25 (4): 848-851

  Abstract

  The purpose of the study was to determine whether breast cancers (BCs) that develop in women previously irradiated for Hodgkin lymphoma (HL) are biologically similar to sporadic BC.We retrospectively reviewed the charts of patients who developed BC after radiotherapy (RT) for HL. Tumors were classified as ductal carcinoma in situ (DCIS) or invasive carcinoma. Invasive carcinomas were further characterized according to the subtype: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. BCs after HL were compared with four age-matched sporadic, non-breast cancer (BRCA) I or II mutated BCs.One hundred forty-seven HL patients who were treated with RT between 1966 and 1999 and subsequently developed BCs were identified. Of these, 65 patients with 71 BCs had complete pathologic information. The median age at HL diagnosis was 23 (range, 10-48). The median age at BC diagnosis was 44 (range, 28-66). The median time to developing BC was 20 years. Twenty cancers (28%) were DCIS and 51 (72%) were invasive. Of the 51 invasive cancers, 24 (47%) were HR+/HER2-, 2 (4%) were HR+/HER2+, 5 (10%) were HR-/HER2+, and 20 (39%) were HR-/HER2-. There were no differences in BC histologic subtype according to the age at which patients were exposed to RT, the use of chemotherapy for HL treatment, or the time from RT exposure to the development of BC. In a 4 : 1 age-matched comparison to sporadic BCs, BCs after HL were more likely to be HR-/HER2- (39% versus 14%) and less likely to be HR+/HER2- (47% versus 61%) or HR+/HER2+ (4% versus 14%) (P = 0.0003).BCs arising in previously irradiated breast tissue were more likely to be triple negative compared with age-matched sporadic invasive cancers and less likely to be HR positive. Further studies will be important to determine the molecular pathways of carcinogenesis in breast tissue that is exposed to RT.

  View details for DOI 10.1093/annonc/mdu017

  View details for PubMedID 24608191

• Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies JOURNAL OF HEMATOLOGY & ONCOLOGY Bartlett, N. L., Chen, R., Fanale, M. A., Brice, P., Gopal, A., Smith, S. E., Advani, R., Matous, J. V., Ramchandren, R., Rosenblatt, J. D., Huebner, D., Levine, P., Grove, L., Forero-Torres, A. 2014; 7

  Abstract

  Brentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856).Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment.The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year.Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment.With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials.Retreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL.United States registry and results database ClinicalTrials.gov NCT00947856.

  View details for DOI 10.1186/1756-8722-7-24

  View details for Web of Science ID 000334637200001

  View details for PubMedID 24642247

  View details for PubMedCentralID PMC3994656

• Bulky Mediastinal Classical Hodgkin Lymphoma in Young Women ONCOLOGY-NEW YORK Percival, M. M., Hoppe, R. T., Advani, R. H. 2014; 28 (3): 253-+

  View details for Web of Science ID 000333550900015

  View details for PubMedID 24855735

• Customized Targeted Therapy in Hodgkin Lymphoma: Hype or Hope? HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Diefenbach, C., Advani, R. 2014; 28 (1): 105-?

  Abstract

  Although most patients with Hodgkin lymphoma (HL) are cured with primary therapy, patients with primary refractory disease or relapse after initial treatment have poor outcomes and represent an unmet medical need. Recent advances in unraveling the biology of HL have yielded a plethora of novel targeted therapies. This review provides an overview of the data behind the hype generated by these advances and addresses the question of whether or not clinically these targeted therapies offer hope for patients with HL.

  View details for DOI 10.1016/j.hoc.2013.10.004

  View details for Web of Science ID 000329086300010

  View details for PubMedID 24287071

  View details for PubMedCentralID PMC4023679

• A Phase 1/2 Single-Arm, Open-Label Study to Evaluate the Safety and Efficacy of Brentuximab Vedotin in Combination with Bendamustine for Patients with Hodgkin Lymphoma in the First Salvage Setting: Interim Results LaCasce, A., Sawas, A., Bociek, R., Ansell, S., Vose, J., O'Meara, M., Advani, R. ELSEVIER SCIENCE INC. 2014: S161

  View details for DOI 10.1016/j.bbmt.2013.12.257

  View details for Web of Science ID 000331155400235

• A Clinicopathologic Review of 215 Cases of Angioimmunoblastic T-Cell Lymphoma with Emphasis on the Significance of B-Cell Proliferations Ohgami, R. S., Chen, J. S., Advani, R., Natkunam, Y., Warnke, R. A. NATURE PUBLISHING GROUP. 2014: 366A–367A

  View details for Web of Science ID 000331502202066

• A Clinicopathologic Review of 215 Cases of Angioimmunoblastic T-Cell Lymphoma with Emphasis on the Significance of B-Cell Proliferations Ohgami, R. S., Chen, J. S., Advani, R., Natkunam, Y., Warnke, R. A. NATURE PUBLISHING GROUP. 2014: 366A–367A

  View details for Web of Science ID 000331155802066

• A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors. Journal of hematology & oncology de Vos, S., Forero-Torres, A., Ansell, S. M., Kahl, B., Cheson, B. D., Bartlett, N. L., Furman, R. R., Winter, J. N., Kaplan, H., Timmerman, J., Whiting, N. C., Drachman, J. G., Advani, R. 2014; 7: 44-?

  Abstract

  Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies.Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity.Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development.ClinicalTrials.gov identifier NCT00435916.

  View details for DOI 10.1186/1756-8722-7-44

  View details for PubMedID 24919462

• Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. Journal of hematology & oncology Bartlett, N. L., Chen, R., Fanale, M. A., Brice, P., Gopal, A., Smith, S. E., Advani, R., Matous, J. V., Ramchandren, R., Rosenblatt, J. D., Huebner, D., Levine, P., Grove, L., Forero-Torres, A. 2014; 7: 24-?

  Abstract

  Brentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856).Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment.The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year.Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment.With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials.Retreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL.United States registry and results database ClinicalTrials.gov NCT00947856.

  View details for DOI 10.1186/1756-8722-7-24

  View details for PubMedID 24642247

• Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. Journal of clinical oncology Evens, A. M., Advani, R., Press, O. W., Lossos, I. S., Vose, J. M., Hernandez-Ilizaliturri, F. J., Robinson, B. K., Otis, S., Nadav Dagan, L., Abdallah, R., Kroll-Desrosiers, A., Yarber, J. L., Sandoval, J., Foyil, K., Parker, L. M., Gordon, L. I., Blum, K. A., Flowers, C. R., Leonard, J. P., Habermann, T. M., Bartlett, N. L. 2013; 31 (32): 4132-4139

  Abstract

  Lymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports.In a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy.Among 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and "B" symptoms predicted inferior PFS.Standard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks gestation, was associated with few complications and expected maternal survival with lymphoma occurring during pregnancy.

  View details for DOI 10.1200/JCO.2013.49.8220

  View details for PubMedID 24043736

• Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. Journal of clinical oncology Evens, A. M., Advani, R., Press, O. W., Lossos, I. S., Vose, J. M., Hernandez-Ilizaliturri, F. J., Robinson, B. K., Otis, S., Nadav Dagan, L., Abdallah, R., Kroll-Desrosiers, A., Yarber, J. L., Sandoval, J., Foyil, K., Parker, L. M., Gordon, L. I., Blum, K. A., Flowers, C. R., Leonard, J. P., Habermann, T. M., Bartlett, N. L. 2013; 31 (32): 4132-4139

  View details for DOI 10.1200/JCO.2013.49.8220

  View details for PubMedID 24043736

• Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas. British journal of haematology Aalipour, A., Advani, R. H. 2013; 163 (4): 436-443

  Abstract

  Constitutive or aberrant signalling of the B cell receptor signalling cascade has been implicated in the propagation and maintenance of a variety of B cell malignancies. Small molecule inhibitors of Bruton tyrosine kinase (BTK), a protein early in this cascade and specifically expressed in B cells, have emerged as a new class of targeted agents. There are several BTK inhibitors, including ONO-WG-307, LFM-A13, dasatinib, CC-292, and PCI-32765 (ibrutinib), in preclinical and/or clinical development of which ibrutinib is currently in phase III trials. Recent clinical data suggest significant activity of ibrutinib as a first in class oral inhibitor of BTK. This review provides an overview of ongoing clinical studies of BTK inhibitors.

  View details for DOI 10.1111/bjh.12573

  View details for PubMedID 24111579

• Management of B-cell non-Hodgkin lymphoma in Asia: resource-stratified guidelines LANCET ONCOLOGY Tan, D., Tan, S. Y., Lim, S. T., Kim, S. J., Kim, W., Advani, R., Kwong, Y. 2013; 14 (12): E548-E561

  Abstract

  Treatment of B-cell non-Hodgkin lymphomas has undergone substantial developments in the past 10 years. The introduction of rituximab has greatly improved survival outcomes in patients. Clinical practice guidelines based on current evidence have been developed to provide recommendations for standard treatment approaches. However, guidelines do not take into account resource limitations in resource-poor countries. The huge disparities in economy, health-care infrastructure, and access to novel drugs between Asian countries can hinder the delivery of optimum care to patients with lymphoma in Asia. We outline guidelines appropriate to different levels of health-care resources and expertise, aiming to provide advice on diagnosis and treatment, unify interpretation of results, and allow the design of future studies in Asia. In this resource-adapted consensus, we summarise recommendations for diagnosis, staging, risk stratification, and treatment of common B-cell non-Hodgkin lymphomas in Asia.

  View details for Web of Science ID 000326275300022

  View details for PubMedID 24176573

• Cancer Vaccines and T Cell Therapy (vol 19, pg S97, 2013) BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Rezvani, K., Brody, J. D., Kohrt, H. E., Logan, A. C., Advani, R., Czerwinski, D., Weng, W., Negrin, R. S., Carlton, V., Faham, M., Levy, R., Barrett, J. 2013; 19 (10): 1530

  View details for DOI 10.1016/j.bbmt.2013.03.005

  View details for Web of Science ID 000324975000023

• ACR APPROPRIATENESS CRITERIA (R) Localized Nodal Indolent Lymphoma ONCOLOGY-NEW YORK Hoppe, B. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Flowers, C. R., Ha, C. S., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2013; 27 (8): 786-794

  Abstract

  The present guidelines review epidemiology, pathology, presentation, workup, staging, prognostic factors, and treatment options for patients with localized nodal indolent lymphoma, with an emphasis on radiation guidelines, including radiation dose, field design, and radiation techniques. Following a discussion of the current literature and available data for treatment and outcomes of patients with indolent lymphoma, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) by which the panel rates the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for Web of Science ID 000323686400009

• ACR Appropriateness Criteria: Localized nodal indolent lymphoma. Oncology (Williston Park, N.Y.) Hoppe, B. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Flowers, C. R., Ha, C. S., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2013; 27 (8): 786-794

  Abstract

  The present guidelines review epidemiology, pathology, presentation, workup, staging, prognostic factors, and treatment options for patients with localized nodal indolent lymphoma, with an emphasis on radiation guidelines, including radiation dose, field design, and radiation techniques. Following a discussion of the current literature and available data for treatment and outcomes of patients with indolent lymphoma, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) by which the panel rates the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for PubMedID 24133827

• A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study LEUKEMIA & LYMPHOMA Foss, F. M., Sjak-Shie, N., Goy, A., Jacobsen, E., Advani, R., Smith, M. R., Komrokji, R., Pendergrass, K., Bolejack, V. 2013; 54 (7): 1373-1379

  Abstract

  This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled patients with newly diagnosed peripheral T-cell lymphoma (PTCL). Forty-nine received DD 18 μg/kg/day (days 1, 2) with CHOP (day 3) every 21 days for ≤ 6-8 cycles. Intent-to-treat (ITT) and safety populations comprised all patients. In the ITT population, the overall response rate was 65%, median duration of response was 30 months and median progression-free survival was 12 months. Median overall survival was not attained at the end of the study, and the overall survival rate was 63.3%. The two most frequent treatment-related adverse events (AEs) were fatigue and nausea. Most frequent AEs ≥ grade 3 within the hematologic system were lymphopenia (24.5%), neutropenia (20.4%) and leukopenia (18.4%). Three treatment-related deaths occurred. DD plus CHOP was well tolerated, and progression-free and overall survival improved versus historical comparison with CHOP alone. Confirmation in larger trials is warranted.

  View details for DOI 10.3109/10428194.2012.742521

  View details for Web of Science ID 000320698300009

  View details for PubMedID 23278639

• Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Han, T. H., Chen, R., Advani, R., Berryman, R. B., Smith, S. E., Forero-Torres, A., Rosenblatt, J. D., Smith, M. R., Zain, J., Hunder, N. N., Engert, A. 2013; 72 (1): 241-249

  Abstract

  Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization.Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF).There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies.There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

  View details for DOI 10.1007/s00280-013-2192-z

  View details for Web of Science ID 000320889300025

  View details for PubMedID 23719719

  View details for PubMedCentralID PMC3932653

• UPDATED INTERIM RESULTS OF AN INTERNATIONAL, MULTICENTER, PHASE 2 STUDY OF IBRUTINIB (PCI-32765) IN RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA Rule, S., Wang, M., Martin, P., Auer, R., Kahl, B., Jurczak, W., Advani, R., Romaguera, J., Williams, M., Barrientos, J., Chmielowska, E., Radford, J., Stilgenbauer, S., Troung, V., McGreivy, J., Clow, F., Beaupre, D., Kunkel, L., Goy, A., Blum, K. FERRATA STORTI FOUNDATION. 2013: 489

  View details for Web of Science ID 000445782800210

• THE BRUTON'S TYROSINE KINASE (BTK) INHIBITOR, IBRUTINIB (PCI-32765), HAS PREFERENTIAL ACTIVITY IN THE ACTIVATED B CELL-LIKE (ABC) SUBTYPE OF RELAPSED/REFRACTORY (R/R) DLBCL: INTERIM PHASE 2 RESULTS deVos, S., Wilson, W., Gerecitano, J., Goy, A., Kenkre, V., Barr, P., Blum, K., Shustov, A., Advani, R., Fowler, N., Vose, J., Lih, C., Williams, M., Schmitz, R., Yang, Y., Pittaluga, S., Wright, G., Kunkel, L., McGreivy, J., Beaupre, D., Balasubramanian, S., Cheng, M., Moussa, D., Chang, L., Buggy, J., Staudt, L. FERRATA STORTI FOUNDATION. 2013: 490

  View details for Web of Science ID 000445782800212

• Non-Hodgkin's Lymphomas, Version 1.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M. A., Naganuma, M. 2013; 11 (3): 257-273

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

  View details for Web of Science ID 000316037400005

• Non-Hodgkin's lymphomas, version 1.2013. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M. A., Naganuma, M. 2013; 11 (3): 257-272

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

  View details for PubMedID 23486452

• Gene Expression-Based Model Using Formalin-Fixed Paraffin-Embedded Biopsies Predicts Overall Survival in Advanced-Stage Classical Hodgkin Lymphoma JOURNAL OF CLINICAL ONCOLOGY Scott, D. W., Chan, F. C., Hong, F., Rogic, S., Tan, K. L., Meissner, B., Ben-Neriah, S., Boyle, M., Kridel, R., Telenius, A., Woolcock, B. W., Farinha, P., Fisher, R. I., Rimsza, L. M., Bartlett, N. L., Cheson, B. D., Shepherd, L. E., Advani, R. H., Connors, J. M., Kahl, B. S., Gordon, L. I., Horning, S. J., Steidl, C., Gascoyne, R. D. 2013; 31 (6): 692-700

  Abstract

  Our aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET).Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.A 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.A gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.

