Sally Arai

All Publications

• A model for predicting day-100 stem cell transplant-related mortality in AL amyloidosis. Bone marrow transplantation Muchtar, E., Dispenzieri, A., Sanchorawala, V., Hassan, H., Mwangi, R., Maurer, M., Buadi, F., Lee, H. C., Qazilbash, M., Kin, A., Zonder, J., Arai, S., Chin, M. M., Chakraborty, R., Lentzsch, S., Magen, H., Shkury, E., Sarubbi, C., Landau, H., Schönland, S., Hegenbart, U., Gertz, M. 2025

  Abstract

  Autologous stem cell Transplant (ASCT)-related mortality (TRM) in AL amyloidosis remains elevated. AL amyloidosis patients (n = 1718) from 9 centers, transplanted 2003-2020 were included. Pre-ASCT variables of interest were assessed for association with day-100 all-cause mortality. A random forest (RF) classifier with 10-fold cross-validation assisted in variable selection. The final model was fitted using logistic regression. The median age at ASCT was 58 years. Day-100 TRM occurred in 75 patients (4.4%) with the predominant causes being shock, high-grade arrhythmia, and organ failure. Ten factors were associated with day-100 TRM on univariate analysis. RF classifier using these variables generated a model with an area under the curve (AUC) of 0.72 ± 0.12. To refine the model selection using importance hierarchy function, a 4-variable model [NT-proBNP/BNP, serum albumin, ECOG performance status (PS), and systolic blood pressure] was built with an AUC of 0.70 ± 0.12. Based on logistic regression coefficients, ECOG PS 2/3 was assigned two points while other adverse predictors 1-point each. The model score range was 0-5, with a day-100 TRM of 0.46%, 3.2%, 5.8%, and 14.5% for 0, 1, 2, and ≥3 points, respectively. This model to predict day-100 TRM in AL amyloidosis allows better-informed decision-making in this heterogeneous disease.

  View details for DOI 10.1038/s41409-025-02535-z

  View details for PubMedID 39994333

  View details for PubMedCentralID 3204906

• Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma. Nature communications Hosoya, H., Carleton, M., Tanaka, K., Sworder, B., Syal, S., Sahaf, B., Maltos, A. M., Silva, O., Stehr, H., Hovanky, V., Duran, G., Zhang, T., Liedtke, M., Arai, S., Iberri, D., Miklos, D., Khodadoust, M. S., Sidana, S., Kurtz, D. M. 2025; 16 (1): 1824

  Abstract

  Despite advances in treatments, multiple myeloma (MM) remains an incurable cancer where relapse is common. We developed a circulating tumor DNA (ctDNA) approach in order to characterize tumor genomics, monitor treatment response, and detect early relapse in MM. By sequencing 412 specimens from 64 patients with newly diagnosed or relapsed/refractory disease, we demonstrate the correlation between ctDNA and key clinical biomarkers, as well as patient outcomes. We further extend our approach to simultaneously track CAR-specific cell-free DNA (CAR-cfDNA) in patients undergoing anti-BCMA CAR T-cell (BCMA-CAR) therapy. We demonstrate that ctDNA levels following BCMA-CAR inversely correlate with relative time to progression (TTP), and that measurable residual disease (MRD) quantified by peripheral blood ctDNA (ctDNA-MRD) was concordant with clinical bone marrow MRD. Finally, we show that ctDNA-MRD can anticipate clinical relapse and identify the emergence of genomically-defined therapy-resistant clones. These findings suggest multiple clinical uses of ctDNA for MM in molecular characterization and disease surveillance.

  View details for DOI 10.1038/s41467-025-56486-6

  View details for PubMedID 39979252

  View details for PubMedCentralID 3783001

• Efficacy of Hedgehog Pathway Inhibitors as Adjuvant in Treating Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease. Journal of the American Academy of Dermatology Mendez-Hernandez, A., Gupta, R., Arai, S., Lowsky, R., Kwong, B., Weng, W. K. 2025

  View details for DOI 10.1016/j.jaad.2025.01.024

  View details for PubMedID 39848586

• Donor Regulatory T-Cell Therapy to Prevent Graft-Versus-Host Disease. Blood Meyer, E., Pavlova, A., Villar-Prados, A., Bader, C. S., Xie, B., Muffly, L., Kim, P., Sutherland, K. C., Bharadwaj, S., Dahiya, S., Frank, M. J., Arai, S., Johnston, L., Miklos, D. B., Rezvani, A. R., Shiraz, P., Sidana, S., Shizuru, J. A., Weng, W. K., Agrawal, V., Putnam, A., Fernhoff, N. B., Tamaresis, J., Lu, Y., Pawar, R. D., McClellan, J. S., Lowsky, R., Negrin, R. S. 2025

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity.We enrolled 44 patients on an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg cell therapy manufactured from donor mobilized peripheral blood improves one-year GVHD-free relapse free survival (GRFS) after myeloablative conditioning (trial NCT01660607). We compared this study arm to a concomitant standard of care (SOC) cohort. All donor Treg cell products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a one-year incidence of acute grade III-IV GVHD of 7%, moderate to severe chronic GVHD of 11% and non-relapse mortality rate of 4.5%. The primary endpoint of significantly improved one-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (p = 0.002) with a realized incidence of 36% in the SOC comparitor. For those trial patients whow developed grade II-IV acute GVHD, 91% responded to front-line steroid therapy wheras 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, as compared to rates common to highly variable unmanipulated donor grafts and multi-agent immune suppression.

  View details for DOI 10.1182/blood.2024026446

  View details for PubMedID 39792934

• Belumosudil combination therapy for chronic graft-versus-host-disease in real-world clinical practice. Bone marrow transplantation Chin, M. M., Tamaresis, J. S., Johnston, L. J., Lowsky, R., Meyer, E., Muffly, L., Shiraz, P., Frank, M. J., Rezvani, A. R., Bharadwaj, S., Weng, W. K., Shizuru, J. A., Arai, S. 2024

  View details for DOI 10.1038/s41409-024-02476-z

  View details for PubMedID 39558138

  View details for PubMedCentralID 9355804

• Phase II study of novel CXCR2 agonist and Plerixafor for rapid stem cell mobilization in patients with multiple myeloma. Blood cancer journal Sidana, S., Bankova, A. K., Hosoya, H., Kumar, S. K., Holmes, T. H., Tamaresis, J., Le, A., Muffly, L. S., Maysel-Auslender, S., Johnston, L., Arai, S., Lowsky, R., Meyer, E., Rezvani, A., Weng, W. K., Frank, M. J., Shiraz, P., Maecker, H. T., Lu, Y., Miklos, D. B., Shizuru, J. A. 2024; 14 (1): 173

  Abstract

  MGTA-145 or GROβT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers. Twenty-five patients with multiple myeloma enrolled in a phase 2 trial evaluating MGTA-145 and plerixafor for HSC mobilization (NCT04552743). Plerixafor was given subcutaneously followed 2 h later by MGTA-145 (0.03 mg/kg) intravenously with same day apheresis. Mobilization/apheresis could be repeated for a second day in patients who collected <6 ×106 CD34+ cells/kg. Lenalidomide and anti-CD38 antibody were part of induction therapy in 92% (n = 23) and 24% (n = 6) of patients, respectively. Median total HSC cell yield (CD34+ cells/kg × 106) was 5.0 (range: 1.1-16.2) and day 1 yield was 3.4 (range: 0.3-16.2). 88% (n = 22) of patients met the primary endpoint of collecting 2 ×106 CD34+ cells/kg in ≤ two days, 68% (n = 17) in one day. Secondary endpoints of collecting 4 and 6 × 106 CD34+ cells/kg in ≤ two days were met in 68% (n = 17) and 40% (n = 10) patients. Grade 1 or 2 adverse events (AE) were seen in 60% of patients, the most common AE being grade 1 pain, usually self-limited. All 19 patients who underwent transplant with MGTA-145 and plerixafor mobilized HSCs engrafted successfully, with durable engraftment at day 100. 74% (17 of 23) of grafts with this regimen were minimal residual disease negative by next generation flow cytometry. Graft composition for HSCs and immune cells were similar to a contemporaneous cohort mobilized with G-CSF and plerixafor.

  View details for DOI 10.1038/s41408-024-01152-1

  View details for PubMedID 39384609

  View details for PubMedCentralID 10040899

• Long-term survival after unrelated donor marrow transplantation for aplastic anaemia after optimized conditioning regimen: a retrospective multicentre cohort study ECLINICALMEDICINE Eapen, M., Antin, J. H., Tolar, J., Arai, S., Horwitz, M. E., Kou, J., Leifer, E., McCarty, J. M., Nakamura, R., Pulsipher, M. A., Rowley, S. D., Horowitz, M. M., Deeg, H. 2024; 76

  View details for DOI 10.1016/j.eclinm.2024.102819

  View details for Web of Science ID 001309308800001

• PHASE 1 TRIAL RESULTS FOR PATIENTS WITH ADVANCED HEMATOLOGIC MALIGNANCIES TREATED WITH ORCA-T CELL THERAPY WITH REDUCED INTENSITY CONDITIONING AND SINGLE AGENT TACROLIMUS Villar-Prados, A., Sutherland, K., Negrin, R., Arai, S., Frank, M., Johnston, L., Lowsky, R., Miklos, D., Muffly, L., Dahiya, S., Rezvani, A., Sidana, S., Shiraz, P., Shizuru, J., Weng, W., Smith, M., Bharadwaj, S., Tamaresis, J., Pavlova, A., McClellan, S., Meyer, E. SPRINGERNATURE. 2024: 287-288