  View details for DOI 10.1200/JCO.2012.43.4589

  View details for Web of Science ID 000315086400017

  View details for PubMedID 23182984

  View details for PubMedCentralID PMC3574267

• Cancer Vaccines and T Cell Therapy BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Rezvani, K., Brody, J. D., Kohrt, H. E., Logan, A. C., Advani, R., Czerwinski, D. K., Weng, W., Negrin, R. S., Carlton, V., Faham, M., Levy, R., Barrett, J. 2013; 19 (1): S97-S101

  View details for DOI 10.1016/j.bbmt.2012.09.020

  View details for Web of Science ID 000313998100024

  View details for PubMedID 23041602

• Non-Hodgkin's Lymphomas, version 3.2012. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Naganuma, M., Dwyer, M. A. 2012; 10 (12): 1487-1498

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

  View details for PubMedID 23221787

• Non-Hodgkin's Lymphomas, Version 3.2012 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Naganuma, M., Dwyer, M. A. 2012; 10 (12): 1487-1498

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

  View details for Web of Science ID 000312114200005

• in Situ Vaccination for Patients with Previously Untreated Follicular Lymphoma: Analysis of Immune Responses 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Czerwinski, D. K., Brody, J., Kohrt, H. E., Hoppe, R. T., Advani, R. H., Levy, R. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049600215

• The Bruton's Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma Fowler, N. H., Advani, R. H., Sharman, J., Smith, S. M., McGreivy, J., Kunkel, L., Vina Troung, Zhou, C., Boyd, T. E. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900301

• A Phase II Trial of R-CHOP Followed by Zevalin Radioimmunotherapy for Patients with Previously Untreated Stages I and II CD20+Diffuse Large Cell Non-Hodgkin's Lymphoma: an Eastern Cooperative Oncology Group Study (E3402). Witzig, T. E., Hong, F., Micallef, I. N., Gascoyne, R. D., Dogan, A., Wagner, H., Advani, R. H., Kahl, B. S., Horning, S. J. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838903106

• Primary Breast Diffuse Large B Cell Lymphoma: A Distinct Clinical Entity Salzberg, M. P., Maragulia, J. C., Press, O. W., Habermann, T. M., Vose, J. M., Bast, M., Advani, R. H., Evens, A. M., Islam, N., Leonard, J. P., Martin, P., Hosein, P. J., Zelenetz, A. D., Lossos, I. S. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049601039

• Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma Pro, B., Advani, R. H., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J. V., Ramchandren, R., Fanale, M. A., Connors, J. M., Yang, Y., Kennedy, D. A., Shustov, A. R. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049603352

• Interim Results of an International, Multicenter, Phase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Follow-up Wang, M., Rule, S. A., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., McGreivy, J., Clow, F., Stevens-Brogan, M., Kunkel, L., Blum, K. A. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838902057

• Interim Results of an International, Multicenter, Phase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Follow-up Wang, M., Rule, S. A., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., McGreivy, J., Clow, F., Stevens-Brogan, M., Kunkel, L., Blum, K. A. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838901233

• A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results Jacobsen, E. D., Advani, R. H., Oki, Y., Sharman, J., Horwitz, S. M., Forero-Torres, A., O'Connor, O. A., Shustov, A. R., Siddiqi, T., Grove, L. E., Bartlett, N. L. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049603351

• A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL) 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R., Lebmic, D., Brunvand, M., Chen, A. I., Goy, A., Chang, J. E., Maeda, L. S., Ho, W., Kahn, R., Lu, D., Su, M., Chu, Y., Cheson, B. D. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900105

• Brentuximab Vedotin Demonstrates Significant Clinical Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 Expression 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Krathen, M., Sundram, U., Bashey, S., Sutherland, K., Salva, K., Wood, G. S., Advani, R. H., Hoppe, R. T., Reddy, S., Armstrong, R., Nagpal, S., Pulitzer, M., Horwitz, S. M., Kim, Y. H. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900162

• A Phase I Study of the Anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A Targeting CD79b in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL) 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Palanca-Wessels, M. C., Flinn, I. W., Sehn, L. H., Patel, M., Sangha, R., Czuczman, M. S., Salles, G. A., Morschhauser, F., Advani, R., Press, O. W., Ho, W., Kahn, R., Lu, D., Su, Z., Chu, Y., Assouline, S. E. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900108

• Mature Results From ECOG Study E1405-A Phase II Study of VcR-CVAD with Maintenance Rituximab for Previously Untreated Mantle Cell Lymphoma 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kahl, B. S., Li, H., Smith, M. R., Gascoyne, R. D., Yang, D. T., Paietta, E., Advani, R. H., Horning, S. J. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900306

• Brentuximab Vedotin Administered Concurrently with Multi-Agent Chemotherapy As Frontline Treatment of ALCL and Other CD3O-Positive Mature T-Cell and NK-Cell Lymphomas 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Fanale, M. A., Shustov, A. R., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Midge, T., Kennedy, D. A., Horwitz, S. M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900104

• Second Cancers After Treatment with Stanford V Regimen in Eastern Cooperative Oncology Group (ECOG) Pilot Study E1492 At a Median Follow up of 17 Years 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R. H., Li, H., Hoppe, R. T., Bartlett, N. L., Bennett, J. M., Neuberg, D. S., Cassileth, P. A., Kahl, B. S., Horning, S. J. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049604223

• Evaluation of Radiation Therapy for NK-T-cell Lymphoma of the Head and Neck Chan, C., Zeidan, Y. H., Advani, R., Le, Q., Hoppe, R. T. ELSEVIER SCIENCE INC. 2012: S618–S619

  View details for DOI 10.1016/j.ijrobp.2012.07.1652

  View details for Web of Science ID 000310542902065

• SEQUENTIAL THERAPY WITH BRENTUXIMAB VEDOTIN IN NEWLY DIAGNOSED PATIENTS WITH SYSTEMIC ANAPLASTIC LARGE CELL LYMPHOMA Fanale, M., Advani, R., Bartlett, N. L., Davies, A., Illidge, T., Kennedy, D. A., Shustov, A. R. OXFORD UNIV PRESS. 2012: 348

  View details for Web of Science ID 000309409002002

• Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation BLOOD Gopal, A. K., Ramchandren, R., O'Connor, O. A., Berryman, R. B., Advani, R. H., Chen, R., Smith, S. E., Cooper, M., Rothe, A., Matous, J. V., Grove, L. E., Zain, J. 2012; 120 (3): 560-568

  Abstract

  Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥ grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT.

  View details for DOI 10.1182/blood-2011-12-397893

  View details for Web of Science ID 000307440100012

  View details for PubMedID 22510871

  View details for PubMedCentralID PMC3731651

• Characteristics and outcomes of extranodal NK/t-cell lymphoma (ENKL): A North American (NA) multi-institutional experience. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Maeda, L. S., Geiger, J. L., Savage, K. J., Rose, J., Pinter-Brown, L. C., Lunning, M. A., Abramson, J. S., Bartlett, N., Vose, J., Drape, J., Muffly, L. S., McMillan, A., Evens, A. M., Smith, S. M., Horwitz, S. M., Ansell, S. M., Advani, R. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803765

• Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study. Advani, R., Oki, Y., Shustov, A. R., Grove, L. E., Bartlett, N. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803855

• Single Cell Profiling of Circulating Tumor Cells: Transcriptional Heterogeneity and Diversity from Breast Cancer Cell Lines PLOS ONE Powell, A. A., Talasaz, A. H., Zhang, H., Coram, M. A., Reddy, A., Deng, G., Telli, M. L., Advani, R. H., Carlson, R. W., Mollick, J. A., Sheth, S., Kurian, A. W., Ford, J. M., Stockdale, F. E., Quake, S. R., Pease, R. F., Mindrinos, M. N., Bhanot, G., Dairkee, S. H., Davis, R. W., Jeffrey, S. S. 2012; 7 (5)

  Abstract

  To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery.We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy.For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.

  View details for DOI 10.1371/journal.pone.0033788

  View details for PubMedID 22586443

• Hodgkin Lymphoma, Version 2.2012 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Poppe, M., Pro, B., Winter, J. N., Yahalom, J., Sundar, H. 2012; 10 (5): 589-597

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin Lymphoma (HL) include the clinical management of classical HL and lymphocyte-predominant HL (LPHL). Major changes have been incorporated into these guidelines since their inception. In the 2012 NCCN Guidelines for HL, PET scans are not recommended for interim restaging of patients with stage I to II favorable disease. After reevaluating the available evidence on the use of interim PET imaging, the panel recommends the use of diagnostic CT scan of involved sites for interim restaging after completion of chemotherapy for this group of patients. Maintenance rituximab for 2 years is included as an option for patients with stage IB to IIB or stage III to IV LPHL treated with rituximab alone in the first-line setting. Brentuximab vedotin is included as an option for patients with progressive disease or relapsed disease after second-line chemotherapy or high-dose therapy with autologous stem cell rescue.

  View details for Web of Science ID 000303557700005

  View details for PubMedID 22570290

• Exploratory study of brentuximab vedotin (SGN-35), a novel monoclonal antibody-drug-conjugate against CD30, in mycosis fungoides (MF) and Sezary syndrome (SS) demonstrates clinical responses regardless of CD30 expression levels 75th Annual Meeting of the Society-for-Investigative-Dermatology Bashey, S., Krathen, M., Sutherland, K., Sundram, U., Lingala, B., Horwitz, S., Hoppe, R., Pulitzer, M., Advani, R., Kim, Y. NATURE PUBLISHING GROUP. 2012: S95–S95

  View details for Web of Science ID 000302866900562

• Resolution of malignant cutaneous lesions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma Advani, R., Pro, B., Kennedy, D., Fanale, M. MOSBY-ELSEVIER. 2012: AB4

  View details for Web of Science ID 000302319800016

• Interim-treatment quantitative PET parameters predict progression and death among patients with hodgkin's disease RADIATION ONCOLOGY Tseng, D., Rachakonda, L. P., Su, Z., Advani, R., Horning, S., Hoppe, R. T., Quon, A., Graves, E. E., Loo, B. W., Tran, P. T. 2012; 7

  Abstract

  We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients.Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS ≥ 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUV mean), maximum SUV (SUV max) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS).Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUV max from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTV int/pre (p < 0.01), SUV mean int/pre (p < 0.05), SUV max int/pre (p = 0.01), and iSUV int/pre (p < 0.01). Absolute value SUV max from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTV int/pre (p = 0.01), SUV max int/pre (p = 0.02) and iSUV int/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01).Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification.

  View details for DOI 10.1186/1748-717X-7-5

  View details for PubMedID 22260710

• In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study BLOOD Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J. D., Czerwinski, D. K., Ai, W. Z., Morales, A., Abdulla, F., Xing, L., Navi, D., Tibshirani, R. J., Advani, R. H., Lingala, B., Shah, S., Hoppe, R. T., Levy, R. 2012; 119 (2): 355-363

  Abstract

  We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.

  View details for DOI 10.1182/blood-2011-05-355222

  View details for PubMedID 22045986

• A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies CLINICAL CANCER RESEARCH Fanale, M. A., Forero-Torres, A., Rosenblatt, J. D., Advani, R. H., Franklin, A. R., Kennedy, D. A., Han, T. H., Sievers, E. L., Bartlett, N. L. 2012; 18 (1): 248-255

  Abstract

  The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies.In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles.The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study.Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted.

  View details for DOI 10.1158/1078-0432.CCR-11-1425

  View details for Web of Science ID 000298758900026

  View details for PubMedID 22080439

• Optimal Therapy of Advanced Hodgkin Lymphoma HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM Advani, R. 2011: 310-316

  Abstract

  Advanced-stage Hodgkin lymphoma (HL) has become a curable disease in the majority of patients. Research during the last decade has challenged chemotherapy with Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) as the standard of care and debates continue regarding the role of radiation therapy (RT) in this patient population. The incorporation of interim positron emission tomography (PET) imaging and, recently, further characterization of HL on cellular and molecular levels are emerging as tools for treatment stratification and predictors of disease status. Newer targeted therapies have emerged that are very effective in the relapsed setting and are actively being explored as frontline therapy. Lastly, the expanding population of survivors cured of HL outnumbers patients with the disease and needs to be monitored for therapy-related late effects.

  View details for DOI 10.1182/asheducation-2011.1.310

  View details for Web of Science ID 000208759700047

• Lymphoma in Pregnancy: Excellent Fetal Outcomes and Maternal Survival in a Large Multicenter Analysis 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Evens, A. M., Advani, R., Lossos, I. S., Press, O. W., Vose, J. M., Hernandez-Ilizaliturri, F. J., Robinson, B. K., Otis, S., Dagan, L. N., Abdallah, R., Kroll, A., Sandoval, J., Yarber, J. L., Foyil, K. V., Parker, L. M., Gordon, L. I., Leonard, J. P., Habermann, T. M., Bartlett, N. L. AMER SOC HEMATOLOGY. 2011: 45–46

  View details for Web of Science ID 000299597100095

• Frontline Therapy of Nodular Lymphocyte Predominant Hodgkin Lymphoma with Rituximab: The Stanford University Experience Advani, R. H., Horning, S. J., Hoppe, R. T., Daadi, S., Allen, J., Natkunam, Y., McMillan, A., Bartlett, N. L. AMER SOC HEMATOLOGY. 2011: 1154

  View details for Web of Science ID 000299597104037

• Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update Advani, R. H., Shustov, A. R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M. A., Connors, J. M., Yang, Y., Kennedy, D. A., Pro, B. AMER SOC HEMATOLOGY. 2011: 204

  View details for Web of Science ID 000299597100444

• Validation of the Elderly IPI (E-IPI) for Patients with Diffuse Large B Cell Lymphoma Using An Independent Data Set From the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R. H., Hong, F., Li, H., Kahl, B. S., Pfreundschuh, M., Ziepert, M. AMER SOC HEMATOLOGY. 2011: 681–81

  View details for Web of Science ID 000299597102163

• A Phase II Trial of Ofatumumab in Subjects with Waldenstrom's Macroglobulinemia 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Furman, R. R., Eradat, H., DiRienzo, C. G., Hayman, S. R., Hofmeister, C. C., Avignon, N. A., Leonard, J. P., Coleman, M., Advani, R., Switzky, J. C., Liao, Q., Shah, D. N., Lisby, S., Lin, T. S. AMER SOC HEMATOLOGY. 2011: 1581–81

  View details for Web of Science ID 000299597105429

• Immunotransplant for Mantle Cell Lymphoma: Phase I/II Study Preliminary Results 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Brody, J. D., Czerwinski, D. K., Carlton, V., Moorhead, M., Zheng, J., Klinger, M., Faham, M., Advani, R., Kohrt, H. E., Alizadeh, A. A., Negrin, R. S., Weng, W., Sheehan, K., Levy, R. AMER SOC HEMATOLOGY. 2011: 1323–23

  View details for Web of Science ID 000299597104419

• Prospective, Multicenter Study of the MTOR Inhibitor Everolimus (RAD001) As Primary Therapy in Waldenstrom's Macroglobulinemia 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Treon, S. P., Tripsas, C. K., Ioakimidis, L., Warren, D., Patterson, C., Heffner, L., Eradat, H., Gregory, S. A., Thomas, S., Advani, R., Baz, R., Badros, A. Z., Matous, J., Anderson, K. C., Ghobrial, I. M. AMER SOC HEMATOLOGY. 2011: 1273–74

  View details for Web of Science ID 000299597104302

• The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Wang, L., Martin, P., Blum, K. A., Kahl, B. S., Maeda, L. S., Advani, R., Williams, M. E., Rule, S., Rodriguez, S., Pang, C., Hedrick, E., Goy, A. AMER SOC HEMATOLOGY. 2011: 203–4

  View details for Web of Science ID 000299597100443

• Allogeneic Transplant Following Brentuximab Vedotin Treatment in Patients with Relapsed or Refractory CD30+Lymphomas 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Illidge, T., Bouabdallah, R., Chen, R. W., Gopal, A. K., Moskowitz, C. H., Ramchandren, R., Rosenblatt, J. D., Shustov, A. R., Tilly, H., Trippett, T., Grove, L. E., Advani, R. H. AMER SOC HEMATOLOGY. 2011: 1335–36

  View details for Web of Science ID 000299597104442

• Patterns of Failure in Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma (HL) Treated with ABVD plus Radiotherapy or the Stanford V Regimen in the Randomized Phase III North American Intergroup Trial: E2496 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R., Hong, F., Gordon, L. I., Gascoyne, R. D., Wagner, H., Hoppe, R. T., Fisher, R. I., Bartlett, N. L., Kahl, B. S., Stiff, P., Cheson, B. D., Belch, A. R., Friedberg, J. W., Kassis, J., Blum, K. A., Habermann, T. M., Tuscano, J., Horning, S. J. AMER SOC HEMATOLOGY. 2011: 696–97

  View details for Web of Science ID 000299597102198

• Multicenter Phase I Trial of Intraventricular Immuno-Chemotherapy in Recurrent CNS Lymphoma 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Rubenstein, J. L., Chen, L., Advani, R., Drappatz, J., Gerstner, E., Batchelor, T., Krouwer, H., Kadoch, C., Munster, P., Cha, S., Shuman, M. A., Damon, L. E. AMER SOC HEMATOLOGY. 2011: 438–39

  View details for Web of Science ID 000299597101230

• Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Forero-Torres, A., Berryman, R. B., Advani, R. H., Bartlett, N. L., Chen, R. W., Fanale, M. A., Gopal, A. K., O'Connor, O. A., Olshefski, R., Smith, S. E., Grove, L. E., Matous, J. AMER SOC HEMATOLOGY. 2011: 1585–86

  View details for Web of Science ID 000299597105439

• Phase I trial of oblimersen (GenasenseA (R)) and gemcitabine in refractory and advanced malignancies INVESTIGATIONAL NEW DRUGS Galatin, P. S., Advani, R. H., Fisher, G. A., Francisco, B., Julian, T., Losa, R., Sierra, M. I., Sikic, B. I. 2011; 29 (5): 971-977

  Abstract

  Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients with refractory malignancies.Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine, and also to measure the effect of oblimersen on Bcl-2 expression.7 women and 9 men, median age 55 years (range 35-74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day (n = 4) or 7 mg/kg/day (n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m(2)/h for a total dose of 1,000 mg/m(2) (n = 7; cohorts I and II), 1,200 mg/m(2) (n = 3; cohort III), or 1,500 mg/m(2) (n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C(ss) and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose. There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than in progressing patients.The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred. There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days 1-5, and gemcitabine 1,500 mg/m(2) on day 5, every two weeks.

  View details for DOI 10.1007/s10637-010-9416-4

  View details for PubMedID 20349264

• Hodgkin lymphoma. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Bello, C. M., Bierman, P. J., Blum, K. A., Dabaja, B., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Poppe, M., Pro, B., Weiss, L., Winter, J. N., Yahalom, J. 2011; 9 (9): 1020-1058

  View details for PubMedID 21917626

• NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Bello, C. M., Bierman, P. J., Blum, K. A., Dabaja, B., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Poppe, M., Pro, B., Weiss, L., Winter, J. N., Yahalom, J. 2011; 9 (9): 1020-1058

  View details for Web of Science ID 000294584900007

• Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment BLOOD Alizadeh, A. A., Gentles, A. J., Alencar, A. J., Liu, C. L., Kohrt, H. E., Houot, R., Goldstein, M. J., Zhao, S., Natkunam, Y., Advani, R. H., Gascoyne, R. D., Briones, J., Tibshirani, R. J., Myklebust, J. H., Plevritis, S. K., Lossos, I. S., Levy, R. 2011; 118 (5): 1350-1358

  Abstract

  Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

  View details for DOI 10.1182/blood-2011-03-345272

  View details for PubMedID 21670469

• Lymphoma in Pregnancy Initially Diagnosed as Vaginal Intraepithelial Neoplasia and Lichen Planus OBSTETRICS AND GYNECOLOGY Thuong-Thuong Nguyen, T. T., Gubens, M., Arber, D. A., Advani, R., Juretzka, M., Aziz, N. 2011; 118 (2): 486-489

  Abstract

  Non-Hodgkin's lymphoma presenting as a vaginal mass in pregnancy is uncommon.A 38-year-old primigravid woman presented at 27 weeks of gestation with vaginal lesions, bleeding, and discharge. Previous vaginal biopsies had been consistent with vaginal intraepithelial neoplasia 1 and lichen planus. After admission for this enlarging vaginal mass and bleeding, she was noted to have a newly palpable breast mass. Biopsy of the breast mass and subsequent re-evaluation of original vaginal biopsies were consistent with diffuse large B-cell lymphoma. She was treated with chemoimmunotherapy during pregnancy and delivered a viable neonate at term.Although benign vaginal conditions are common, non-Hodgkin's lymphoma should be considered in the differential diagnosis of persistent or enlarging vaginal lesions in pregnancy.

  View details for DOI 10.1097/AOG.0b013e3182234d12

  View details for PubMedID 21768862

• IMMUNOTRANSPLANT FOR MANTLE CELL LYMPHOMA: PHASE I/II STUDY PRELIMINARY RESULTS 11th International Conference on Malignant Lymphoma Brody, J., Advani, R., Czerwinski, D., Negrin, R., Levy, R. OXFORD UNIV PRESS. 2011: 102–102

  View details for Web of Science ID 000291996300079

• EFFICACY AND TOLERABILITY OF ABVD AND STANFORD V FOR ELDERLY ADVANCED-STAGE HODGKIN LYMPHOMA (HL): ANALYSIS FROM THE PHASE III RANDOMIZED US INTERGROUP TRIAL E2496 Evens, A. M., Hong, F., Gordon, L. I., Fisher, R. I., Bartlett, N., Connors, J. M., Wagner, H., Gospodarowicz, M., Cheson, B. D., Advani, R., Kahl, B. S., Hoppe, R. T., Horning, S. J. OXFORD UNIV PRESS. 2011: 117–18

  View details for Web of Science ID 000291996300119

• DURABLE REMISSIONS WITH SGN-35 (BRENTUXIMAB VEDOTIN): UPDATED RESULTS OF A PHASE 2 STUDY IN PATIENTS WITH RELAPSED OR REFRACTORY SYSTEMIC ANAPLASTIC LARGE CELL LYMPHOMA (SALCL) Shustov, A., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M., Connors, J. M., Yang, Y., Sievers, E. L., Kennedy, D. A., Pro, B. OXFORD UNIV PRESS. 2011: 125

  View details for Web of Science ID 000291996300137

• A PHASE 2B TRIAL COMPARING DACETUZUMAB plus R-ICE VS PLACEBO plus R-ICE IN PATIENTS WITH RELAPSED DIFFUSE LARGE B-CELL LYMPHOMA Fayad, L., Ansell, S. M., Advani, R., Coiffier, B., Bartlett, N. L., Stuart, R., Forero-Torres, A., Kuliczkowski, K., Drachman, J. G. OXFORD UNIV PRESS. 2011: 132

  View details for Web of Science ID 000291996300157

• THE BTK INHIBITOR PCI-32765 IS HIGHLY ACTIVE AND WELL TOLERATED IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY B CELL MALIGNANCIES: FINAL RESULTS FROM A PHASE I STUDY Advani, R. H., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B. W., Kolibaba, K. S., Furman, R. R., Buggy, J. J., Loury, D. J., Hedrick, E., Izumi, R., Hamdy, A. M., Fowler, N. H. OXFORD UNIV PRESS. 2011: 135

  View details for Web of Science ID 000291996300165

• ABBREVIATED 8 WK CHEMOTHERAPY (CT) plus INVOLVED NODE RADIOTHERAPY (INRT) FOR NON-BULKY STAGE I-II HODGKIN LYMPHOMA: PRELIMINARY RESULTS OF THE STANFORD G5 STUDY Advani, R. H., Horning, S. J., Jonathan, E., Daadi, S., Allen, J., Rosenberg, S. A., Hoppe, R. T. OXFORD UNIV PRESS. 2011: 179

  View details for Web of Science ID 000291996300297

• OUTCOME OF LYMPHOMA DURING PREGNANCY: AN INDIVIDUALIZED THERAPEUTIC APPROACH RESULTS IN EXCELLENT PATIENT OUTCOMES AND MINIMAL OBSTETRIC OR FETAL COMPLICATIONS 11th International Conference on Malignant Lymphoma YARBER, J. L., Otis, S. A., Robinson, B. K., Gordon, L. I., Winter, J. N., Advani, R. H., Evens, A. M. OXFORD UNIV PRESS. 2011: 191–191

  View details for Web of Science ID 000291996300337

• PHASE II STUDY OF R-CHOP FOLLOWED BY Y-90-IBRITUMOMAB TIUXETAN IN UNTREATED MANTLE CELL LYMPHOMA (MCL): 5 YEAR FOLLOW-UP OF EASTERN COOPERATIVE ONCOLOGY GROUP E1499 11th International Conference on Malignant Lymphoma Smith, M. R., Li, H., Gordon, L., Gascoyne, R., Paietta, E., Forero-Torres, A., Kahl, B., Advani, R., Hong, F., Horning, S. OXFORD UNIV PRESS. 2011: 86–87

  View details for Web of Science ID 000291996300034

• Efficacy and tolerability of ABVD and Stanford V for elderly advanced-stage Hodgkin lymphoma (HL): Analysis from the phase III randomized US Intergroup Trial E2496 Evens, A. M., Hong, F., Gordon, L. I., Fisher, R. I., Bartlett, N., Connors, J. M., Wagner, H., Gospodarowicz, M. K., Cheson, B. D., Advani, R., Kahl, B. S., Hoppe, R. T., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.8035

  View details for Web of Science ID 000208880302349

• Immunotransplant for mantle cell lymphoma: Phase I/II study preliminary results. Brody, J., Advani, R., Weng, W., Czerwinski, D., Alizadeh, A. A., Kohrt, H. E., Negrin, R., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.2509

  View details for Web of Science ID 000208880301324

• Non-Hodgkin's Lymphomas JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Wierda, W. G., Yahalom, J., Zafar, N. 2011; 9 (5): 484-560

  View details for Web of Science ID 000290292400005

  View details for PubMedID 21550968

• ACR Appropriateness Criteria (R) on Hodgkin's Lymphoma-Unfavorable Clinical Stage I and II JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Das, P., Ng, A., Constine, L. S., Advani, R., Flowers, C., Friedberg, J., Hodgson, D. C., Schwartz, C. L., Wilder, R. B., Wilson, L. D., Yunes, M. J. 2011; 8 (5): 302-308

  Abstract

  Combined-modality therapy, consisting of chemotherapy followed by radiation therapy (RT), represents the standard of care for most patients with unfavorable-prognosis early-stage Hodgkin's lymphoma. The most widely accepted chemotherapy regimen is ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine); however, recent trials have evaluated other regimens such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V. After chemotherapy, the standard radiation field is involved-field RT, although there is increasing interest now in involved-node RT. The authors review recent trials on chemotherapy and RT for unfavorable-prognosis early-stage Hodgkin's lymphoma. This article presents illustrative clinical cases, with treatment recommendations from an expert panel of radiation oncologists and medical oncologists.