  View details for Web of Science ID 001365375001209

• Allogeneic Hematopoietic Cell Transplantation for the Treatment of Severe Aplastic Anemia: Evidence-Based Guidelines from the American Society for Transplantation and Cellular Therapy. Transplantation and cellular therapy Iftikhar, R., DeFilipp, Z., DeZern, A. E., Pulsipher, M. A., Bejanyan, N., Burroughs, L. M., Kharfan-Dabaja, M. A., Arai, S., Kassim, A., Nakamura, R., Saldaña, B. J., Aljurf, M., Hamadani, M., Carpenter, P. A., Antin, J. H. 2024

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA). Existing guidance about HCT in SAA is primarily derived from expert reviews, registry data and societal guidelines; however, transplant-specific guidelines for SAA are lacking. A panel of SAA experts, both pediatric and adult transplant physicians, developed consensus recommendations using Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology employing a GRADE guideline development tool. The panel agrees with previous recommendations for the preferential use of bone marrow as a graft source and the use of rabbit over horse antithymocyte globulin (ATG) for HCT conditioning. Fludarabine containing regimens are preferred for patients at high risk of graft failure and those receiving matched unrelated or haploidentical donor transplant. Given advancements in HCT, the panel does not endorse the historical 40-year age cut-off for considering upfront HCT in adults, acknowledging that fit older patients may also benefit from HCT. The panel also endorses increased utilization of HCT by prioritizing matched unrelated or haploidentical donor HCT over immunosuppressive therapy in children and adults who lack a matched related donor. Finally, the panel suggests either calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis for matched related or matched unrelated donor recipients. These recommendations reflect a significant advancement in transplant strategies for SAA and highlight the importance of ongoing and further research to revisit current evidence in terms of donor choice, conditioning chemotherapy, GVHD prophylaxis and post-transplant immunosuppression.

  View details for DOI 10.1016/j.jtct.2024.09.017

  View details for PubMedID 39307421

• Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. The New England journal of medicine Wolff, D., Cutler, C., Lee, S. J., Pusic, I., Bittencourt, H., White, J., Hamadani, M., Arai, S., Salhotra, A., Perez-Simon, J. A., Alousi, A., Choe, H., Kwon, M., Bermudez, A., Kim, I., Socie, G., Chhabra, S., Radojcic, V., O'Toole, T., Tian, C., Ordentlich, P., DeFilipp, Z., Kitko, C. L., AGAVE-201 Investigators, Bhattacharyya, A., Deeren, D., Schoemans, H., Popradi, G., Bittencourt, H., White, J., Yeh, S., Ko, B., Socie, G., Huynh, A., Souchet, L., Lioure, B., Forcade, E., Loron, S., Stelljes, M., Wolff, D., Sakellari, I., Tsirigotis, P., Shimoni, A., Ram, R., Rosenvald-Zuckerman, T., Avni, B., Zecca, M., Ciceri, F., Sica Fondazione, S., Porta, F., Kim, I., Shin, H., Giebel, S., Piu, L., Jurado, M., Sanz Caballer, J., Kwon, M., Sola Soto, M., Martinez, C., Lopez, L., Perez-Simon, J. A., Bermudez Rodriguez, M., Duarte, R., Nicholson, E., Parker, A., Ingram, W., Olavarria, E., Avenoso, D., Holtan, S., Lee, S., Kitko, C., Di Stasi, A., Abu Zaid, M., DeFilipp, Z., Couriel, D., Uberti, J., Wang, T., Khimani, F., Salhotra, A., Pusic, I., Alousi, A., Hamadani, M., Cutler, C., Hall, A., Kosuri, S., Gallogly, M., Choe, H., Tam, E., Shore, T., Im, A., Arai, S., Khawandanah, M., Gandhi, A., Hamilton, B., Ramanathan, M., Qayed, M., Jacobsohn, D., Farhadfar, N., Khandelwal, P., Volodin, L., Howard, D., Schuster, M., Litzow, M., Schaar, D. G., Solomon, S., Motyckova, G., Iqbal, M., Magenau, J. 2024; 391 (11): 1002-1014

  Abstract

  BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.METHODS: In this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.RESULTS: A total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.CONCLUSIONS: Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.).

  View details for DOI 10.1056/NEJMoa2401537

  View details for PubMedID 39292927

• Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial. medRxiv : the preprint server for health sciences Dehn, J. G., Logan, B., Shaw, B. E., Devine, S., Ciurea, S. O., Horowitz, M., He, N., Pusic, I., Srour, S. A., Arai, S., Juckett, M., Uberti, J., Hill, L., Vasu, S., Hogan, W. J., Hayes-Lattin, B., Westervelt, P., Bashey, A., Farhadfar, N., Grunwald, M. R., Leifer, E., Symons, H., Saad, A., Vogel, J., Erickson, C., Buck, K., Lee, S. J., Pidala, J. 2024

  Abstract

  Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood.To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor.This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months.National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers.Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available.Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (~25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective.Cumulative incidence of transplantation by Search Prognosis arm.Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113).A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor.

  View details for DOI 10.1101/2024.09.16.24313494

  View details for PubMedID 39371123

  View details for PubMedCentralID PMC11451755

• CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. Lancet (London, England) Frank, M. J., Baird, J. H., Kramer, A. M., Srinagesh, H. K., Patel, S., Brown, A. K., Oak, J. S., Younes, S. F., Natkunam, Y., Hamilton, M. P., Su, Y. J., Agarwal, N., Chinnasamy, H., Egeler, E., Mavroukakis, S., Feldman, S. A., Sahaf, B., Mackall, C. L., Muffly, L., Miklos, D. B. 2024

  Abstract

  Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

  View details for DOI 10.1016/S0140-6736(24)00746-3

  View details for PubMedID 38996463

• A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. Blood Srinagesh, H. K., Jackson, C., Shiraz, P., Jeyakumar, N., Hamilton, M. P., Egeler, E., Mavroukakis, S., Kuo, A., Cancilla, J., Sahaf, B., Agarwal, N., Kanegai, A. M., Kramer, A. M., Arai, S., Bharadwaj, S., Dahiya, S., Hosoya, H., Johnston, L. J., Kennedy, V. E., Liedtke, M., Lowsky, R., Mikkilineni, L., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J. A., Smith, M., Weng, W. K., Feldman, S. A., Frank, M. J., Lee, Z., Tagliaferri, M., Marcondes, A. M., Miklos, D. B., Mackall, C. L., Muffly, L. 2024

  Abstract

  While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

  View details for DOI 10.1182/blood.2024024952

  View details for PubMedID 38968138

• Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma. Journal for immunotherapy of cancer Bharadwaj, S., Lau, E., Hamilton, M. P., Goyal, A., Srinagesh, H., Jensen, A., Lee, D., Mallampet, J., Elkordy, S., Syal, S., Patil, S., Latchford, T., Sahaf, B., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R., Rezvani, A. R., Shizuru, J., Meyer, E. H., Shiraz, P., Mikkilineni, L., Weng, W. K., Smith, M., Sidana, S., Muffly, L., Maecker, H. T., Frank, M. J., Mackall, C., Miklos, D., Dahiya, S. 2024; 12 (7)

  Abstract

  Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

  View details for DOI 10.1136/jitc-2024-008975

  View details for PubMedID 38955420

• Comparison of treatment response measures in cutaneous sclerosis after allogeneic hematopoietic cell transplantation. Blood advances Pidala, J. A., Onstad, L., Baumrin, E., Carpenter, P. A., Cutler, C. S., Arai, S., Kitko, C. L., Chen, G. L., Lee, S. J. 2024

  Abstract

  Cutaneous sclerosis, a highly morbid subtype of chronic graft vs. host disease (cGVHD), demonstrates limited treatment response under current NIH Response Measures. We explored novel sclerosis-specific response measures using Chronic GVHD Consortium data. A training cohort included patients with cutaneous sclerosis from a randomized trial of imatinib vs. rituximab, and a Consortium observational study. The validation cohort was a different Consortium observational study. Clinician-reported measures (baseline, and baseline to 6-month change) were examined for association with 6-month clinician-reported response. Patient-reported measures (baseline and baseline to 6-month change) were studied for association with 6-month patient-reported response. A total of 347 subjects were included (training 183, validation 164). While multiple skin and joint measures were associated with clinician-reported response on univariate analysis, PROM total score, PROM total score change, and NIH 0-3 skin change were retained in the final multivariate model (AUC 0.83 training, 0.75 validation). Similarly, many patient-reported measures were associated, but final multivariate analysis retained the HAP AAS, SF36 vitality change, LSS skin, and LSS skin change in the model (AUC 0.86 training, 0.75 validation). We identified which sclerosis measures have greatest association with 6-month clinician- and patient-reported treatment response, a previously unstudied area. However, given the observed performance in the validation cohorts, we conclude that further work is needed. Novel response measures may be needed to optimally assess treatment response in cutaneous sclerosis.

  View details for DOI 10.1182/bloodadvances.2024013233

  View details for PubMedID 38885484

• A predictive model for day-100 transplant-related mortality in AL amyloidosis Muchtar, E., Dispenzieri, A., Sanchorawala, V., Hassan, H., Mwangi, R., Maurer, M., Lee, H., Qazilbash, M., Kin, A., Zonder, J., Buadi, F. K., Arai, S., Chin, M., Chakraborty, R., Lentzsch, S., Magen, H., Shkury, E., Sarubbi, C., Landau, H., Schonland, S., Hegenbart, U., Gertz, M. TAYLOR & FRANCIS LTD. 2024: S186-S187

  View details for Web of Science ID 001332706900268

• Management of post-autologous transplant relapse in patients with T-cell lymphomas. American journal of hematology Veilleux, O., Socola, F., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Shizuru, J., Meyer, E., Muffly, L., Rezvani, A. R., Shiraz, P., Sidana, S., Dahiya, S., Miklos, D. B., Negrin, R. S., Weng, W. K. 2024

  Abstract

  Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.