  View details for DOI 10.1016/j.jacr.2011.01.009

  View details for Web of Science ID 000306201300006

  View details for PubMedID 21531305

• Brentuximab vedotin (SGN-35) treatment in relapsed CD30-positive Hodgkin's lymphoma patients following allogeneic stem cell transplant: a multi-centre case series Gopal, A. K., Ramchandren, R., Berryman, R. B., Advani, R. H., Chen, R., Smith, S., Cooper, M., Engert, A., Matous, J., Zain, J., Grove, L. E., Hunder, N. N., O'Connor, O. A. NATURE PUBLISHING GROUP. 2011: S36

  View details for Web of Science ID 000289195400086

• CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma SCIENCE TRANSLATIONAL MEDICINE Burington, B., Yue, P., Shi, X., Advani, R., Lau, J. T., Tan, J., Stinson, S., Stinson, J., Januario, T., de Vos, S., Ansell, S., Forero-Torres, A., Fedorowicz, G., Yang, T. T., Elkins, K., Du, C., Mohan, S., Yu, N., Modrusan, Z., Seshagiri, S., Yu, S., Pandita, A., Koeppen, H., French, D., Polson, A. G., Offringa, R., Whiting, N., Ebens, A., Dornan, D. 2011; 3 (74)

  Abstract

  The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.

  View details for DOI 10.1126/scitranslmed.3001620

  View details for Web of Science ID 000292974200002

  View details for PubMedID 21411738

• Sezary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC) JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Olsen, E. A., Rook, A. H., Zic, J., Kim, Y., Porcu, P., Querfeld, C., Wood, G., Demierre, M., Pittelkow, M., Wilson, L. D., Pinter-Brown, L., Advani, R., Parker, S., Kim, E. J., Junkins-Hopkins, J. M., Foss, F., Cacchio, P., Duvic, M. 2011; 64 (2): 352-404

  Abstract

  Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

  View details for DOI 10.1016/j.jaad.2010.08.037

  View details for Web of Science ID 000286780400016

  View details for PubMedID 21145619

• Prediction of Survival In Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes Reflecting Tumor and Microenvironment 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Alizadeh, A. A., Gentles, A. J., Alencar, A. J., Kohrt, H. E., Houot, R., Goldstein, M. J., Zhao, S., Natkunam, Y., Advani, R., Gascoyne, R. D., Briones, J., Tibshirani, R. J., Myklebust, J. H., Plevritis, S. K., Lossos, I. S., Levy, R. AMER SOC HEMATOLOGY. 2010: 836–37

  View details for Web of Science ID 000289662202229

• The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity In Patients with Relapsed/Refractory B-Cell Malignancies: Results From a Phase I Study Fowler, N., Sharman, J., Smith, S. M., Boyd, T., Grant, B., Kolibaba, K. S., Furman, R. R., Buggy, J., Loury, D., Hamdy, A., Advani, R. AMER SOC HEMATOLOGY. 2010: 425

  View details for Web of Science ID 000289662201067

• Complete Remissions with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma Shustov, A. R., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramachandren, R., Fanale, M. A., Connors, J. M., Yang, Y., Sievers, E. L., Kennedy, D. A., Pro, B. AMER SOC HEMATOLOGY. 2010: 423–24

  View details for Web of Science ID 000289662201064

• The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies Burger, J. A., O'Brien, S., Fowler, N., Advani, R., Sharman, J., Furman, R. R., Izumi, R., Buggy, J., Loury, D., Hamdy, A., Byrd, J. C., Blum, K. A. AMER SOC HEMATOLOGY. 2010: 32

  View details for Web of Science ID 000289662200058

• A Randomized Phase III Trial of ABVD Vs. Stanford V +/- Radiation Therapy In Locally Extensive and Advanced Stage Hodgkin's Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperatve Oncology Group (E2496) Gordon, L. I., Hong, F., Fisher, R. I., Bartlett, N. L., Connors, J. M., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Gospodarowicz, M., Advani, R., Kahl, B., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J., Hoppe, R., Horning, S. J. AMER SOC HEMATOLOGY. 2010: 185

  View details for Web of Science ID 000289662200416

• Randomized Phase III Trial Comparing ABVD plus Radiotherapy and the Stanford V.Regimen In Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma: A-Subset Analysis of the US Intergroup Trial E2496 Advani, R., Hong, F., Fisher, R. I., Bartlett, N. L., Robinson, S., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Gordon, L. I., Kahl, B., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J., Hoppe, R., Horning, S. J. AMER SOC HEMATOLOGY. 2010: 185–86

  View details for Web of Science ID 000289662200417

• A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML) 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Pollyea, D. A., Kohrt, H. E., Gallegos, L., Berube, C., Coutre, S., Gotlib, J., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 1347–47

  View details for Web of Science ID 000289662203619

• Navitoclax (ABT-263) Plus Rituximab: Interim Results of a Phase 1 Study In Patients with CD20-Positive Lymphoid Malignancies 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kahl, B., Roberts, A. W., Seymour, J. F., Advani, R. H., Persky, D. O., Yang, J., Cui, Y., Busman, T., Krivoshik, A., Enschede, S., Humerickhouse, R. AMER SOC HEMATOLOGY. 2010: 1608–

  View details for Web of Science ID 000289662204363

• Clinical and Pathological Features of Non-Hodgkin Lymphomas Harboring Concurrent t(14;18) and 8q24 Anomalies 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Alizadeh, A. A., Anderson, M., Kohrt, H. E., Shyam, R. M., Bangs, C. D., Cherry, A. M., Advani, R., Natkunam, Y., Levy, R. AMER SOC HEMATOLOGY. 2010: 1291–92

  View details for Web of Science ID 000289662203465

• In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J., Czerwinski, D., Xing, L., Morales, A., Ai, W., Abdulla, F., Navi, D., Tibshirani, R. J., Advani, R., Natkunam, Y., Hoppe, R. T., Levy, R. AMER SOC HEMATOLOGY. 2010: 130–30

  View details for Web of Science ID 000289662200287

• In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study JOURNAL OF CLINICAL ONCOLOGY Brody, J. D., Ai, W. Z., Czerwinski, D. K., Torchia, J. A., Levy, M., Advani, R. H., Kim, Y. H., Hoppe, R. T., Knox, S. J., Shin, L. K., Wapnir, I., Tibshirani, R. J., Levy, R. 2010; 28 (28): 4324-4332

  Abstract

  Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

  View details for DOI 10.1200/JCO.2010.28.9793

  View details for Web of Science ID 000282272700032

  View details for PubMedID 20697067

  View details for PubMedCentralID PMC2954133

• Classical Hodgkin Lymphoma in First Complete Remission: Is There a Role for F-18 FDG PET/CT Surveillance? 23rd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) Lagaru, A., Maeda, L. S., Lin, F. I., Hoppe, R. T., Rosenberg, S. A., Gambhir, S. S., Advani, R. H. SPRINGER. 2010: S212–S213

  View details for Web of Science ID 000283023800065

• A PHASE I TRIAL OF BTK INHIBITOR PCI-32765 IN PATIENTS WITH RELAPSED NON-HODGKIN'S LYMPHOMA: EVIDENCE OF ANTITUMOR ACTIVITY Fowler, N., Sharman, J., Smith, S., Pollyea, D., Boyd, T., Grant, B., Kathryn, K., Buggy, J., Loury, D., Hamdy, A., Advani, R. FERRATA STORTI FOUNDATION. 2010: 371

  View details for Web of Science ID 000496828403188

• PHASE 1 STUDY OF NAVITOCLAX (ABT-263) PLUS RITUXIMAB IN CD20-POSITIVE LYMPHOID MALIGNANCIES Roberts, W., Advani, R., Kahl, B., Persky, D., Xiong, H., Cui, Y., Busman, T., Krivoshik, A., Enschede, S., Humerickhouse, R. FERRATA STORTI FOUNDATION. 2010: 371

  View details for Web of Science ID 000496828403189

• PHASE 1 STUDY OF NAVITOCLAX (ABT-263) PLUS RITUXIMAB IN CD20-POSITIVE LYMPHOID MALIGNANCIES 15th Annual Meeting of the European-Hematology-Association Roberts, W., Advani, R., Kahl, B., Persky, D., Xiong, H., Cui, Y., Busman, T., Krivoshik, A., Enschede, S., Humerickhouse, R. FERRATA STORTI FOUNDATION. 2010: 371–371

  View details for Web of Science ID 000279051301215

• A PHASE I TRIAL OF BTK INHIBITOR PCI-32765 IN PATIENTS WITH RELAPSED NON-HODGKIN'S LYMPHOMA: EVIDENCE OF ANTITUMOR ACTIVITY Fowler, N., Sharman, J., Smith, S., Pollyea, D., Boyd, T., Grant, B., Kathryn, K., Buggy, J., Loury, D., Hamdy, A., Advani, R. FERRATA STORTI FOUNDATION. 2010: 371

  View details for Web of Science ID 000279051301214

• Prognostic significance of CD15 expression in classical Hodgkin lymphoma (cHL): The Stanford University experience Maeda, L. S., Hoppe, R. T., Warnke, R. A., Natkunam, Y., Rosenberg, S. A., Homing, S. J., Advani, R. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.e18521

  View details for Web of Science ID 000208852001496

• Effect of Btk inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL: Evidence of antitumor activity from a phase I study Advani, R., Sharman, J. P., Smith, S. M., Pollyea, D. A., Boyd, T. E., Grant, B. W., Kolibaba, K. S., Buggy, J. J., Hamdy, A., Fowler, N. H. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.8012

  View details for Web of Science ID 000208852005032

• Phase II study of denileukin diftitox with CHOP chemotherapy in newly-diagnosed PTCL: CONCEPT trial Foss, F. M., Sjak-Shie, N. N., Goy, A., Advani, R., Jacobsen, E. D. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for Web of Science ID 000208852005065

• ACR Appropriateness Criteria (R): Follow-Up of Hodgkin's Lymphoma CURRENT PROBLEMS IN CANCER Ng, A., Constine, L. S., Advani, R., Das, P., Flowers, C., Friedberg, J., Hodgson, D. C., Schwartz, C. L., Wilder, R. B., Wilson, L. D., Yunes, M. J. 2010; 34 (3): 211-227

  Abstract

  In the follow-up of Hodgkin's lymphoma patients, the focus in the first 5 years is to detect recurrence, while after 5 years, the focus is on limiting and detecting late effects of treatment. In the first 5 years post-treatment, routine history and physical and computed tomography (CT) imaging (more frequent in the first 2 years) are generally appropriate. However, there are limited data to support the role of positron emission tomography scanning as routine follow-up. Beyond 5 years post-treatment, annual history and physical is appropriate, although there is no longer a role for routine imaging for recurrences. Women irradiated to the chest area at a young age (<35) would benefit from annual mammogram screening given the increased breast cancer risk. Magnetic resonance imaging can be considered, although there is a lack of data supporting its role in this population. Low-dose chest CT for lung cancer screening in patients with history of mediastinal irradiation and/or alkylating chemotherapy exposures and a smoking history can be considered, although data on its utility is lacking. Cardiac screening with echocardiogram and exercise tolerance tests in patients with history of mediastinal irradiation and/or adriamycin exposure may be appropriate, although the optimal screening interval would depend on mediastinal dose, adriamycin dose, presence of other cardiac risk factors and findings at the baseline screening. Patients at risk for cardiac disease due to treatment exposure would also benefit from lipid screening every 1-3 years.

  View details for DOI 10.1016/j.currproblcancer.2010.04.007

  View details for Web of Science ID 000279038500006

  View details for PubMedID 20541059

• Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules CLINICAL CANCER RESEARCH Advani, R. H., Hurwitz, H. I., Gordon, M. S., Ebbinghaus, S. W., Mendelson, D. S., Wakelee, H. A., Hoch, U., Silverman, J. A., Havrilla, N. A., Berman, C. J., Fox, J. A., Allen, R. S., Adelman, D. C. 2010; 16 (7): 2167-2175

  Abstract

  Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity.Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history.In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m(2)). At 60 mg/m(2), four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m(2), two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m(2) (HP patients) and 60 mg/m(2) (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m(2)). At 18 mg/m(2), two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m(2). Voreloxin exhibited low clearance (2 L/h/m(2)), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria.Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia.

  View details for DOI 10.1158/1078-0432.CCR-09-2236

  View details for PubMedID 20233886

• Non-Hodgkin's Lymphomas JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Abramson, J. S., Advani, R. H., Andreadis, C. B., Byrd, J. C., Czuczman, M. S., Fayad, L., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kim, Y. H., LaCasce, A. S., Mughal, T. I., Nademanee, A., Porcu, P., Press, O., Prosnitz, L., Reddy, N., Smith, M. R., Sokol, L., Swinnen, L., Vose, J. M., Wierda, W. G., Yahalom, J., Yunus, F. 2010; 8 (3): 288-334

  View details for Web of Science ID 000275349900005

• NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Abramson, J. S., Advani, R. H., Andreadis, C. B., Byrd, J. C., Czuczman, M. S., Fayad, L., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kim, Y. H., LaCasce, A. S., Mughal, T. I., Nademanee, A., Porcu, P., Press, O., Prosnitz, L., Reddy, N., Smith, M. R., Sokol, L., Swinnen, L., Vose, J. M., Wierda, W. G., Yahalom, J., Yunus, F. 2010; 8 (3): 288-334

  View details for PubMedID 20202462

• Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study BLOOD Horning, S. J., Juweid, M. E., Schoeder, H., Wiseman, G., McMillan, A., Swinnen, L. J., Advani, R., Gascoyne, R., Quon, A. 2010; 115 (4): 775-777

  Abstract

  Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET(+) interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: kappa statistic = 0.445 using ECOG criteria, and kappa statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924 [corrected].