  View details for DOI 10.1002/ajh.27345

  View details for PubMedID 38661220

• CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity. Blood advances Hamilton, M. P., Craig, E., Gentille Sanchez, C., Mina, A., Tamaresis, J., Kirmani, N., Ehlinger, Z., Syal, S., Good, Z., Sworder, B., Schroers-Martin, J., Lu, Y., Muffly, L., Negrin, R. S., Arai, S., Lowsky, R., Meyer, E., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Kurtz, D. M., Mackall, C. L., Tibshirani, R., Alizadeh, A. A., Frank, M. J., Miklos, D. B. 2024

  Abstract

  Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

  View details for DOI 10.1182/bloodadvances.2024012637

  View details for PubMedID 38498731

• CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia Schultz, L. M., Jeyakumar, N., Kramer, A. M., Sahaf, B., Srinagesh, H., Shiraz, P., Agarwal, N., Hamilton, M., Erickson, C., Jacobs, A., Moon, J., Baggott, C., Arai, S., Bharadwaj, S., Johnston, L. J., Liedtke, M., Lowsky, R., Meyer, E., Negrin, R., Rezvani, A., Shizuru, J., Sidana, S., Egeler, E., Mavroukakis, S., Tunuguntla, R., Gkitsas-Long, N., Retherford, A., Brown, A. K., Gramstrap-Petersen, A. L., Ibañez, R. M., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L., Frank, M., Ramakrishna, S., Muffly, L. 2024

  Abstract

  Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

  View details for DOI 10.1038/s41375-024-02220-y

  View details for PubMedID 38491306

  View details for PubMedCentralID 4993814

• Long-Term Clinical Outcomes and B Cell Immune Reconstitution following Allo-HCT with Prophylactic, Post-Transplant Rituximab. Transplantation and cellular therapy Kennedy, V. E., Sahaf, B., Wu, F., Ehlinger, Z. J., Arai, S., Miklos, D. B. 2024

  Abstract

  Chronic graft-versus-host disease (cGVHD) remains a significant source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Post-transplant, prophylactic rituximab has successfully decreased cGHVD rates in clinical trials, but the durability of this strategy is uncertain. The long-terms effect of post-HCT B cell depletion on immune reconstitution, B cell function, and infectious complications are also unknown.In this study, we provide 10 year follow-up and correlative analyses on patients given post-HCT, prophylactic rituximab. The objective of the study is to examine the durability of cGVHD protection as well as the long-term effect of rituximab prophylaxis on protective immune reconstitution, B cell function, and alloantibody formation.We analyzed 35 patients given prophylactic rituximab on phase II clinical trial. Clinical outcomes included cGVHD development, relapse and survival outcomes, and infectious outcomes. Correlative analyses included B cell subset analysis, development of antibodies to infectious antigens, and, for male patients receiving female donor grafts, development of antibodies to HY antigens. To further investigate the effect of rituximab on immune reconstitution and function, we also analyzed 43 similarly transplanted patients who did not receive post- or peri-HCT rituximab as a comparator group.For patients who received rituximab, the 8-year cumulative incidence of cGHVD and freedom from immunosuppression were 20.0% and 76.2%, respectively. Importantly, no late incidences of cGVHD developed beyond 14 months post-HCT. Relative to patients who did not receive rituximab, post-HCT rituximab was associated with increased B cell aplasia at 1 year post-HCT (42.9% vs 11% of patients, p = 0.037); by 3 years post-HCT, this aplasia resolved. Patients who received rituximab also had a significantly lower proportion of IgD+/CD38+ transitional B cells at 3 years post-HCT (78.8% vs 89.9%, p = 0.039); at 10 years post-HCT, this percentage remained markedly decreased at 50.7%. Rituximab prophylaxis altered B cell function. In male patients receiving female donor grafts, fewer patients developed HY antibodies at 3 years post-HCT (20% vs 78%, p = 0.04). At 10 years post-HCT, HY antibody production remained decreased at 33%. Rituximab prophylaxis was also associated with significantly lower antibody response to tetanus and EBV infectious antigens as well as lower IgG levels. Despite these changes, post-HCT was not associated with increased infections, although patients who received rituximab required intravenous immunoglobulin (IVIG) supplementation more frequently than those who did not (62.9% vs 32.6% of patients, p = 0.01).Prior data on the efficacy and feasibility of rituximab prophylaxis are durable, with persistent reduction in cGVHD. Rituximab prophylaxis also results in lasting B cell immunologic changes, with altered B cell subset composition and decreased alloantibody formation. Associated infectious risks were not increased, perhaps mitigated by high IVIG use.

  View details for DOI 10.1016/j.jtct.2024.02.025

  View details for PubMedID 38458479

• A NOVEL DONOR SEARCH AND SELECTION ALGORITHM FACILITATES A COMPARABLE INCIDENCE OF TRANSPLANT FOR PATIENTS REGARDLESS OF BASELINE SEARCH PROGNOSIS: REPORT FROM BMTCTN 1702 TRIAL Dehn, J., Logan, B., He, N., Shaw, B. E., Devine, S., Vogel, J., Erickson, C., Ciurea, S., Lee, S. J., Westervelt, P., Srour, S., Arai, S., Juckett, M., Uberti, J., Saad, A., Hill, L., Hogan, W. J., Hayes-Lattin, B., Buck, K., Pidala, J. SPRINGERNATURE. 2023: 150-152

  View details for Web of Science ID 001110902800172

• Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR-T cell therapy in multiple myeloma. Blood cancer journal Sidana, S., Hosoya, H., Jensen, A., Liu, L., Goyal, A., Hovanky, V., Sahaf, B., Bharadwaj, S., Latchford, T., Arai, S., Leahy, S., Mei, M., Budde, L. E., Muffly, L. S., Frank, M. J., Dahiya, S., Htut, M., Miklos, D., Janakiram, M. 2023; 13 (1): 158

  View details for DOI 10.1038/s41408-023-00929-0

  View details for PubMedID 37833271

  View details for PubMedCentralID PMC10576036

• Prevalence, mutational spectrum and clinical implications of clonal hematopoiesis of indeterminate potential in plasma cell dyscrasias. Seminars in oncology Testa, S., Kumar, J., Goodell, A. J., Zehnder, J. L., Alexander, K. M., Sidana, S., Arai, S., Witteles, R. M., Liedtke, M. 2022

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is common both in healthy individuals and patients with hematological cancers. Recent studies have showed worse prognosis for patients with multiple myeloma (MM) and non-Hodgkin lymphoma undergoing stem cell transplant, that have concomitant presence of CHIP. Data regarding the clinical and biological role of CHIP in plasma cell dyscrasias (PCDs) is rapidly increasing. However, the prevalence and prognostic implication of CHIP in patients with MM outside of the transplant setting, and in those with other more indolent PCDs remains elusive. Here we explored the prevalence and clinical implications of CHIP detected through next-generation sequencing in 209 patients with PCDs including MM, light chain (AL) amyloidosis (ALA), monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma (SMM). To avoid attributing the mutations to the plasma cell clone, CHIP was defined as the presence of DNMT3A, TET2, or ASXL1 mutations in the peripheral blood or bone marrow (DTA-CH). The prevalence of DTA-CH was 19% in patients with PCDs, with no difference between each PCD. TET2 (23%) and DNMT3A (22%), were the most frequently mutated genes. DTA-CH correlated with older age in MM (P = .001) and MGUS/SMM (P = 0.0007), as well as with coronary artery disease or congestive heart failure in MM (P = .03). DTA-CH did not predict worse OS or PFS in either MM or ALA, nor it predict higher risk of progression to MM in patients with MGUS/SMM. Our results overall further elucidate the prevalence and mutational spectrum of CHIP in PCDs, providing more information regarding the clinical relevance of CHIP in this patient population.

  View details for DOI 10.1053/j.seminoncol.2022.11.001

  View details for PubMedID 36503855

• Multi-Omics Profiling of Skin Biopsies of Patients with Sclerodermatous Graft-Vs-Host Disease Suggests Therapeutic Potential of Targeting Don't Eat Me Signals Cui, L., De Souza, C., Lerbs, T., Poyser, J., Yu, C., Rieger, K., Arai, S., Brown, R., Shizuru, J. A., Mueller, A., Wernig, G. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-169789

  View details for Web of Science ID 000893223200111

• Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects Hamilton, M. P., Liu-Fei, F. C., Alig, S. K., Tamaresis, J., Esfahani, M., Good, Z., Sworder, B., Schroers-Martin, J., Liu, C., Severinsen, F., Hanson, P. J., Lu, Y., Lowsky, R., Negrin, R. S., Meyer, E. H., Smith, M., Bharadwaj, S., Shizuru, J. A., Sidana, S., Shiraz, P., Rezvani, A. R., Johnston, L. J., Weng, W., Arai, S., Muffly, L., Dahiya, S., Diehn, M., Kurtz, D. M., Sahaf, B., Mackall, C. L., Frank, M. J., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 7545-7547

  View details for DOI 10.1182/blood-2022-165600

  View details for Web of Science ID 000893230300247

• The Development of Carhlh after Axicabtagene Ciloleucel Is Associated with Poor Outcomes Philip, S., Srinagesh, H. K., Hamilton, M. P., Gentille, C., Mina, A., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Dahiya, S., Muffly, L., Smith, M., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2022: 12775-12777

  View details for DOI 10.1182/blood-2022-170877

  View details for Web of Science ID 000893230305401

• Analysis of Bendamustine Lymphodepletion, CD19 CART Expansion, Safety and Efficacy in Patients with Rel/Ref NonHodgkin Lymphoma Bharadwaj, S., Hamilton, M. P., Sahaf, B., Tamaresis, J., Patil, S., Hanson, P. J., Latchford, T., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Meyer, E. H., Shiraz, P., Sidana, S., Smith, M., Weng, W., Muffly, L., Mackall, C. L., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2022: 10371-10373

  View details for DOI 10.1182/blood-2022-170759

  View details for Web of Science ID 000893230303169

• Belumosudil Combination Therapy in Refractory Chronic Graft-Versus-Host Disease Chin, M., Shizuru, J. A., Muffly, L., Shiraz, P., Johnston, L. J., Lowsky, R., Rezvani, A. R., Frank, M. J., Bharadwaj, S., Weng, W., Negrin, R. S., Miklos, D. B., Arai, S. AMER SOC HEMATOLOGY. 2022: 4788-4789

  View details for DOI 10.1182/blood-2022-165547

  View details for Web of Science ID 000893223204356

• Outcomes for Acute Myeloid Leukemia Relapse after Allogeneic Hematopoietic Cell Transplantation Remain Poor in the Modern Era Philip, S., Lowsky, R., Johnston, L. J., Arai, S., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Frank, M. J., Miklos, D. B., Smith, M., Muffly, L., Agrawal, V. AMER SOC HEMATOLOGY. 2022: 4825-4827

  View details for DOI 10.1182/blood-2022-168546

  View details for Web of Science ID 000893223204372

• Idecabtagene Vicleucel Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma with Renal Insufficiency: Real World Experience Sidana, S., Peres, L. C., Hashmi, H., Hosoya, H., Ferreri, C. J., Atrash, S., Khouri, J., Voorhees, P. M., Dima, D., Simmons, G., Kalariya, N., Hovanky, V., Bharadwaj, S., Arai, S., Miklos, D. B., Wagner, C. B., Davis, J., Sborov, D. W., Nishihori, T., Alsina, M., Locke, F. L., Gonzalez, R., Kocoglu, M., Sannareddy, A., Afrough, A., McGuirk, J. P., Shune, L. O., Patel, K., Hansen, D. K. AMER SOC HEMATOLOGY. 2022: 10377-10379

  View details for DOI 10.1182/blood-2022-166058

  View details for Web of Science ID 000893230303171

• The Prevalence and Effects of Frailty in Chronic Graft-Versus-Host Disease Rashid, N., Arora, M., Carpenter, P. A., Alousi, A. M., Hamilton, B. K., Pidala, J., Onstad, L. E., Cutler, C., Flowers, M. D., Arai, S., Bhatia, S., Lee, S. J. AMER SOC HEMATOLOGY. 2022: 10519-10520

  View details for DOI 10.1182/blood-2022-167901

  View details for Web of Science ID 000893230303231

• Disease Characterization and Response Prediction in Myeloma Patients Undergoing Conventional and Cellular Therapies from Circulating Tumor DNA Hosoya, H., Carleton, M., Tanaka, K. L., Sworder, B., Hovanky, V., Duran, G. E., Zhang, T. Y., Khodadoust, M. S., Miklos, D. B., Arai, S., Iberri, D., Liedtke, M., Sidana, S., Kurtz, D. M. AMER SOC HEMATOLOGY. 2022: 1546-1548

  View details for DOI 10.1182/blood-2022-160370

  View details for Web of Science ID 000893223201226

• Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial. The Lancet. Haematology DeZern, A. E., Eapen, M., Wu, J., Talano, J. A., Solh, M., Dávila Saldaña, B. J., Karanes, C., Horwitz, M. E., Mallhi, K., Arai, S., Farhadfar, N., Hexner, E., Westervelt, P., Antin, J. H., Deeg, H. J., Leifer, E., Brodsky, R. A., Logan, B. R., Horowitz, M. M., Jones, R. J., Pulsipher, M. A. 2022

  Abstract

  Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation.We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in the USA. Included patients were children and adults (75 years or younger) with severe aplastic anaemia that was refractory (fulfilment of severe aplastic anaemia disease criteria at least 3 months after initial immunosuppressive therapy) or relapsed (initial improvement of cytopenias after first-line immunosuppressive therapy but then a later return to fulfilment of severe aplastic anaemia disease criteria), adequate performance status (Eastern Cooperative Oncology Group score 0 or 1, Karnofsky or Lansky score ≥60%), and the presence of an eligible related haploidentical donor. The regimen used reduced-intensity conditioning (rabbit anti-thymocyte globulin 4·5 mg/kg in total, cyclophosphamide 14·5 mg/kg daily for 2 days, fludarabine 30 mg/kg daily for 5 days, total body irradiation 200 cGy in a single fraction), related HLA-haploidentical donors, and post-transplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Additionally, for GVHD prophylaxis, mycophenolate mofetil was given orally at a dose of 15 mg/kg three times a day up to 1 g three times a day (maximum dose 3000 mg per day) from day 5 to day 35, and tacrolimus was given orally or intravenously from day 5 to day 180 as per institutional standards to maintain a serum concentration of 10-15 ng/mL. The primary endpoint was overall survival 1 year after bone marrow transplantation. All patients treated per protocol were analysed. This study is complete and is registered with ClinicalTrials.gov, NCT02918292.Between May 1, 2017, and Aug 30, 2020, 32 patients with relapsed or refractory severe aplastic anaemia were enrolled from 14 centres, and 31 underwent bone marrow transplantation. The median age was 24·9 years (IQR 10·4-51·3), and median follow-up was 24·3 months (IQR 12·1-29·2). Of the 31 patients who received a transplant, 19 (61%) were male and 12 (39%) female. 13 (42%) patients were site-reported as non-White, and 19 (61%) were from under-represented racial and ethnic groups; there were four (13%) patients who were Asian, seven (23%) Black, one (3%) Hawaiian/Pacific Islander, and one (3%) more than one race, with seven (23%) patients reporting Hispanic ethnicity. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62-91). The most common grade 3-5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation.Haploidentical bone marrow transplantation using this approach results in excellent overall survival with minimal GVHD in patients who have not responded to immunosuppressive therapy, and can expand access to bone marrow transplantation across all populations. In clinical practice, this could now be considered a standard approach for salvage treatment of severe aplastic anaemia. Attention to obtaining high cell doses (>2·5 × 108 nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial to the success of this approach.US National Heart, Lung, and Blood Institute and US National Cancer Institute.

  View details for DOI 10.1016/S2352-3026(22)00206-X

  View details for PubMedID 35907408

• Epidemiology of lower respiratory tract infections and community-acquired respiratory viruses in patients with bronchiolitis obliterans syndrome after hematopoietic cell transplant: a retrospective cohort study. Transplantation and cellular therapy Epstein, D. J., Liang, E. C., Sharifi, H., Lai, Y. K., Arai, S., Graber-Naidich, A., Sundaram, V., Nelson, J., Hsu, J. L. 2022

  Abstract

  Among 55 patients with bronchiolitis obliterans syndrome, 34 (61.8%) developed lower respiratory tract infections, which were associated with impaired lung function and a trend toward increased mortality. Rhinovirus/enterovirus and Pseudomonas aeruginosa infections predominated; 10 (18.2%) patients developed non-tuberculous mycobacterial infections.

  View details for DOI 10.1016/j.jtct.2022.07.016

  View details for PubMedID 35872303

• Durable discontinuation of systemic therapy in patients affected by chronic graft versus host disease. Haematologica Chen, G. L., Onstad, L., Martin, P. J., Carpenter, P., Pidala, J., Arai, S., Cutler, C., Hamilton, B. K., Lee, S. J., Arora, M. 2022

  Abstract

  Successful treatment of chronic graft-versus-host disease (GVHD) often requires long term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GVHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from 2 prospectively followed cohorts from the chronic GVHD Consortium (N=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half received non-myeloablative conditioning. The median time from HCT to chronic GVHD diagnosis was 7.7 (range 1.0 - 141.3) months, and the median time from chronic GVHD onset to enrollment into the cohorts was 0.9 (range 0.0-12.0) months. The cumulative incidence estimate of durable ST discontinuation was 32% (95% CI: 28%-37%) at 10 years after cohort enrollment. Among patients who discontinued ST, the median time from chronic GVHD diagnosis to durable ST discontinuation was 3.6 (range 1.2-10.5) years. In multivariate analysis, patients who received myeloablative conditioning, had chronic GVHD manifested as moderate / severe lower gastrointestinal (GI) involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower GI involvement and cord blood (vs. peripheral blood) as a graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue systemic treatment permanently, most patients require prolonged systemic treatment. Viewing chronic GVHD in this way has implications for management approaches.

  View details for DOI 10.3324/haematol.2021.279814

  View details for PubMedID 35615925

• Exploring Potential Innate Immune Targets to Treat Fibrosis and Chronic Inflammation in Chronic Graft-Versus-Host Disease Paulson, N., De Souza, C., Cui, L., Lerbs, T., Poyser, J., Kooshesh, M., Saleem, A., Rieger, K., Brown', R., Kwong, B., Fernandez-Po, S., Arai, S., Shizuru, J., Mueller, A., Wernig, G. SPRINGERNATURE. 2022: 557

  View details for Web of Science ID 000770361801147

• Real-world Experience of Cryopreserved Allogeneic Hematopoietic Grafts in the COVID-19 Pandemic: A Single Center Report. Transplantation and cellular therapy Bankova, A. K., Caveney, J., Yao, B., Ramos, T. L., Bogeholz, J., Heydari, K., Diaz, N., Jackson, M. L., Lowsky, R., Brown, J. W., Johnston, L., Rezvani, A. R., Frank, M. J., Muffly, L., Weng, W., Sidana, S., Negrin, R. S., Miklos, D. B., Shiraz, P., Meyer, E. H., Shizuru, J. A., Arai, S. 1800

  Abstract

  BACKGROUND: As a result of the COVID-19 widespread pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear.OBJECTIVES: To compare the outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT).STUDY DESIGN: We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 as compared to 60 consecutive patients who received fresh allografts prior to the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment, graft failure (GF) and secondary outcomes were overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved versus prospectively collected fresh apheresis samples.RESULTS: Compared to fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced intensity conditioning (RIC) allo-HCT with median times to engraftment of 24 days vs 18 days (P = .01) and 27 days vs 18 days (P = .069), respectively. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) vs only one of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid and T-cell donor chimerism at 1 month. OS and RFS were inferior for cryograft recipients with hazard ratio [HR (95%Cl)]: 2.16 (1.00, 4.67) and 1.90 (0.95, 3.79), respectively. Using an extended immunophenotype analysis we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both decrease in total cell viability and significantly reduced absolute numbers of NK cells (CD3-CD56+) in the cryopreserved apheresis samples.CONCLUSION: In this single institution study we note delayed engraftment and a trend toward clinical inferiority of cryopreserved vs fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.