  View details for DOI 10.1182/blood-2009-08-234351

  View details for PubMedID 19767508

• Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP) BRITISH JOURNAL OF HAEMATOLOGY Gratzinger, D., Advani, R., Zhao, S., Talreja, N., Tibshirani, R. J., Shyam, R., Horning, S., Sehn, L. H., Farinha, P., Briones, J., Lossos, I. S., Gascoyne, R. D., Natkunam, Y. 2010; 148 (2): 235-244

  Abstract

  Diffuse large B cell lymphoma (DLBCL) is clinically and biologically heterogeneous. In most cases of DLBCL, lymphoma cells co-express vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, suggesting autocrine in addition to angiogenic effects. We enumerated microvessel density and scored lymphoma cell expression of VEGF, VEGFR1, VEGFR2 and phosphorylated VEGFR2 in 162 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone)-like regimens. VEGFR2 expression correlated with shorter overall survival (OS) independent of International Prognostic Index (IPI) (P = 0.0028). Phosphorylated VEGFR2 (detected in 13% of cases) correlated with shorter progression-free survival (PFS, P = 0.044) and trended toward shorter OS on univariate analysis. VEGFR1 was not predictive of survival on univariate analysis, but it did correlate with better OS on multivariate analysis with VEGF, VEGFR2 and IPI (P = 0.036); in patients with weak VEGFR2, lack of VEGFR1 coexpression was significantly correlated with poor OS independent of IPI (P = 0.01). These results are concordant with our prior finding of an association of VEGFR1 with longer OS in DLBCL treated with chemotherapy alone. We postulate that VEGFR1 may oppose autocrine VEGFR2 signalling in DLBCL by competing for VEGF binding. In contrast to our prior results with chemotherapy alone, microvessel density was not prognostic of PFS or OS with R-CHOP-like therapy.

  View details for DOI 10.1111/j.1365-2141.2009.07942.x

  View details for PubMedID 19821819

• Analysis of Breast Cancer Subtypes in Women who Develop Breast Cancer following Mantle Irradiation for Hodgkin's Disease Horst, K. C., Hancock, S., Advani, R., Horning, S., Rosenberg, S., Hoppe, R. T. ELSEVIER SCIENCE INC. 2010: S206–S207

  View details for DOI 10.1016/j.ijrobp.2010.07.499

  View details for Web of Science ID 000288775700442

• Mid-treatment Metabolic Tumor Volume Predicts Progression and Death among Patients with Hodgkin's Disease 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Tseng, D., Rachakonda, L. P., Su, Z., Advani, R., Horning, S., Rosenberg, S. A., Hoppe, R. T., Quon, A., Graves, E. E., Loo, B. W., Tran, P. T. ELSEVIER SCIENCE INC. 2010: S546–S547

  View details for Web of Science ID 000288775701265

• The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405-A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Kahl, B. S., Li, H., Smith, M. R., Gascoyne, R. D., Paietta, E., Advani, R., Horning, S. J. AMER SOC HEMATOLOGY. 2009: 663–63

  View details for Web of Science ID 000272725802029

• Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies: Phase 1 Results. Horwitz, S. M., Vose, J. M., Advani, R., Sankhala, K., Padmanabhan, S., Hamlin, P. A., Chen, A., Zain, J. M., Fruchtman, S., O'Connor, O. A. AMER SOC HEMATOLOGY. 2009: 667–68

  View details for Web of Science ID 000272725802042

• Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma Pohlman, B., Advani, R., Duvic, M., Hymes, K. B., Intragumtornchai, T., Lekhakula, A., Shpilberg, O., Lerner, A., Ben-Yehuda, D., Beylot-Barry, M., Hillen, U., Fagerberg, J., Foss, F. M. AMER SOC HEMATOLOGY. 2009: 379

  View details for Web of Science ID 000272725801100

• Cardiac Toxicity Associated with the Anti-VEGF Monoclonal Antibody Bevacizumab (Avastin) in Combination with CROP (A-CHOP) Chemotherapy for Peripheral T Cell Lymphoma (PTCL): The ECOG 2404 Trial. Advani, R. H., Hong, F., Ganjoo, K. N., Manola, J. B., Swinnen, L. J., Habermann, T. M., Horning, S. J. AMER SOC HEMATOLOGY. 2009: 667

  View details for Web of Science ID 000272725802039

• MicroRNA Are Useful Biomarkers for Prediction of Response to Therapy and Survival of Patients with Diffuse Large B-Cell Lymphoma Alencar, A. J., Malumbres, R., Advani, R., Talreja, N., Shyam, R., Briones, J., Natkunam, Y., Gascoyne, R. D., Tibshirani, R., Lossos, I. S. AMER SOC HEMATOLOGY. 2009: 258–59

  View details for Web of Science ID 000272725800625

• A Phase I Dose Escalation Study of the Btk Inhibitor PCI-32765 in Relapsed and Refractory B Cell Non-Hodgkin Lymphoma and Use of a Novel Fluorescent Probe Pharmacodynamic Assay. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Pollyea, D. A., Smith, S., Fowler, N., Boyd, T. E., Smith, A. M., Sirisawad, M., Honigberg, L. A., Hamdy, A., Advani, R. AMER SOC HEMATOLOGY. 2009: 1430–30

  View details for Web of Science ID 000272725804377

• Role or FDG-PET/CT Surveillance for Patients with Classical Hodgkin's Disease in First Complete Response: The Stanford University Experience. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Maeda, L. S., Horning, S. J., Iagaru, A. H., Lin, F. I., Hoppe, R. T., Rosenberg, S. A., Advani, R. H. AMER SOC HEMATOLOGY. 2009: 626–26

  View details for Web of Science ID 000272725801743

• CD40 Pathway Activation Status Predicts Response to CD40 Targeted Therapy in Diffuse Large b-Cell Lymphoma. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Dornan, D., Burington, B., Yue, P., Shi, X., Advani, R., Yu, N., Lau, J. T., Yu, S., de Vos, S., Ansell, S. M., Forero-Torres, A., Modrusan, Z., Koeppen, H., Yang, T., Du, C., Elkins, K., Polson, A. G., Offringa, R., Whiting, N., Ebens, A. J. AMER SOC HEMATOLOGY. 2009: 1065–65

  View details for Web of Science ID 000272725803276

• The emerging role for rituximab in the treatment of nodular lymphocyte predominant Hodgkin lymphoma CURRENT OPINION IN ONCOLOGY Maeda, L. S., Advani, R. H. 2009; 21 (5): 397-400

  Abstract

  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma that is distinct from classical Hodgkin lymphoma (cHL). The unique malignant 'popcorn' cells express the B-cell antigen CD20 and lack expression of the cHL markers CD15 and CD30. Traditionally, NLPHL has been included with cHL in clinical trials with excellent prognosis reported in several series. The reliable expression of CD20 has led to the evaluation of the chimeric monoclonal anti-CD20 antibody rituximab in several recent trials.Three series have reported the efficacy of 4 weekly doses of rituximab in all stages of NLPHL, both in the treatment-naive and relapsed settings. Emerging data also suggest that longer courses of antibody therapy may improve the duration of response.Rituximab appears to offer a nonchemotherapy-based effective treatment option, which is well tolerated. Ongoing studies are required to further define the optimal patient population who may benefit from rituximab and evaluate its role in maintenance as well as in combination with radiotherapy and chemotherapy.

  View details for DOI 10.1097/CCO.0b013e32832f3ca3

  View details for PubMedID 19606035

• Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma Characterization of Clinical Subset With Worse Outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D. K., Jones, C. R., Vanoli-Storz, M. N., Kohler, S., Reddy, S., Advani, R., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2009: 667–74

  Abstract

  To identify prognostic factors in primary cutaneous anaplastic large cell lymphoma (pcALCL), focusing on extensive limb disease (ELD), defined as initial presentation or progression to multiple skin tumors in 1 limb or contiguous body regions, and to study gene expression profiles of patients with pcALCL.Retrospective cohort study.The Stanford Comprehensive Cancer Center and dermatology ambulatory clinics.A total of 48 patients with pcALCL evaluated from 1990 through 2005.Hazard ratios (HRs) for prognostic factors for overall survival (OS) and disease-specific survival (DSS) and risk factors for progression to extracutaneous disease were identified using Cox regression. Gene expression profiles of 9 typical pcALCL and 3 ELD samples were investigated using complementary DNA microarrays.Univariate analysis demonstrated age, ELD, and progression to extracutaneous disease as significant prognostic factors for OS, whereas ELD and progression to extracutaneous disease were significant for DSS. In multivariate analysis, age (HR, 1.83; 95% confidence interval [CI], 1.02-3.26) and progression to extracutaneous disease (HR, 6.42; 95% CI, 1.39-29.68) remained significant for OS, whereas ELD (HR, 29.31; 95% CI, 1.72-500.82) and progression to extracutaneous disease (HR, 13.12; 95% CI, 1.03-167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a risk factor for progression to extracutaneous disease (HR, 10.20; 95% CI, 1.84-56.72). Microarray data revealed that patients with ELD and typical pcALCL formed distinct clusters.Patients with ELD have a more aggressive course associated with a differential gene expression profile. More aggressive treatments may be indicated for patients with ELD and those whose disease progresses to extracutaneous disease because they have poorer outcomes.

  View details for PubMedID 19528422

• Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP) 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Gratzinger, D., Advani, R., Zhao, S., Talreja, N., Tibshirani, R. J., Horning, S. J., Levy, R., Lossos, I. S., Gascoyne, R. D., Natkunam, Y. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605490

• A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients Robert, F., Verschraegen, C., Hurwitz, H., Uronis, H., Advani, R., Chen, A., Taverna, P., Wollman, M., Fox, J., Michelson, G. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606602302

• Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Kohrt, H. E., Advani, R., Hoppe, R., Rosenberg, S., Horning, S., Lee, P. P. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605482

• A gene signature predicts sensitivity to the partial CD40 agonist, dacetuzumab (SGN-40), in patients with diffuse large B-cell lymphoma Burington, B., Advani, R., Shi, X., Yue, P., Lau, J., Yu, S., Januario, T., de Vos, S., Ansell, S., Forero-Torres, A., Ebens, A., Whiting, N., Dornan, D. AMER ASSOC CANCER RESEARCH. 2009

  View details for Web of Science ID 000209701805315

• Targeting CD40 in Waldenstrom's Macroglobulinemia 5th International Workshop on Waldenstroms Macroglobulinemia Lee, M., Advani, R. CIG MEDIA GROUP, LP. 2009: 87–89

  Abstract

  CD40 is a member of the tumor necrosis factor (TNF) receptor family and is expressed in a majority of B-cell malignancies. In Waldenström's macroglobulinemia (WM), CD40 expression is a common feature of bone marrow infiltrating lymphoplasmacytic cells, and preclinical evidence suggests that CD40 signaling is functionally important for WM growth and survival. Two antibodies targeting CD40 (SGN-40 and HCD 122 [Chir 12.12]) are currently undergoing clinical testing in multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody while SGN-40 is a humanized IgG1 partial agonistic antibody. Both agents have demonstrated activity in preclinical models and are potent mediators of antibodydependent cellular cytotoxicity (ADCC). Clinically, phase I data suggest both agents are well tolerated with no immunogenicity and have early evidence of single-agent clinical activity in relapsed and refractory NHL and MM. These observations support the testing of CD40-targeted agents in WM.

  View details for DOI 10.3816/CLM.2009.n.023

  View details for PubMedID 19362983

• Extranodal natural killer/T-cell lymphoma: current concepts in biology and treatment LEUKEMIA & LYMPHOMA Kohrt, H., Advani, R. 2009; 50 (11): 1773-1784

  Abstract

  Natural killer/T-cell (NK/T) lymphomas represent a group of rare tumors of NK and NK-T cells. The World Health Organization classifies NK-cell tumors into three types, extranodal NK/T-cell lymphomas (ENKL, nasal and non-nasal), NK-cell leukemias, and a blastic variant (CD4-positive, CD56-positive hematodermic neoplasms). We focus our review to the current concepts in biology and treatment of ENKL. Though considerable advances have been made in our understanding of NK-cell biology, malignant transformation including the role of Epstein-Barr virus, and prognosis, the rare nature of ENKL and its heterogeneity limit the ability to standardize therapy. Radiotherapy is fundamental to treatment of early-stage disease with a role for chemoradiotherapy among high-risk patients. The clinical course of advanced disease is highly aggressive with frequent chemotherapy resistance and a poor prognosis. Therapeutic approaches to advanced-stage or relapsed and refractory disease, including the appropriate sequence of chemotherapy, combined modality therapy, and stem cell transplantation is not well-established. International and multicenter clinical trials are needed for this rare and aggressive disease.

  View details for DOI 10.3109/10428190903186502

  View details for PubMedID 19883307

• CD81 Protein Is Expressed in Normal Germinal Center B-Cells and in Subtypes of Human Non-Hodgkin Lymphomas Luo, R. F., Zhao, S., Tibshirani, R., Lossos, I. S., Advani, R., Gratzinger, D., Wong, A., Talrega, N., Levy, R., Levy, S., Natkunam, Y. NATURE PUBLISHING GROUP. 2009: 275A

  View details for Web of Science ID 000262486301249

• CD81 Protein Is Expressed in Normal Germinal Center B-Cells and in Subtypes of Human Non-Hodgkin Lymphomas 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Luo, R. F., Zhao, S., Tibshirani, R., Lossos, I. S., Advani, R., Gratzinger, D., Wong, A., Talrega, N., Levy, R., Levy, S., Natkunam, Y. NATURE PUBLISHING GROUP. 2009: 275A–275A

  View details for Web of Science ID 000262371501249

• Dynamic CD8 T-Cell Responses to Tumor-Associated Epstein-Barr Virus Antigens in Patients With Epstein-Barr Virus-Negative Hodgkin's Disease ONCOLOGY RESEARCH Kohrt, H., Johannsen, A., Hoppe, R., Horning, S. J., Rosenberg, S. A., Advani, R., Lee, P. P. 2009; 18 (5-6): 287-292

  Abstract

  In almost half of patients diagnosed with Hodgkin's disease (HD), the malignant Reed-Sternberg (RS) cells express Epstein-Barr virus (EBV) antigens. Multiple translational efforts are actively investigating antitumor immune strategies by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. In an effort to explore the EBV-specific immune response, here we characterize EBV-specific CTL responses to lytic and latent EBV antigens in 12 consecutive EBV carriers with EBV-negative HD. Compared to healthy donors, we detected weak, baseline EBV-specific responses to both lytic and latent antigens by IFN-gamma ELISPOT in patients with EBV-negative HD at diagnosis. Chemoradiotherapy was associated temporally with a decrease EBV-specific responses. At final follow-up (24 months), recovery of EBV-specific CTL responses was observed with robustness of lytic-specific response equivalent to healthy controls. We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment. Our observation challenges prior belief that patients with HD remain immunodeficient following therapy and argues that the clinical significance of the EBV-specific immune response in EBV-negative HD should be further investigated.