  View details for DOI 10.1016/j.jtct.2022.01.010

  View details for PubMedID 35042013

• Post-Hematopoietic Stem Cell Transplantation Immune-Mediated Anemia: A Literature Review and Novel Therapeutics. Blood advances Migdady, Y., Pang, Y., Kalsi, S. S., Childs, R. W., Arai, S. 1800

  Abstract

  Anemia following allogeneic hematopoietic stem cell transplantation (HCT) can be immune- or non-immune mediated. Auto- or alloimmunity due to blood groups incompatibility remain an important cause if post-HCT immune-mediated anemia. ABO incompatibility is commonly encountered in HCT and may lead to serious clinical complications including acute hemolysis, pure red cell aplasia, and passenger lymphocyte syndrome. It remains controversial whether ABO incompatibility may affect HCT outcomes, such as relapse, non-relapse mortality, graft-versus-host disease and survival. Non-ABO incompatibility is less frequently encounterd but can have similar complications to ABO incompatibility, causing adverse clinical outcomes. It is crucial to identify the driving etiology of post-HCT anemia in order to prevent and treat this condition. This requires a comprehensive understanding of the mechanism of anemia in blood group incompatible HCT, and the temporal association between HCT and anemia. In this review, we summarized the literature on post-HCT immune-mediated anemia with a focus on ABO and non-ABO blood group incompatibility, described the underlying mechanism of anemia, and outlined preventive and treatment approaches.

  View details for DOI 10.1182/bloodadvances.2021006279

  View details for PubMedID 34972204

• CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy Frank, M. J., Baird, J. H., Patel, S., Craig, J., Spiegel, J. Y., Ehlinger, Z., Chinnasamy, H., Younes, S. F., Oak, J. S., Natkunam, Y., Reynolds, W. D., Iglesias, M., Crawford, E., Srinagesh, H. K., Egeler, E. L., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shiraz, P., Sidana, S., Weng, W., Schultz, L. M., Ramakrishna, S., Davis, K. L., Sahaf, B., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffl, L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-152145

  View details for Web of Science ID 000736398803041

• Selective Targeting of Immune Modulatory Proteins to Mitigate Fibrosis and Inflammation in Sclerodermatous Graft-Vs-Host Disease Cui, L., De Souza, C., Lerbs, T., Poyser, J., Kooshesh, M., Saleem, A., Rieger, K., Brown, B., Kwong, B., Fernandez-Pol, S., Arai, S., Shizuru, J. A., Mueller, A. S., Wernig, G. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-151223

  View details for Web of Science ID 000736398802184

• 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

• Mgta-145+Plerixafor Provides GCSFFree Rapid and Reliable Hematopoietic Stem Cell Mobilization for Autologous Stem Cell Transplant in Patients with Multiple Myeloma: A Phase 2 Study Sidana, S., Bankova, A. K., Hosoya, H., Kumar, S., Tamaresis, J., Le, A., Muffly, L., Johnston, L. J., Arai, S., Lowsky, R., Meyer, E. H., Rezvani, A. R., Weng, W., Frank, M. J., Shiraz, P., Girgenti, D., Goncalves, K. A., Schmelmer, V., Davis, J. C., Lu, Y., Shizuru, J. A., Miklos, D. B. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-149306

  View details for Web of Science ID 000736413908010

• Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy BLOOD ADVANCES Johnsrud, A., Craig, J., Baird, J., Spiegel, J., Muffly, L., Zehnder, J., Tamaresis, J., Negrin, R., Johnston, L., Arai, S., Shizuru, J., Lowsky, R., Meyer, E., Weng, W., Shiraz, P., Rezvani, A., Latchford, T., Mackall, C., Miklos, D., Frank, M., Sidana, S. 2021; 5 (21): 4465-4475

  View details for DOI 10.1182/bloodadvances.2021004716.

  View details for Web of Science ID 000718993700016

• Initial therapy of chronic graft vs. host disease: Analysis of practice variation and failure-free survival. Blood advances Pidala, J., Onstad, L., Martin, P. J., Hamilton, B. K., Cutler, C. S., Kitko, C. L., Carpenter, P. A., Chen, G. L., Arora, M., Flowers, M. E., Arai, S., Alousi, A., White, J., Jacobsohn, D. A., Pusic, I., Lee, S. J. 2021

  Abstract

  Prior clinical trials largely considered prednisone 1mg/kg/day with or without calcineurin inhibitor as standard initial therapy for chronic graft vs. host disease (cGVHD) but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 cGVHD patients treated with initial systemic immune suppressive (IS) therapy from three prior Chronic GVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥ 0.4mg/kg/day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were non-prednisone IS therapies (n=137, 18%), prednisone alone (n=411, 55%), or prednisone plus other IS therapy (n=197, 26%). In multivariate analysis, initial therapy group was not associated with FFS (failure-free survival, a composite of death, relapse, new IS therapy), overall survival (OS) or non-relapse mortality (NRM). Among the prednisone-based approaches, steroid dose (mg/kg/day) was <0.25 (9%), 0.25-0.74 (36%), 0.75-1.25 (42%), or >1.25 (13%). Prednisone dose within the steroid-treated patients was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of non-steroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.

  View details for DOI 10.1182/bloodadvances.2021005286

  View details for PubMedID 34535015

• Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium. Blood advances DeFilipp, Z., Alousi, A., Pidala, J., Carpenter, P. A., Onstad, L., Arai, S., Arora, M., Cutler, C. S., Flowers, M. E., Kitko, C. L., Chen, G. L., Lee, S. J., Hamilton, B. K. 2021

  Abstract

  Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.

  View details for DOI 10.1182/bloodadvances.2021004941

  View details for PubMedID 34521116

• Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia. Blood advances Muffly, L., Sundaram, V., Chen, C., Yurkiewicz, I., Kuo, E., Burnash, S., Spiegel, J. Y., Arai, S., Frank, M. J., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Sidana, S., Shiraz, P., Shizuru, J. A., Weng, W., Liedtke, M., Vempaty, H. T., Miklos, D. B. 2021; 5 (16): 3147-3151

  Abstract

  Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

  View details for DOI 10.1182/bloodadvances.2021004234

  View details for PubMedID 34424318

• CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nature medicine Spiegel, J. Y., Patel, S., Muffly, L., Hossain, N. M., Oak, J., Baird, J. H., Frank, M. J., Shiraz, P., Sahaf, B., Craig, J., Iglesias, M., Younes, S., Natkunam, Y., Ozawa, M. G., Yang, E., Tamaresis, J., Chinnasamy, H., Ehlinger, Z., Reynolds, W., Lynn, R., Rotiroti, M. C., Gkitsas, N., Arai, S., Johnston, L., Lowsky, R., Majzner, R. G., Meyer, E., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J., Weng, W., Mullins, C., Jacob, A., Kirsch, I., Bazzano, M., Zhou, J., Mackay, S., Bornheimer, S. J., Schultz, L., Ramakrishna, S., Davis, K. L., Kong, K. A., Shah, N. N., Qin, H., Fry, T., Feldman, S., Mackall, C. L., Miklos, D. B. 2021

  Abstract

  Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n=17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n=21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

  View details for DOI 10.1038/s41591-021-01436-0

  View details for PubMedID 34312556

• Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study. Blood Cutler, C. S., Lee, S. J., Arai, S., Rotta, M., Zoghi, B., Lazaryan, A., Ramakrishnan, A., DeFilipp, Z., Salhotra, A., Chai-Ho, W., Mehta, R. S., Wang, T., Arora, M., Pusic, I., Saad, A., Shah, N. N., Abhyankar, S., Bachier, C., Galvin, J. P., Im, A., Langston, A., Liesveld, J. L., Juckett, M., Logan, A., Schachter, L., Alavi, A., Howard, D. S., Waksal, H., Ryan, J., Eiznhamer, D., Aggarwal, S. K., Ieyoub, J., Schueller, O., Green, L. S., Yang, Z., Krenz, H., Jagasia, M., Blazar, B. R., Pavletic, S. Z. 2021

  Abstract

  Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).

  View details for DOI 10.1182/blood.2021012021

  View details for PubMedID 34265047

• A fructo-oligosaccharide prebiotic is well-tolerated in adults undergoing allogeneic hematopoietic stem cell transplantation: a phase I dose-escalation trial. Transplantation and cellular therapy Andermann, T. M., Fouladi, F., Tamburini, F. B., Sahaf, B., Tkachenko, E., Greene, C., Buckley, M. T., Brooks, E. F., Hedlin, H., Arai, S., Mackall, C. L., Miklos, D., Negrin, R. S., Fodor, A. A., Rezvani, A. R., Bhatt, A. S. 2021

  Abstract

  BACKGROUND: Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOS) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate, and consequently induce proliferation of immunomodulatory FOXP3+ CD4+ T-regulatory cells (Tregs), that impact GVHD risk.METHODS: We conducted a pilot Phase I trial to assess the investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity (RIC) allo-HCT (n=15) compared to concurrent controls (n=16). We administered FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool SCFAs using LC-MS, and determined peripheral T-cell concentrations using CyTOF.RESULTS: We found that FOS was safe and well-tolerated at 10g per day without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition was significantly different on the day of transplant (day 0) between patients receiving FOS compared to concurrent controls, however FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or in peripheral Tregs although Tregs trended higher in those patients who received FOS. A marker of CD4+ T-cell activation, namely CTLA4+, was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3+CD4+ T-regulatory cells that were higher in those receiving FOS compared to controls.CONCLUSIONS: FOS is well-tolerated at 10g per day in patients undergoing RIC allo-HCT. While alterations in the gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients.