  View details for DOI 10.3727/096504009X12596189659169

  View details for PubMedID 20225766

• Indolent primary cutaneous B-cell lymphoma: Experience using systemic rituximab JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Morales, A. V., Advani, R., Horwitz, S. M., Riaz, N., Reddy, S., Hoppe, R. T., Kim, Y. H. 2008; 59 (6): 953-957

  Abstract

  Optimal treatment of indolent primary cutaneous B-cell lymphoma (CBCL), marginal zone lymphoma, and follicle center lymphoma, presenting as multiple lesions, has yet to be established. Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen of B cells. Clinical efficacy of systemic rituximab in CBCL has yet to be established.We sought to assess the efficacy of systemic rituximab in the treatment of CBCL.This was a retrospective study of 15 patients with indolent CBCL treated with intravenous rituximab (375 mg/m(2)) as a single agent. Variable maintenance regimen was used in a subset of patients. Responses were categorized as complete response, partial response, stable disease, or progressive disease. The efficacy end points included were objective response rate, time to response, time to progression, and duration of response.Ten patients with follicle center lymphoma and 5 with marginal zone lymphoma were included. The objective response rate was 87% (60% complete response, 27% partial response). All patients with follicle center lymphoma had a response with 80% achieving complete response. Of the patients with marginal zone lymphoma, 3 had a response, one stable disease, and one progressive disease. Median follow-up was 36 months. Median time to response, duration of response, and time to progression was 30 days, 24 months, and 24 months, respectively.The study was limited by the small sample size and retrospective design.This study, although small, suggests that rituximab is a reasonable first-line treatment option for indolent CBCL with multiple lesions where local treatment is not effective or desirable.

  View details for DOI 10.1016/j.jaad.2008.08.005

  View details for Web of Science ID 000261141600006

  View details for PubMedID 18817999

• Evaluation and management of angioimmunoblastic T-cell lymphoma: a review of current approaches and future strategies. Clinical advances in hematology & oncology : H&O Alizadeh, A. A., Advani, R. H. 2008; 6 (12): 899-909

  Abstract

  Angioimmunoblastic T-cell lymphoma (AITL) is a rare and complex lymphoproliferative disorder, clinically characterized by widespread lymphadenopathy, extranodal disease, immune-mediated hemolysis, and polyclonal hypergammaglobulinemia. Significant progress has been made in the understanding of AITL since its recognition as a clonal T-cell disorder with associated deregulation of B-cells and endothelial cells within a unique malignant microenvironment. However, as the responses to conventional chemotherapy have not been durable, prognosis with current treatment approaches has remained dismal. Here we review the clinical presentation, prognosis, and management of patients with AITL. We discuss recent developments in the understanding of the pathogenesis of AITL at a cellular and molecular level, including the implication of the follicular helper T-cell as the corresponding cell of origin, the roles of Epstein-Barr virus, B-cell deregulation, angiogenesis, and other signaling pathways in AITL, and the therapeutic implications of these findings. Finally, we discuss recent clinical trials and novel treatment approaches in the management of patients with AITL.

  View details for PubMedID 19209140

• LMO2 Protein Expression Predicts Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with Immunochemotherapy (RCHOP): A Multicenter Validation Study. 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Advani, R., Talreja, N., Tibshirani, R., Zhao, S., Alizadeh, A., Briones, J., Bordes, R., Cohen, J., Horning, S., Levy, R., Lossos, I. S., Natkunam, Y. AMER SOC HEMATOLOGY. 2008: 1291–91

  View details for Web of Science ID 000262104704387

• Interim Positron Emission Tomography (PET) in Diffuse Large B-Cell Lymphoma: Independent Expert Nuclear Medicine Evaluation of ECOG 3404 Horning, S. J., Juweid, M. E., Schoder, H., Wiseman, G., McMillan, A., Swinnen, L. J., Advani, R., Gascoyne, R. D., Quon, A. AMER SOC HEMATOLOGY. 2008: 145

  View details for Web of Science ID 000262104700373

• A Phase 2 Clinical Trial of SGN-40 Monotherapy in Relapsed Diffuse Large B-Cell Lymphoma. Advani, R., De Vos, S., Ansell, S. M., Kahl, B., Cheson, B. D., Bartlett, N. L., Furman, R. R., Winter, J. N., Kaplan, H., Dornan, D., Whiting, N., Drachman, J., Forero-Torres, A. AMER SOC HEMATOLOGY. 2008: 368

  View details for Web of Science ID 000262104701224

• A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lympboprolifierative Malignancies 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Horwitz, S. M., Vose, J. M., Advani, R., Sankhala, K., Padmanabhan, S., Hamlin, P. A., Chen, A., Wilroy, S., Zain, J. M., Wright, D., Weissbrot, H., Hohenstein, M., Cagnoni, P. J., Saunders, M. E., O'Connor, O. A. AMER SOC HEMATOLOGY. 2008: 557–57

  View details for Web of Science ID 000262104701791

• Phase I trial of SNS-314, a novel selective inhibitor of Aurora kinases A, B, and C, in advanced solid tumor patients Robert, F., Hurwitz, H., Uronis, H., Verschraegen, C., Advani, R., Chen, A., Messerschmidt, G. L., Havrilla, N., Taverna, P., Evanchik, M. PERGAMON-ELSEVIER SCIENCE LTD. 2008: 91–92

  View details for DOI 10.1016/S1359-6349(08)72217-1

  View details for Web of Science ID 000261221200282

• Hodgkin disease/lymphoma. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Ambinder, R. F., Bierman, P. J., Bloomfield, C. D., Blum, K., Dabaja, B., Djulbegovic, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hudson, M. M., Kaminski, M. S., Love, G., Maloney, D. G., Mansur, D., Mauch, P. M., Moore, J. O., Schilder, R. J., Weiss, L. M., Winter, J. N., Yahalom, J., Zelenetz, A. D. 2008; 6 (6): 594-622

  View details for PubMedID 18597713

• Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP BLOOD Malumbres, R., Chen, J., Tibshirani, R., Johnson, N. A., Sehn, L. H., Natkunam, Y., Briones, J., Advani, R., Connors, J. M., Byrne, G. E., Levy, R., Gascoyne, R. D., Lossos, I. S. 2008; 111 (12): 5509-5514

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by variable clinical outcomes. Outcome prediction at the time of diagnosis is of paramount importance. Previously, we constructed a 6-gene model for outcome prediction of DLBCL patients treated with anthracycline-based chemotherapies. However, the standard therapy has evolved into rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Herein, we evaluated the predictive power of a paraffin-based 6-gene model in R-CHOP-treated DLBCL patients. RNA was successfully extracted from 132 formalin-fixed paraffin-embedded (FFPE) specimens. Expression of the 6 genes comprising the model was measured and the mortality predictor score was calculated for each patient. The mortality predictor score divided patients into low-risk (below median) and high-risk (above median) subgroups with significantly different overall survival (OS; P = .002) and progression-free survival (PFS; P = .038). The model also predicted OS and PFS when the mortality predictor score was considered as a continuous variable (P = .002 and .010, respectively) and was independent of the IPI for prediction of OS (P = .008). These findings demonstrate that the prognostic value of the 6-gene model remains significant in the era of R-CHOP treatment and that the model can be applied to routine FFPE tissue from initial diagnostic biopsies.

  View details for DOI 10.1182/blood-2008-02-136374

  View details for Web of Science ID 000256786500021

  View details for PubMedID 18445689

  View details for PubMedCentralID PMC2424149

• Clinical and immunologic responses to a novel in situ lymphoma vaccine maneuver: Results of a phase II trial of intra-tumoral CPG-[PF-3512676] 10th International Conference on Malignant Lymphoma Brody, J. D., Ai, W. Z., Czerwinski, D. K., Advani, R., Horning, S. J., Hoppe, R. T., Levy, R. OXFORD UNIV PRESS. 2008: 158–158

  View details for Web of Science ID 000256693500263

• SGN-40 shows evidence of activity in patients with relapsed non-Hodgkin lymphoma: Final results of a phase I dose-escalation study Advani, R., Forero-Torres, A., Furman, R. R., Rosenblatt, J. D., Younes, A., Harrop, K., Whiting, N. C., Drachman, J. G. OXFORD UNIV PRESS. 2008: 115

  View details for Web of Science ID 000256693500116

• Improved prognosis after histologic transformation (HT) of follicular lymphoma (FL): The Stanford experience 1960-2003 10th International Conference on Malignant Lymphoma Tan, D., Rosenberg, S. A., Lavori, P., Levy, R., Hoppe, R., Warnke, R., Advani, R., Natkuunam, Y., Yuen, A., Horning, S. J. OXFORD UNIV PRESS. 2008: 111–112

  View details for Web of Science ID 000256693500106

• Attitudes and beliefs towards surviorship issues in Hodgkin's disease (HD). Results of focus group discussions with patients treated at stanford university 10th International Conference on Malignant Lymphoma Advani, R., Rosenberg, S., Talreja, N., Hoppe, R., Horning, S. OXFORD UNIV PRESS. 2008: 137–137

  View details for Web of Science ID 000256693500185

• Clinical and immunologic responses to a novel in situ lymphoma vaccine maneuver: Preliminary results of a phase II trial of intra-tumoral CpG 7909 Brody, J., Ai, W. Z., Czerwinski, D., Advani, R., Horning, S. J., Ganjoo, K. N., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457400598

• Closing the gap: A comparison of observed versus expected survival in follicular lymphoma (FL) at Stanford University from 1960-2003 Tan, D., Rosenberg, S. A., Lavori, P., Sigal, B. M., Levy, R., Hoppe, R. T., Warnke, R., Advani, R., Natkunam, Y., Plevritis, S. K., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457403064

• Beyond the guidelines in the treatment of peripheral T-cell lymphoma: new drug development. Journal of the National Comprehensive Cancer Network Chen, A. I., Advani, R. H. 2008; 6 (4): 428-435

  Abstract

  Peripheral T-cell lymphomas (PTCLs) are a rare and diverse group of neoplasms with a poor prognosis. Management of these disorders has been largely extrapolated from the treatment of aggressive B-cell lymphomas; however, therapeutic responses to this approach are neither adequate nor durable for most patients with PTCL. Given the rarity of PTCL, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed/refractory PTCL. This article reviews promising novel approaches in the treatment of PTCL and its subtypes. Investigation into the pathogenesis of PTCL has also identified new targets for treatment. These emerging therapies include new uses of existing agents and the development of novel agents specifically targeted against T-cell lymphoma. Results using antimetabolites, immunotherapies, and histone deacetylase inhibitors have been particularly encouraging. These novel therapies are being tested as single agents and in combination with conventional lymphoma regimens in the frontline and salvage settings. Because of the rarity and heterogeneity of PTCL, national and international cooperation is needed to conduct the clinical studies required for the development of more effective treatment paradigms. These efforts are ongoing and will hopefully guide new strategies to improve the historically poor outcome of PTCL.

  View details for PubMedID 18433608

• Non-Hodgkin's lymphomas. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Advani, R. H., Byrd, J. C., Czuczman, M. S., Damon, L. E., Duvic, M., Fayad, L., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kim, Y. H., LaCasce, A. S., Nademanee, A., Olsen, E. A., Porcu, P., Press, O., Prosnitz, L., Smith, M. R., Sotomayor, E. M., Vose, J. M., Yahalom, J., Yunus, F. 2008; 6 (4): 356-421

  View details for PubMedID 18433606

• Denileukin diftitox (ONTAK) plus CHOP chemotherapy in patients with peripheral T-Cell lymphomas (PTCL), the CONCEPT trial 49th Annual Meeting of the American-Society-of-Hematology Foss, F., Sjak-Shie, N., Goy, A., Jacobsen, E., Advani, R., Smith, M., Komrokji, R., Pendergrass, K., Bolejack, V., Watts, K., Acosta, M. AMER SOC HEMATOLOGY. 2007: 1011A–1011A

  View details for Web of Science ID 000251100804486

• Results of a prospective phase II trial of limited and extended rituximab treatment in nodular lymphocyte predominant Hodgkin's disease (NLPHD) Horning, S. J., Bartlett, N. L., Breslin, S., Advani, R. H., Hoppe, R. T., Ekstrand, B. C., Lucas, J. B. AMER SOC HEMATOLOGY. 2007: 198A

  View details for Web of Science ID 000251100800645

• Belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-Cell lymphoma: Results of a phase II study 49th Annual Meeting of the American-Society-of-Hematology Advani, R., Hymes, K., Pohlman, B., Jacobsen, E., McDonnell, J., Belt, R., LERNER, A., Kim, Y., MUNDIS, R., MANSFIELD, T., Buhl-Jensen, P., Ooi, C. E., Duvic, M., Foss, F. AMER SOC HEMATOLOGY. 2007: 1012A–1012A

  View details for Web of Science ID 000251100804490

• Stage I/II Hodgkin's disease: Comparison of outcomes of patients with bulky mediastinal disease versus other risk factors; the Stanford V experience Advani, R. H., Hoppe, R. T., Rosenberg, S. A., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 685A–685A