  View details for DOI 10.1016/j.jtct.2021.07.009

  View details for PubMedID 34274493

• Inferior Clinical Outcomes in Recipients of Cryopreserved Grafts Following Reduced Intensity Allogeneic Hematopoietic Cell Transplantation: A Single Center Report Bankova, A., Caveney, J., Ramos, T., Bogeholz, J., Heydari, K., Diaz, N., Jackson, M., Lowsky, R., Brown, J., Johnston, L., Rezvani, A., Frank, M., Muffly, L., Weng, W., Sidana, S., Negrin, R., Miklos, D., Shiraz, P., Meyer, E., Shizuru, J., Arai, S. SPRINGERNATURE. 2021: 181

  View details for Web of Science ID 000668928500152

• Phase 2 study of MGTA-145+plerixafor for rapid and reliable hematopoietic stem cell (HSC) mobilization for autologous transplant in multiple myeloma. Sidana, S., Bankova, A., Hosoya, H., Muffly, L. S., Kumar, S., Johnston, L. J., Lowsky, R., Meyer, E., Rezvani, A., Weng, W., Arai, S., Frank, M., Shiraz, P., Howell, H., Goncalves, K. A., Schmelmer, V., Davis, J., Shizuru, J., Miklos, D. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.8023

  View details for Web of Science ID 000708120604186

• Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor vs. G-CSF +/- Plerixafor in the Lenalidomide Era. Transplantation and cellular therapy Johnsrud, A., Ladha, A., Muffly, L., Shiraz, P., Goldstein, G., Osgood, V., Shizuru, J. A., Johnston, L., Arai, S., Weng, W., Lowsky, R., Rezvani, A. R., Meyer, E. H., Frank, M. J., Negrin, R. S., Miklos, D. B., Sidana, S. 2021

  Abstract

  Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used for patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017-2020 using either cyclophosphamide (4g/m2) plus granulocyte colony stimulating factor (GCSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. While total CD34+yield was higher after chemo-mobilization compared to GCSF+/-PXF (median 13.6 vs. 4.4 * 106/kg,P< .01), achievement of≥2 * 106CD34+ cells (95% vs 93.7%,P= .61), and rates of mobilization failure (5% vs. 6.3%,P= .61) were similar. Fewer patients required PXF with chemo-mobilization (12.3% vs 49.5%,P< .01), and apheresis sessions were fewer (median: 1, range 1-4 vs. 2, range 1-5). Complications were higher after chemo-mobilization (30% vs. 7.4%,P< .01), including neutropenic fever, ED visits, and hospitalizations. Prior lenalidomide≤6 cycles did not impair cell yield in either group.Median cost of mobilization was 17.4% lower in the GCSF +/- PXF group (P= .01).Differences in time to engraftment were not clinically significant. Given similar rates mobilization success, engraftment time, and less toxicity and lower costs compared to chemo-mobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.

  View details for DOI 10.1016/j.jtct.2021.04.016

  View details for PubMedID 33915323

• Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. Transplantation and cellular therapy Liang, E. C., Muffly, L. S., Shiraz, P., Shizuru, J. A., Johnston, L., Arai, S., Frank, M. J., Weng, W., Lowsky, R., Rezvani, A., Meyer, E. H., Negrin, R., Miklos, D. B., Sidana, S. 2021

  Abstract

  Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n=240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2*106/kg (range, 3.4-112.4). A median of 5.7*106 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1*106 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n=27) used backup stem cells, with 2.3% (n=10) using them for stem cell boost, 4.6% (n=18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6*106 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.

  View details for DOI 10.1016/j.jtct.2021.02.026

  View details for PubMedID 33775587

• Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma BLOOD ADVANCES Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143–55

  View details for DOI 10.1182/bloodadvances.2020002732

  View details for Web of Science ID 000607932700016

• Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma. Leukemia Merryman, R. W., Castagna, L. n., Giordano, L. n., Ho, V. T., Corradini, P. n., Guidetti, A. n., Casadei, B. n., Bond, D. A., Jaglowski, S. n., Spinner, M. A., Arai, S. n., Lowsky, R. n., Shah, G. L., Perales, M. A., De Colella, J. M., Blaise, D. n., Herrera, A. F., Shouse, G. n., Spilleboudt, C. n., Ansell, S. M., Nieto, Y. n., Badar, T. n., Hamadani, M. n., Feldman, T. A., Dahncke, L. n., Singh, A. K., McGuirk, J. P., Nishihori, T. n., Chavez, J. n., Serritella, A. V., Kline, J. n., Mohty, M. n., Dulery, R. n., Stamatoulas, A. n., Houot, R. n., Manson, G. n., Moles-Moreau, M. P., Orvain, C. n., Bouabdallah, K. n., Modi, D. n., Ramchandren, R. n., Lekakis, L. n., Beitinjaneh, A. n., Frigault, M. J., Chen, Y. B., Lynch, R. C., Smith, S. D., Rao, U. n., Byrne, M. n., Romancik, J. T., Cohen, J. B., Nathan, S. n., Phillips, T. n., Joyce, R. M., Rahimian, M. n., Bashey, A. n., Ballard, H. J., Svoboda, J. n., Torri, V. n., Sollini, M. n., De Philippis, C. n., Magagnoli, M. n., Santoro, A. n., Armand, P. n., Zinzani, P. L., Carlo-Stella, C. n. 2021

  Abstract

  Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.

  View details for DOI 10.1038/s41375-021-01193-6

  View details for PubMedID 33658659

• Jun Activation in Dermal Fibroblasts Promotes Fibrosis and Inflammation in Sclerodermatous Graft-vs-host Disease in Mice and Humans Mueller, A., Cui, L., Lerbs, T., King, M., Muscat, C., Shibata, T., Lee, J., Brown, R., Fernandez-Pol, S., Arai, S., Shizuru, J., Wernig, G. SPRINGERNATURE. 2020: 13–14

  View details for Web of Science ID 000600556200003

• Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Lemieux, C., Johnston, L. J., Lowsky, R., Muffly, L. S., Craig, J. K., Shiraz, P., Rezvani, A., Frank, M. J., Weng, W., Meyer, E., Shizuru, J., Arai, S., Negrin, R., Miklos, D. B., Sidana, S. 2020

  Abstract

  Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (autoSCT) or allogeneic (alloSCT) transplant is not clear as there is lack of clinical trial based evidence. This single center retrospective study describes the outcomes of 16 patients with PCL (N=14 primary PCL) who underwent either autoSCT (N=9) or alloSCT (N=7) for PCL in the era of novel agents, between 2007 and 2019. Median age of the cohort was 58 years. High-risk cytogenetics were seen in 50% of patients. All patients received a proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD) based regimen before transplant. At transplant, 10 (62%) patients obtained at least a very good partial response. Response after autoSCT (3 month) was at least VGPR in 6 (67%, CR=5) patients. All patients undergoing alloSCT achieved CR at 3 months. Maintenance was used in 5 patients (56%) after autoSCT. Median PFS from transplant in the autoSCT vs. alloSCT group was 6 vs. 18 months, p=0.09, while median OS from transplant was 19 vs. 40 months (p=0.41), respectively. The median OS from diagnosis was 27 vs. 49 months, p=0.50, respectively. Of all the deaths, 10 (91%) patients died of relapsed disease. In conclusion, alloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, which is comparable to other recent reports and relapse remains the primary cause of death.

  View details for DOI 10.1016/j.bbmt.2020.08.035

  View details for PubMedID 32961371

• Autologous stem cell transplantation versus no transplant in patients above 70 with multiple myeloma. Lemieux, C., Muffly, L. S., Iberri, D., Rezvani, A., Lowsky, R., Frank, M., Craig, J. K., Liedtke, M., Negrin, R., Weng, W., Meyer, E., Johnston, L. J., Shizuru, J., Shiraz, P., Arai, S., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307442

• Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM). Tam, E., Iberri, D., Liedtke, M., Muffly, L. S., Shiraz, P., Frank, M., Lowsky, R., Rezvani, A., Negrin, R., Meyer, E., Arai, S., Johnston, L. J., Shizuru, J., Weng, W., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307484

• Successful treatment of thrombocytopenia with daratumumab after allogeneic transplant: a case report and literature review. Blood advances Migdady, Y., Ediriwickrema, A., Jackson, R. P., Kadi, W., Gupta, R., Socola, F., Arai, S., Martin, B. A. 2020; 4 (5): 815–18

  View details for DOI 10.1182/bloodadvances.2019001215

  View details for PubMedID 32119735

• Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Significant Increase in Survival in the Post-Targeted Immunotherapy Era Muffly, L., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Miklos, D. B., Negrin, R. S., Rezvani, A., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Cunanan, K. ELSEVIER SCIENCE INC. 2020: S106

  View details for Web of Science ID 000516887900144

• Organ responses with daratumumab therapy in previously treated AL amyloidosis. Blood advances Chung, A. n., Kaufman, G. P., Sidana, S. n., Eckhert, E. n., Schrier, S. L., Lafayette, R. A., Arai, S. n., Witteles, R. M., Liedtke, M. n. 2020; 4 (3): 458–66

  Abstract

  Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

  View details for DOI 10.1182/bloodadvances.2019000776

  View details for PubMedID 32027745

• Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation. JACC. Heart failure Barrett, C. D., Alexander, K. M., Zhao, H. n., Haddad, F. n., Cheng, P. n., Liao, R. n., Wheeler, M. T., Liedtke, M. n., Schrier, S. n., Arai, S. n., Weisshaar, D. n., Witteles, R. M. 2020

  Abstract

  The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

  View details for DOI 10.1016/j.jchf.2019.12.013

  View details for PubMedID 32387068

• CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma. Blood Baird, J. H., Frank, M. J., Craig, J. n., Patel, S. n., Spiegel, J. Y., Sahaf, B. n., Oak, J. S., Younes, S. n., Ozawa, M. n., Yang, E. n., Natkunam, Y. n., Tamaresis, J. S., Ehlinger, Z. n., Reynolds, W. D., Arai, S. n., Johnston, L. n., Lowsky, R. n., Meyer, E. n., Negrin, R. S., Rezvani, A. R., Shiraz, P. n., Sidana, S. n., Weng, W. K., Davis, K. L., Ramakrishna, S. n., Schultz, L. n., Mullins, C. D., Jacob, A. P., Kirsch, I. R., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffly, L. n. 2020

  Abstract

  The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890).

  View details for DOI 10.1182/blood.2020009432

  View details for PubMedID 33512414

• Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma. Blood advances Weng, W. K., Arai, S. n., Rezvani, A. n., Johnston, L. n., Lowsky, R. n., Miklos, D. n., Shizuru, J. n., Muffly, L. n., Meyer, E. n., Negrin, R. S., Wang, E. n., Almazan, T. n., Million, L. n., Khodadoust, M. n., Li, S. n., Hoppe, R. T., Kim, Y. H. 2020; 4 (18): 4474–82

  Abstract

  The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.

  View details for DOI 10.1182/bloodadvances.2020001627

  View details for PubMedID 32941647

• Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma. Bone marrow transplantation Lemieux, C. n., Muffly, L. S., Rezvani, A. n., Lowsky, R. n., Iberri, D. J., Craig, J. K., Frank, M. J., Johnston, L. J., Liedtke, M. n., Negrin, R. n., Weng, W. K., Meyer, E. n., Shizuru, J. n., Shiraz, P. n., Arai, S. n., Miklos, D. B., Sidana, S. n. 2020

  Abstract

  We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

  View details for DOI 10.1038/s41409-020-01026-7

  View details for PubMedID 32782351

• Grading cardiac response in AL amyloidosis: implications for relapse and survival BRITISH JOURNAL OF HAEMATOLOGY Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2019; 186 (1): 144–46

  View details for DOI 10.1111/bjh.15717

  View details for Web of Science ID 000472576700020

• Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients JCI INSIGHT Meyer, E. H., Laport, G., Xie, B. J., MacDonald, K., Heydari, K., Sahaf, B., Tang, S., Baker, J., Armstrong, R., Tate, K., Tadisco, C., Arai, S., Johnston, L., Lowsky, R., Muffly, L., Rezvani, A. R., Shizuru, J., Weng, W., Sheehan, K., Miklos, D., Negrin, R. S. 2019; 4 (10)

  View details for DOI 10.1172/jci.insight.127244

  View details for Web of Science ID 000468146300016

• Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). The Lancet. Haematology Bolanos-Meade, J., Reshef, R., Fraser, R., Fei, M., Abhyankar, S., Al-Kadhimi, Z., Alousi, A. M., Antin, J. H., Arai, S., Bickett, K., Chen, Y., Damon, L. E., Efebera, Y. A., Geller, N. L., Giralt, S. A., Hari, P., Holtan, S. G., Horowitz, M. M., Jacobsohn, D. A., Jones, R. J., Liesveld, J. L., Logan, B. R., MacMillan, M. L., Mielcarek, M., Noel, P., Pidala, J., Porter, D. L., Pusic, I., Sobecks, R., Solomon, S. R., Weisdorf, D. J., Wu, J., Pasquini, M. C., Koreth, J. 2019; 6 (3): e132–e143

  Abstract

  BACKGROUND: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.METHODS: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.FINDINGS: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).INTERPRETATION: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.FUNDING: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

  View details for PubMedID 30824040

• A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis. JACC. Heart failure Barrett, C. D., Dobos, K. n., Liedtke, M. n., Tuzovic, M. n., Haddad, F. n., Kobayashi, Y. n., Lafayette, R. n., Fowler, M. B., Arai, S. n., Schrier, S. n., Witteles, R. M. 2019

  Abstract

  The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

  View details for DOI 10.1016/j.jchf.2019.07.007

  View details for PubMedID 31606365

• Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort. Blood advances Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Arai, S. n., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Hoppe, R. T., Strober, S. n., Lowsky, R. n. 2019; 3 (16): 2454–64

  Abstract

  Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.

  View details for DOI 10.1182/bloodadvances.2019000297

  View details for PubMedID 31427277

• Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI insight Meyer, E. H., Laport, G. n., Xie, B. J., MacDonald, K. n., Heydari, K. n., Sahaf, B. n., Tang, S. W., Baker, J. n., Armstrong, R. n., Tate, K. n., Tadisco, C. n., Arai, S. n., Johnston, L. n., Lowsky, R. n., Muffly, L. n., Rezvani, A. R., Shizuru, J. n., Weng, W. K., Sheehan, K. n., Miklos, D. n., Negrin, R. S. 2019; 4 (10)

  Abstract

  BACKGROUNDIn preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defined ratios of CD4+CD25+FoxP3+ Tregs to conventional T cells (Tcons) results in the prevention of graft-versus-host disease and improved immune reconstitution. The use of highly purified primary graft Tregs for direct cell infusion has potential advantages over impure immunomagnetic selection or culture expansion, but has not been tested clinically. We performed a phase I study of the timed addition of CD34-selected hematopoietic stem cells and Tregs, followed by Tcons for the treatment of patients with high-risk hematological malignancies.METHODSWe present interim evaluation of a single-center open phase I/II study of administration of human leukocyte-matched Tregs and CD34-selected hematopoietic cells, followed by infusion of an equal ratio of Tcons in adult patients undergoing myeloablative hematopoietic stem cell transplantation (HCT) for high-risk or active hematological malignancies. Tregs were purified by immunomagnetic selection and high-speed cell sorting.RESULTSHere we report results for the first 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the first cohort of 5 patients, who received cryopreserved Tregs, but neither acute nor chronic GVHD was noted in the second cohort of 7 patients, who received fresh Tregs and single-agent GVHD prophylaxis. Patients in the second cohort appeared to have normal immune reconstitution compared with patients who underwent transplantation and did not develop GVHD.CONCLUSIONOur study shows that the use of highly purified fresh Tregs is clinically feasible and supports continued investigation of the strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT01660607.FUNDINGNIH NHBLI R01 HL114591 and K08HL119590.

  View details for PubMedID 31092732

• Grading cardiac response in AL amyloidosis: implications for relapse and survival. British journal of haematology Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2018

  View details for PubMedID 30569572

• Nonmyeloablative Allogeneic Transplantation Using TLI-ATG Conditioning for Lymphoid and Myeloid Malignancies: Mature Follow-up from a Large, Single Institution Cohort Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Elder, L. V., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Hoppe, R. T., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113597

  View details for Web of Science ID 000454842804265

• A Case Report of Refractory Immune Thrombocytopenia (ITP) Following Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Myelodysplastic Syndrome (MDS) Successfully Treated with Off-Label Use of Daratumumab Migdady, Y., Gupta, R., Ediriwickrema, A., Socola, F., Arai, S., Martin, B. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-116560

  View details for Web of Science ID 000454842805252

• Elevated Axicabtagene Ciloleucel (CAR-19) Expansion By Immunophenotyping Is Associated with Toxicity in Diffuse Large B-Cell Lymphoma Spiegel, J. Y., Sahaf, B., Hossain, N., Frank, M. J., Claire, G., Abramian, M., Latchford, T., Villa, B., Cancilla, J., Oak, J., Natkunam, Y., Long, S. R., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Kong, K. A., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113261

  View details for Web of Science ID 000454837601285

• Hedgehog Pathway Inhibitor for Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) Gupta, R., Albabtain, A., Arai, S., Kwong, B., Weng, W. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113915

  View details for Web of Science ID 000454842801189

• Graded Cardiac Response Correlates with Relapse and Survival in AL Amyloidosis Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113577

  View details for Web of Science ID 000454842804139

• Donor-derived MDS/AML in families with germline GATA2 mutation BLOOD Galera, P., Hsu, A. P., Wang, W., Droll, S., Chen, R., Schwartz, J. R., Klco, J. M., Arai, S., Maese, L., Zerbe, C., Parta, M. J., Young, N. S., Holland, S. M., Hickstein, D. D., Calvo, K. R. 2018; 132 (18): 1994–98

  View details for PubMedID 30232126

• Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802 BLOOD ADVANCES Holtan, S. G., DeFor, T. E., Panoskaltsis-Mortari, A., Khera, N., Levine, J. E., Flowers, M. D., Lee, S. J., Inamoto, Y., Chen, G. L., Mayer, S., Arora, M., Palmer, J., Cutler, C. S., Arai, S., Lazaryan, A., Newell, L. F., Jagasia, M. H., Pusic, I., Wood, W. A., Renteria, A. S., Yanik, G., Hogan, W. J., Hexner, E., Ayuk, F., Holler, E., Bunworasate, U., Efebera, Y. A., Ferrara, J. M., Pidala, J., Howard, A., Wu, J., Bolanos-Meade, J., Ho, V., Alousi, A., Blazar, B. R., Weisdorf, D. J., MacMillan, M. L. 2018; 2 (15): 1882–88

  Abstract

  Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; P < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; P = .02); greater 2-year NRM (42% vs 15%; P < .01); and inferior OS (40% vs 66%; P < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; P = .03) and 2-year NRM (53% vs 11%; P < .01), with a trend toward inferior 2-year OS (37% vs 60%; P = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.