  View details for Web of Science ID 000251100803098

• Phase II study of R-CHOP followed by Y-90-ibritumomab tiuxetan in untreated mantle cell lymphoma: Eastern cooperative oncology group study E1499 49th Annual Meeting of the American-Society-of-Hematology Smith, M. R., Zhang, L., Gordon, L. I., Foran, J., Kahl, B., Gascoyne, R. D., Advani, R., Paietta, E., Weller, E., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 121A–121A

  View details for Web of Science ID 000251100800390

• Survival in follicular lymphoma: The Stanford experience, 1960-2003. 49th Annual Meeting of the American-Society-of-Hematology Tan, D., Rosenberg, S. A., Levy, R., Lavori, P., Tibshirani, R., Hoppe, R. T., Warnke, R., Advani, R., Natkunam, Y., Yuen, A., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 1005A–1005A

  View details for Web of Science ID 000251100804465

• Prognostic factors in primary cutaneous anaplastic large cell lymphoma: Clinical and molecular characterization of a subset with worse outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D., Jones, C., Vanoli-Storz, M., Kohler, S., Reddy, S., Advani, R., Hoppe, R., Kim, Y. AMER SOC HEMATOLOGY. 2007: 1045A–1045A

  View details for Web of Science ID 000251100804610

• Stage I/II Hodgkin's disease (HD) with bulky mediastinal disease or other risk factors (RF) the Stanford V experience 7th International Symposium on Hodgkins Lymphoma Advani, R. H., Hoppe, R. T., Rosenberg, S. A., Horning, S. J. FERRATA STORTI FOUNDATION. 2007: 27–27

  View details for Web of Science ID 000250470800070

• A prospective trial of involved field radiation (IFRT) plus chemotherapy vs extended field (EFRT) radiation for favorable Hodgkin's disease (HD): Long-term follow-up and implications for current combined modality therapy 7th International Symposium on Hodgkins Lymphoma Horning, S. J., Hoppe, R. T., Advani, R. H., Breslin, S., McCormick, E., Allen, J., Hancock, S. L., Rosenberg, S. A. FERRATA STORTI FOUNDATION. 2007: 53–53

  View details for Web of Science ID 000250470800147

• Intra-CSF rituximab for lymhomatous meningitis - Reply JOURNAL OF CLINICAL ONCOLOGY Rubenstein, J., Abrey, L., Advani, R., Shuman, M., Tsai, T., O'Brien, J. 2007; 25 (28): 4509-4511

  View details for DOI 10.1200/JCO.2007.13.1284

  View details for Web of Science ID 000251073300039

• Non-Hodgkin lymphoma of the breast CANCER Ganjoo, K., Advani, R., Mariappan, M. R., McMillan, A., Horning, S. 2007; 110 (1): 25-30

  Abstract

  Primary lymphoma of the breast has been reported to have a high local and central nervous system recurrence (CNS) rate, suggesting the need for consolidation radiotherapy and CNS prophylaxis. A retrospective study was done to evaluate the institutional experience in this patient population.In all, 37 patients with lymphoma involving the breast at initial diagnosis and managed at Stanford University from 1981-2005 were included. Diagnostic tissue biopsies were obtained either from the breast mass or an involved lymph node. Treatment and response data, patterns of recurrence, and outcomes were reviewed.Diffuse large B cell lymphoma (DLBCL) was the most common histologic subtype seen in 18 of 37 (49%) patients. Follicular and marginal zone subtypes were seen in 38%. Most patients presented with an incidental breast mass in stage I(E) or II(E). Four (11%) patients presented with bilateral breast involvement, with only 1 patient presenting with CNS disease. DLBCL patients received doxorubicin-based chemotherapy, with 70% receiving involved field radiotherapy and a single patient receiving intrathecal therapy. No recurrences occurred in the involved breast and a single parenchymal CNS recurrence was recorded. Among the DLBCL patients, the 5-year progression-free survival (PFS) was 61%, with a median follow-up of 3.8 years (range, 5 months to 19 years) and the 5-year overall survival (OS) was estimated at 82%. Patients with indolent lymphoma had an estimated 5-year PFS of 76% and an OS of 92%.DLBCL of the breast was successfully treated with doxorubicin-based chemotherapy alone or with involved field radiotherapy in an estimated 61% of patients at 5 years. A single CNS recurrence was observed in our series of patients, most of whom presented with limited disease.

  View details for DOI 10.1002/cncr.22753

  View details for PubMedID 17541937

• Confirmation of the prognostic value of the EORTC/WHO classification of primary cutaneous B-cell lymphoma in the United States: The Stanford University experience Reddy, S. A., Kim, Y. H., Advani, R. H., Hoppe, R. T. AMER SOC CLINICAL ONCOLOGY. 2007

  View details for Web of Science ID 000455043702147

• A prospective trial of involved field radiation (IFRT) plus chemotherapy compared to extended field (EFRT) radiation for favorable Hodgkin disease: Survival differences and implications of mature follow-up for current combined modality therapy Horning, S. J., Hoppe, R. T., Advani, R. H., Breslin, S., Allen, J., Hancock, S. L., Rosenberg, S. A. AMER SOC CLINICAL ONCOLOGY. 2007

  View details for Web of Science ID 000455043702135

• Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom's macroglobulinemia: Results of WMCTG trial 03-248 CLINICAL CANCER RESEARCH Treon, S. P., Hunter, Z. R., Matous, J., Joyce, R. M., Mannion, B., Advani, R., Cook, D., Songer, J., Hill, J., Kaden, B. R., Sharon, D., Steiss, R., Leleu, X., Branagan, A. R., Badros, A. 2007; 13 (11): 3320-3325

  Abstract

  Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM.In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m(2) on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease.Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P < 0.0001). The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of 1.4 months. The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months. The most common grade III/IV toxicities occurring in > or =5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.

  View details for DOI 10.1158/1078-0432.CCR-06-2511

  View details for Web of Science ID 000246788700030

  View details for PubMedID 17545538

• A phase II study of derdleukin diftitox (Ontak (R)) with CHOP chemotherapy in patients with newly-diagnosed aggressive T-cell lymphomas, the CONCEPT trial: Interim analysis. Foss, F. M., Sjak-Shie, N., Goy, A., Advani, R., Jacobsen, E., Acosta, M. AMER SOC HEMATOLOGY. 2006: 696A–697A

  View details for Web of Science ID 000242440003251

• SGN-40 (Anti-huCD40 mAb) monotherapy induces durable objective responses in patients with relapsed aggressive non-Hodgkin's lymphoma: Evidence of antitumor activity from a phase I study. Advani, R., Forero-Torres, A., Furman, R. R., Rosenblatt, J. D., Younes, A., Shankles, B., Harrop, K., Drachman, J. G. AMER SOC HEMATOLOGY. 2006: 209A

  View details for Web of Science ID 000242440000696

• Phase II study of rituximab plus CHOP followed by Y-90-ibritumomab tiuxetan in patients with previously untreated mantle cell lymphoma: An Eastern Cooperative Oncology Group Study (E1499). 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Smith, M. R., Chen, H., Gordon, L., Foran, J., Kahl, B., Advani, R., Gascoyne, R. D., Weller, E., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2006: 422S–422S

  View details for Web of Science ID 000239009402559

• SNS-595 demonstrates clinical activity and dose-proportional pharmacokinetics (PK) in two phase I clinical studies. Hurwitz, H., Gordon, M., Advani, R., Ebbinghaus, S., Mendelson, D., Wakelee, H., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER SOC CLINICAL ONCOLOGY. 2006: 136S

  View details for Web of Science ID 000239009400534

• A humanized antibody against CD40 (SGN-40) is well tolerated and active in non-Hodgkin's lymphoma (NHL): Results of a phase I study. Forero-Torres, A., Furman, R. R., Rosenblatt, J. D., Younes, A., Harrop, K., Drachman, J. G., Advani, R. AMER SOC CLINICAL ONCOLOGY. 2006: 430S

  View details for Web of Science ID 000239009403023

• Incidence of secondary leukemia/myelodysplasia (AML/MDS) in Hodgkin's disease (HD) with three generations of therapy at Stanford University. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Advani, R. H., Hoppe, R. T., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2006: 426S–426S

  View details for Web of Science ID 000239009403005

• Treatment of mantle cell lymphoma: Current approach and future directions CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY Brody, J., Advani, R. 2006; 58 (3): 257-265

  Abstract

  Although mantle cell lymphoma has been described as "moderately aggressive" it has become clear that it carries a worse long-term prognosis than other subtypes of non-Hodgkin's lymphoma. In recent years, this has prompted numerous clinical trials of novel and more aggressive therapies in hopes of impacting these poor outcomes. These include more intensive combination chemotherapy regimens, monoclonal antibody therapy in conjunction with other treatments or conjugated to radioactive isotopes, high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation, and newer targeted therapies based on increasing understanding of the molecular pathways of this malignancy.

  View details for DOI 10.1016/j.critrevonc.2005.10.001

  View details for PubMedID 16751087

• Staging accuracy in mycosis fungoides and Sezary syndrome using integrated positron emission tomography and computed tomography 65th Annual Meeting of the Society-for-Investigative-Dermatology Tsai, E. Y., Taur, A., Espinosa, L., Quon, A., Johnson, D., Dick, S., Chow, S., Advani, R., Warnke, R., Kohler, S., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2006: 577–84

  Abstract

  To evaluate the usefulness of integrated positron emission tomography and computed tomography (PET/CT) in staging mycosis fungoides (MF) and Sézary syndrome and to correlate PET/CT data with histopathologic diagnosis of lymph nodes (LNs).A single-center, prospective cohort analysis.Academic referral center for cutaneous lymphoma.Thirteen patients with MF and SS at risk for secondary LN involvement. Interventions Patients were clinically evaluated based on general physical examination, total body skin examination, and laboratory screening. They underwent integrated PET/CT followed by excisional biopsy of LNs.We used PET/CT to assess LN size and metabolic activity. Enlarged LNs were defined as axillary or inguinal LNs with a short axis 1.5 cm or larger; or cervical LN, with a short axis 1.0 cm or larger. We classified LN pathologic results according to National Cancer Institute (LN1-4) and World Health Organization (WHO 1-3) criteria. We quantified PET activity using standardized uptake value (SUV) and correlated with LN grade.Based on CT size criteria alone, only 5 patients had enlarged LNs, whereas PET revealed hypermetabolic LNs in all 13 patients. Six patients had LN1-3, and 7 had effacement of LN architecture by lymphoma cells (LN4). Of the 7 patients with LN4 nodes, 4 had SS, and 3 had tumorous MF. Two patients with LN4 nodes had inguinal LNs smaller than 1.5 cm and would have been assigned an N0 classification without the use of integrated PET/CT. Correlation of SUV with LN grade revealed that LN1-3 nodes were associated with a mean SUV of 2.7 (median SUV, 2.2; range, 2.0-4.7) and LN4 nodes were associated with a mean SUV of 5.4 (median SUV, 3.9; range, 2.1-11.8). Patients with large cell transformation had the highest SUVs.For staging MF and SS, PET/CT was more sensitive in detecting LN involved by lymphoma compared with CT data alone and thus may provide more accurate staging and prognostic information. The intensity of PET activity correlated with histologic LN grade.

  View details for PubMedID 16702495

• A phase 1 trial of weekly SNS-595 in patients (PTS) with refractory cancer Ebbinghaus, S., Gordon, M., Advani, R., Hurwitz, H., Mendelson, D., Wakelee, H., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER ASSOC CANCER RESEARCH. 2006

  View details for Web of Science ID 000454608800014

• Management of advanced stage Hodgkin lymphoma. Journal of the National Comprehensive Cancer Network Advani, R., Ai, W. Z., Horning, S. J. 2006; 4 (3): 241-247

  Abstract

  Although advanced Hodgkin lymphoma is highly curable, balancing the high cure rate with long-term toxicity is challenging. ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) is the standard chemotherapy regimen, producing a high cure rate with acceptable toxicity. Stanford V and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) are new regimens with encouraging results and are undergoing randomized clinical trials. The International Prognostic Score provides a clinical tool that may help identify patients with high-risk disease who may require a more aggressive regimen. Consolidative radiation's role in managing advanced Hodgkin lymphoma is still controversial, but it is most accepted for bulky or residual disease or after brief chemotherapy. The development and integration of newer imaging tools, such as fluorodeoxyglucose-positron emission tomography imaging, may allow a more precise evaluation of disease and help define which patients might benefit from consolidative treatment.

  View details for PubMedID 16507271

• Non-Hodgkin's lymphoma. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Advani, R. H., Buadi, F., Cabanillas, F., Caligiuri, M. A., Czuczman, M. S., Damon, L. E., Fayad, L., Flinn, I. W., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Kaminski, M. S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Prosnitz, L., Smith, M. R., Sotomayor, E. M., Vose, J. M., Yahalom, J. 2006; 4 (3): 258-310

  View details for PubMedID 16507273

• Hodgkin disease/lymphoma. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Bierman, P. J., Bloomfield, C. D., Buadi, F., Djulgegovic, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Kaminski, M. S., Love, G., Maloney, D. G., Mauch, P. M., Moore, J. O., Schilder, R. J., Weiss, L., Winter, J. N., Yahalom, J., Zelenetz, A. D. 2006; 4 (3): 210-230

  View details for PubMedID 16507269

• Phase I trial of SNS-595 in patients (pts) with advanced malignancies. Advani, R., Gordon, M., Hurwitz, H., Mendelson, D., Wakelee, H., Ebbinghaus, S., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER ASSOC CANCER RESEARCH. 2005: 9056S

  View details for Web of Science ID 000234382700373

• A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance ANNALS OF ONCOLOGY Advani, R., Lum, B. L., Fisher, G. A., Halsey, J., Chin, D. L., Jacobs, C. D., Sikic, B. I. 2005; 16 (12): 1968-1973

  Abstract

  The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.

  View details for DOI 10.1093/annonc/mdi396

  View details for PubMedID 16126736

• Motexafin gadolinium (MGd) has clinical activity in relapsed/refractory low grade lymphomas (LG) and relapsed/refractory chronic lymphocytic leukemia (CLL). 47th Annual Meeting of the American-Society-of-Hematology Kahl, B. S., Advani, R., Kay, N., Lossos, I. S., Evens, A., Gordon, L., MILLER, R. A., Phan, S. C. AMER SOC HEMATOLOGY. 2005: 269B–270B

  View details for Web of Science ID 000233426101460

• A phase I study of humanized anti-CD40 immunotherapy with SGN-40 in non-Hodgkin's lymphoma. Advani, R. H., Furman, R. R., Rosenblatt, J. D., Younes, A., Forero-Torres, A., Harrop, K. L., Baumgartner, K. T., McDonald, M., Drachman, J. G. AMER SOC HEMATOLOGY. 2005: 433A

  View details for Web of Science ID 000233426002439

• Bexarotene is highly active in the treatment of subcutaneous Panniculitis-like T-cell lymphoma. 47th Annual Meeting of the American-Society-of-Hematology Molina, A. M., Advani, R., Reddy, S., Hoppe, R., Friedberg, J. W., Sadan, S., Myskowski, P., Kim, Y. H., Horwitz, S. M. AMER SOC HEMATOLOGY. 2005: 934A–934A

  View details for Web of Science ID 000233426006128

• Phase II study of bortezomib in Waldenstrom's Macroglobulinemia: Results of WMCTG trial 03-248. 47th Annual Meeting of the American-Society-of-Hematology Treon, S., Hunter, Z. R., Matous, J., Badros, A., Joyce, R. M., Mannion, B., Advani, R., Cook, D., Songer, J., Hill, J., Kaden, B. R., Sharon, D., Steiss, R., Branagan, A. R., Patterson, C. J. AMER SOC HEMATOLOGY. 2005: 147A–147A

  View details for Web of Science ID 000233426000491

• Assessment of favorable (F) versus unfavorable (U) early stage Hodgkin's disease (HD); the Stanford V plus radiotherapy (RT) experience. 47th Annual Meeting of the American-Society-of-Hematology Advani, R., Maeda, L., Hoppe, R. T., Breslin, S., Rosenberg, S. A., Baer, D., Mason, J., Horning, S. J. AMER SOC HEMATOLOGY. 2005: 548A–548A

  View details for Web of Science ID 000233426003294

• A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer 36th Annual Meeting of the American-Society-of-Clinical-Oncology Advani, R., Lum, B. L., Fisher, G. A., Halsey, J., Geary, R. S., Holmlund, J. T., Kwoh, T. J., DORR, F. A., Sikic, B. I. SPRINGER. 2005: 467–77

  Abstract

  A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to protein kinase C-alpha, in patients with refractory solid tumors.Fourteen patients were treated in sequential cohorts of aprinocarsen by 24-hour continuous infusion (CIV), weekly, at doses of 6, 12, 18 and 24 mg/kg.One grade 4 toxicity was observed, transient grade 4 neutropenia at 18 mg/kg. Grade 3 toxicities included neutropenia at 12 mg/kg, fever and hemorrhage at 18 mg/kg, and neutropenia, nausea, and chills at 24 mg/kg. Grade 2 toxicities included thrombocytopenia myalgias, chills, headache, fatigue, fever and nausea/vomiting. Mean prothrombin times and activated partial thromboplastin times (aPTT) increased by 10% and 29% from baseline (p = 0.006 and 0.005). Mean complement split products (Bb and C3a) increased 1.6-fold and 3.6-fold (from p = 0.014 and 0.004, respectively). These changes correlated with dose and were transient with recovery to baseline by day 7. Steady state plasma concentrations (Css) of aprinocarsen were achieved within four hours. Css better described changes in aPTT than dose. Clinical evidence of complement activation was not observed.In contrast to 21-day protracted infusion schedules, delivery of aprinocarsen over a 24-hour infusion schedule showed concentration-dependent effects on coagulation and complement, which are consistent with nonclinical toxicology studies performed in the phosphorothioate DNA antisense drug class. These coagulation and complement changes resulted in a maximum tolerated dose 24 mg/kg.

  View details for DOI 10.1007/s10637-005-2906-0

  View details for PubMedID 16133798

• PET status after Stanford V chemotherapy predicts outcome in Hodgkins disease 9th International Conference on Malignant Lymphoma Advani, R., Maeda, L., Lavori, P., Hoppe, R., Breslin, S., Rosenberg, S., Horning, S. OXFORD UNIV PRESS. 2005: 121–121

  View details for Web of Science ID 000233670100285

• Phase I trial of SNS-595 in patients with advanced malignancies. Advani, R., Gordon, M., Hurwitz, H., Mendelson, D., Wakelee, H., Ebbinghaus, S., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER SOC CLINICAL ONCOLOGY. 2005: 159S

  View details for Web of Science ID 000230326601051

• A phase I trial of oblimersen and gemcitabine in refractory and advanced malignancies 41st Annual Meeting of the American-Society-of-Clinical-Oncology Fisher, G., Advani, R., Wakelee, H., Jacobs, C., Gladysheva, K., Fitzgerald, A. M., Sikic, B. AMER SOC CLINICAL ONCOLOGY. 2005: 234S–234S

  View details for Web of Science ID 000230326601349

• A Phase I Trial of Aprinocarsen (ISIS 3521/LY900003), an Antisense Inhibitor of Protein Kinase C-alpha Administered as a 24-hour Weekly Infusion Schedule in Patients with Advanced Cancer. Investigational New Drugs, Advani R, Lum BL, Fisher GA, Halsey J, Geary RS, Holmlund JT, Kwoh TJ, Dorr FA, Sikic BI. 2005; In Press
• Efficacy and late effects of Stanford V chemotherapy and radiotherapy in untreated Hodgkin's disease: Mature data in early and advanced stage patients. 46th Annual Meeting of the American-Society-of-Hematology Horning, S. J., Hoppe, R. T., Advani, R., Warnke, R., Baer, D., Mason, J., Rosenberg, S. A. AMER SOC HEMATOLOGY. 2004: 92A–92A

  View details for Web of Science ID 000225127500310

• Marked improvement in staging accuracy in mycosis fungoides/Sezary syndrome using integrated positron emission tomography and computed tomography (PET/CT) Tsai, E. Y., Taur, A., Espinosa, L., Quon, A., Dick, S. E., Chow, S., Advani, R., Warnke, R. A., Kohler, S., Hoppe, R. T., Kim, Y. H. AMER SOC HEMATOLOGY. 2004: 854A–855A

  View details for Web of Science ID 000225127503129

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Fishe, G. A., Kuo, T., Cho, C. D., Halsey, J., Jambalos, C. N., Schwartz, E. J., Robert, R. V., Advani, R. H., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2004: 248S–248S

  View details for Web of Science ID 000223512400981

• Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: A phase III trial (E2995) JOURNAL OF CLINICAL ONCOLOGY Greenberg, P. L., Lee, S. J., Advani, R., Tallman, M. S., Sikic, B. I., Letendre, L., Dugan, K., Lum, B., Chin, D. L., Dewald, G., Paietta, E., Bennett, J. M., Rowe, J. M. 2004; 22 (6): 1078-1086

  Abstract

  To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to treat patients with relapsed or refractory AML and high-risk MDS.For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P=not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P=.09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents.CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

  View details for DOI 10.1200/JCO.2004.07.048

  View details for PubMedID 15020609

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Cho, C. D., Fisher, G. A., Halsey, J., Jambalos, C. N., Schwartz, E. J., Rouse, R. V., Advani, R. H., Wakelee, H. A., Lum, B. L., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2003: 6103S–6103S

  View details for Web of Science ID 000187467300140

• Treatment of angioimmunoblastic T-cell lymphoma (AILD) with cyclosporine. Advani, R., Horwitz, S., Harandi, A., Lee, M., Noy, A., Zelenetz, A. D., Horning, S. J. AMER SOC HEMATOLOGY. 2003: 180A

  View details for Web of Science ID 000186536700626

• Phase I and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies CLINICAL CANCER RESEARCH Advani, R., Fisher, G. A., Lum, B. L., Jambalos, C., Cho, C. D., Cohen, M., Gollerkeri, A., Sikic, B. I. 2003; 9 (14): 5187-5194

  Abstract

  The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly.Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797.Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m(2). The number of patients evaluated at each dose level was as follows: 35 mg/m(2) (n = 3); 50 mg/m(2) (n = 9); and 65 mg/m(2) (n = 6). At 65 mg/m(2), three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m(2) dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration (C(max)) and area under the curve (AUC(0-48)) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC.The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m(2). The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.

  View details for PubMedID 14613998

• A phase I study of ZD 1839 (Iressa) in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) in advanced solid malignancies 14th EORTC/NCI/AACR Symposium on Molecular Targets and Cancer Therapeutics Fisher, G. A., Cho, C. D., Halsey, J. Z., Advani, R. H., Yuen, A. R., Lum, B. L., Sikic, B. I. ELSEVIER SCI LTD. 2002: S63–S63

  View details for Web of Science ID 000179895700204

• Functional characterization of Rab14 GTPase and its role in membrane trafficking and vesicular transport Junutula, Advani, R. J., Peden, A. A., de Maziere, A., Klumperman, J., Scheller, R. H. AMER SOC CELL BIOLOGY. 2002: 227A–228A

  View details for Web of Science ID 000179569101277

• The effect of oral valspodar (psc 833), a modulator of multidrug resistance, on the pharmacokinetics of liposomal doxorubicin. Lum, B. L., Chin, D. L., Cho, C. D., Advani, R., Fisher, G. A., Halsey, J., Sikic, B. I. NATURE PUBLISHING GROUP. 2002: P48–P48

  View details for Web of Science ID 000174178600176

• Phase II trial of ISIS 3521, an antisense inhibitor of PKC-alpha, with carboplatin and paclitaxel in non-small cell lung cancer: Updated survival and time to progression data. Yuen, A., Halsey, J., Fisher, G., Advani, R., Moore, M., Saleh, M., Ritch, P., Harker, G., Ahmed, F., Jones, C., Polikoff, J., Keiser, W., Kwoh, T. J., Holmlund, J., Dorr, A., Sikic, B. AMER ASSOC CANCER RESEARCH. 2001: 3681S

  View details for Web of Science ID 000172121800140

• A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance 34th Annual Meeting of the American-Society-of-Clinical-Oncology Advani, R., Fisher, G. A., Lum, B. L., Hausdorff, J., Halsey, J., Litchman, M., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2001: 1221–29

  Abstract

  P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel.For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses.Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m(2) doxorubicin and 150 mg/m(2) paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m(2) doxorubicin and 70 mg/m(2) paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m(2) doxorubicin and 90 mg/m(2) paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel.PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring approximately 60% dose reductions for equivalent degrees of myelosuppression.

  View details for PubMedID 11350887

• Enhanced bioavailability of oral paclitaxel by valspodar (PSC 833), an inhibitor of small bowel P-glycoprotein and cytochrome P450. Sikic, B. I., Advani, R., Fisher, G. A., Halsey, J., Cohen, P., Lum, B. L. AMER ASSOC CANCER RESEARCH. 2000: 4580S

  View details for Web of Science ID 000165409000528

• Phase I/II trial of ISIS3521, an antisense inhibitor of PKC alpha, with carboplatin and paclitaxel in non-small cell lung cancer. Yuen, A., Halsey, J., Lum, B., Fisher, G., Advani, R., Geary, R., Kwoh, T. J., Holmlund, J. T., Dorr, A., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2000: 4572S

  View details for Web of Science ID 000165409000487

• A phase I trial of doxil, paclitaxel and valspodar (PSC 833). Advani, R., Fisher, G., Lum, B., Halsey, J., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2000: 4504S

  View details for Web of Science ID 000165409000152

• Treatment of refractory/relapsed AML with PSC833 plus mitoxantrone, etoposide, cytarabine (PSC-MEC) vs MEC: Randomized phase III trial (E2995). Greenberg, P., Advani, R., Tallman, M., Letendre, L., Saba, H., Dugan, K., Lee, S. J., Lum, B., Sikic, B. I., Paietta, E., Bennett, J., Rowe, J. M. AMER SOC HEMATOLOGY. 1999: 383A–383A

  View details for Web of Science ID 000083790301752

• Schedule and concentration dependent increase of coagulation times and complement split products in phase I/II trials of an antisense oligonucleotide targeted to protein kinase C-alpha(ISIS 3521/ISI641A). Advani, R., Lum, B. L., Fisher, G. A., Grant, P., Halsey, J., Yuen, A., Holmland, J. T., Kwoh, T. J., Dorr, A., Geary, R., Sikic, B. I. AMER SOC HEMATOLOGY. 1999: 94B

  View details for Web of Science ID 000083790700428

• A phase I trial of ISIS 3521 (IS1641A), an antisense inhibitor of protein kinase C alpha, combined with carboplatin and paclitaxel in patients with cancer. Yuen, A., Sikic, B. I., Advani, R., Fisher, G., Halsey, J., Lum, B., Geary, R., Kwoh, T. J., Holmlund, J. T., Dorr, A. AMER ASSOC CANCER RESEARCH. 1999: 3846S–3847S

  View details for Web of Science ID 000083945700577

• Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Blood Advani R, Saba HI, Tallman M, Rowe JM, Wiernik PH, Ramek J, Dugan K, Lum B, Villena J, Sikic BI, Davis E, Paietta E, Litchman M , Greenberg P. 1999; 93: 787-95
• Treatment of poor prognosis AML with PSC833 plus mitoxantrone, etoposide, cytarabine (PSC-MEC). Advani, R., Saba, H. I., Tallman, M., Rowe, J. M., Wiernik, P. H., Ramek, J., Dugan, K., Lum, B., Villena, J., Sikic, B. I., Davis, E., Paietta, E., Litchman, M., Greenberg, P. W B SAUNDERS CO. 1997: 2260

  View details for Web of Science ID A1997YG42402256

• Treatment of refractory/relapsed AML with PSC833 plus mitoxantrone, etoposide, cytarabine (PSC-MEC) Advani, R., Saba, H., Rowe, J. M., Tallman, M., Wiernik, P., Ramek, J., Dugan, K., Litchman, M., Dorr, R., Lum, B., Sikic, B., Davis, E., Paietta, E., Greenberg, P. W B SAUNDERS CO. 1996: 847

  View details for Web of Science ID A1996VT98300847