  View details for PubMedID 30087106

  View details for PubMedCentralID PMC6093743

• Design and Patient Characteristics of the Chronic Graft-versus-Host Disease Response Measures Validation Study BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Lee, S. J., Flowers, M. D., Storer, B., Onstad, L., Kurukulasuriya, C., Jagasia, M., Hamilton, B., Chen, G., Cutler, C., Broady, R., Arora, M., Pidala, J., Alousi, A., Arai, S., Sarantopoulos, S., Jaglowski, S., Chronic GVHD Consortium 2018; 24 (8): 1727–32

  Abstract

  In 2014, the National Institutes of Health sponsored the second Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease (GVHD). The purpose was to update recommendations about key elements of chronic GVHD research, including definitions for diagnosis, severity scoring, and response measures, based on empirical data published since the first 2005 Consensus Conference. The most significant modifications were to the response assessments, based on studies demonstrating difficulty with the first consensus definitions. The Response Measures Validation Study is a multicenter, prospective cohort study of patients who are starting initial or subsequent treatments for chronic GVHD. The aim of the study is to evaluate the performance of the 2014 response measures and determine whether any other combination of assessments is superior. Clinical data, clinician assessments, patient-reported outcomes, and research samples are collected at enrollment and 3, 6, and 18 months later, and whenever another chronic GVHD systemic treatment is added. The target enrollment of 368 evaluable patients from 12 transplantation centers has been reached. This report describes the rationale, design, and methods of the Chronic GVHD Response Measures Validation Study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.

  View details for DOI 10.1016/j.bbmt.2018.02.010

  View details for Web of Science ID 000443668100028

  View details for PubMedID 29476954

  View details for PubMedCentralID PMC6103904

• Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome BRITISH JOURNAL OF HAEMATOLOGY Kernan, N. A., Grupp, S., Smith, A. R., Arai, S., Triplett, B., Antin, J. H., Lehmann, L., Shore, T., Ho, V. T., Bunin, N., Iacobelli, M., Liang, W., Hume, R., Tappe, W., Soiffer, R., Richardson, P. 2018; 181 (6): 816–27

  Abstract

  Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi-organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded-access treatment programme (T-IND; NCT00628498). In the completed T-IND, the Kaplan-Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7-61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8-71·6%) and 47·1% (95% CI, 42·3-51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T-IND study was similar to previous reports.

  View details for PubMedID 29767845

• Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation BLOOD ADVANCES Muffly, L., Sheehan, K., Armstrong, R., Jensen, K., Tate, K., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. 2018; 2 (6): 681–90

  Abstract

  Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.

  View details for PubMedID 29572391

• Phase I/II Trial for Patients with Advanced Hematologic Malignancies Undergoing Myeloablative Allogeneic HCT with a T Cell Depleted Graft with Infusion of Conventional T Cells and Regulatory T Cells Meyer, E., Laport, G. G., Tantsura, I., Tang, S., Sahaf, B., Rangarajan, K., Armstrong, R., Tate, K., Tudisco, C., Sheehan, K., Arai, S., Johnston, L., Muffly, L., Lowsky, R., Rezvani, A., Weng, W., Miklos, D., Negrin, R. S. ELSEVIER SCIENCE INC. 2018: S145

  View details for Web of Science ID 000425476000186

• Donor Derived MDS/AML in Patients with Germline GATA2 Mutations Galera, P., Hsu, A., Wang, W., Schwartz, J. R., Klco, J., Arai, S., Holland, S. M., Hickstein, D., Calvo, K. NATURE PUBLISHING GROUP. 2018: 516–17

  View details for Web of Science ID 000429308603316

• Amphiregulin Modifies the Minnesota Acute Graft-Versus-Host Disease Risk Score: Results from BMT CTN Acute Gvhd Therapy Trials Holtan, S. G., Defor, T. E., Howard, A., Pidala, J. A., Levine, J. E., Wu, J., Khera, N., Lee, S. J., Bolanos-Meade, J., Ho, V. T., Alousi, A. M., Inamoto, Y., Chen, G. L., Arora, M., Palmer, J., Flowers, M. E., Cutler, C., Renteria, A. S., Lukez, A., Arai, S., Lazaryan, A., Hogan, W. J., Newell, L. F., Jagasia, M., Wood, W. A., Krupski, M., Yanik, G. A., Bunworasate, U., Hexner, E. O., Ayuk, F., Holler, E., Mayer, S., Pusic, I., Duong, H. K., Efebera, Y. A., Ferrara, J., Blazar, B. R., Mortari, A., Weisdorf, D. J., MacMillan, M. L. ELSEVIER SCIENCE INC. 2018: S177–S178

  View details for Web of Science ID 000425476000235

• Association of Socioeconomic Status with Chronic Graft-versus-Host Disease Outcomes BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Hamilton, B. K., Rybicki, L., Arai, S., Arora, M., Cutler, C. S., Flowers, M. D., Jagasia, M., Martin, P. J., Palmer, J., Pidala, J., Majhail, N. S., Lee, S. J., Khera, N. 2018; 24 (2): 393–99

  Abstract

  Chronic graft-versus host disease (GVHD) is a chronic and disabling complication after hematopoietic cell transplantation (HCT). It is important to understand the association of socioeconomic status (SES) with health outcomes in patients with chronic GVHD because of the impaired physical health and dependence on intensive and prolonged health care utilization needs in these patients. We evaluated the association of SES with survival and quality of life (QOL) in a cohort of 421 patients with chronic GVHD enrolled on the Chronic GVHD Consortium Improving Outcomes Assessment study. Income, education, marital status, and work status were analyzed to determine the associations with patient-reported outcomes at the time of enrollment, nonrelapse mortality (NRM), and overall mortality. Higher income (P = .004), ability to work (P < .001), and having a partner (P = .021) were associated with better mean Lee chronic GVHD symptom scores. Higher income (P = .048), educational level (P = .044), and ability to work (P < .001) also were significantly associated with better QOL and improved activity. In multivariable models, higher income and ability to return to work were both significantly associated with better chronic GVHD Lee symptom scores, but income was not associated with activity level, QOL, or physical/mental functioning. The inability to return to work (hazard ratio, 1.82; P = .019) was associated with worse overall mortality, whereas none of the SES indicators were associated with NRM. Income, race, and education did not have statistically significant associations with survival. In summary, we did not observe an association between SES variables and survival or NRM in patients with chronic GVHD, although we found some association with patient-reported outcomes, such as symptom burden. Higher income status was associated with less severe chronic GVHD symptoms. More research is needed to understand the psychosocial, biological, and environmental factors that mediate this association of SES with major HCT outcomes.

  View details for PubMedID 29032275

  View details for PubMedCentralID PMC5767523

• Anti-Platelet-Derived Growth Factor Receptor Alpha Chain Antibodies Predict for Response to Nilotinib in Steroid-Refractory or -Dependent Chronic Graft-Versus-Host Disease BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Chen, G. L., Carpenter, P. A., Broady, R., Gregory, T. K., Johnston, L. J., Storer, B. E., Beumer, J. H., Qiu, J., Cerda, K., Le, R., Otani, J. M., Liu, H., Ross, M. A., Arai, S., Flowers, M. D., McCarthy, P. L., Miklos, D. B. 2018; 24 (2): 373–80

  Abstract

  Imatinib has clinical activity in chronic graft-versus-host disease (cGVHD), a significant complication of allogeneic hematopoietic cell transplant. Nilotinib is a tyrosine kinase inhibitor that targets the same receptors as imatinib but with different affinities. We tested the hypothesis that nilotinib is safe and has clinical activity in cGVHD. Thirty-three participants were enrolled in a phase I/II dose escalation and dose extension clinical trial of nilotinib for the treatment of steroid-refractory or- dependent cGVHD (ClinicalTrials.gov, NCT01155817). We assessed safety, clinical response, and pretreatment anti-platelet-derived growth factor receptor alpha chain (anti-PDGFRA) antibody levels. The 200-mg dose was identified as the maximum tolerated dose and used for the phase II dose extension study. At 6 months the incidence of failure-free survival (FFS), cGVHD progression, and nilotinib intolerance resulting in its discontinuation was 50%, 23%, and 23%, respectively. cGVHD responses in skin, joints, and mouth were observed at 3 and 6 months based on improvement in respective National Institutes of Health organ severity scores. Pretreatment anti-PDGFRA antibody levels ≥ .150 optical density as measured by ELISA correlated with longer FFS time (P < .0005) and trended with time until cGVHD progression (P < .06) but not drug intolerance. Nilotinib may be effective for corticosteroid-resistant or -refractory cGVHD in some patients, but its use is limited by intolerable side effects. Selection of patients with high pretreatment anti-PDGFRA antibody levels might improve the risk-to-benefit ratio of nilotinib and better justify its side effects.

  View details for PubMedID 29051021

• Potential Association of Anti-CCR4 Antibody Mogamulizumab and Graft-vs-Host Disease in Patients With Mycosis Fungoides and Sézary Syndrome. JAMA dermatology Dai, J. n., Almazan, T. H., Hong, E. K., Khodadoust, M. S., Arai, S. n., Weng, W. K., Kim, Y. H. 2018

  View details for PubMedID 29800117

• The Cost of Hematopoietic Stem-Cell Transplantation in the United States AMERICAN HEALTH AND DRUG BENEFITS Broder, M. S., Quock, T. P., Chang, E., Reddy, S. R., Agarwal-Hashmi, R., Arai, S., Villa, K. F. 2017; 10 (7): 366–73

  Abstract

  Hematopoietic stem-cell transplantation (HSCT) requires highly specialized, resource-intensive care. Myeloablative conditioning regimens used before HSCT generally require inpatient stays and are more intensive than other preparative regimens, and may therefore be more costly.To estimate the costs associated with inpatient HSCT according to the type of the conditioning regimen used and other potential contributors to the overall cost of the procedure.We used data from the Truven Health MarketScan insurance claims database to analyze healthcare costs for pediatric (age <18 years) and adult (age ≥18 years) patients who had autologous or allogeneic inpatient HSCT between January 1, 2010, and September 23, 2013. We developed an algorithm to determine whether conditioning regimens were myeloablative or nonmyeloablative/reduced intensity.We identified a sample of 1562 patients who had inpatient HSCT during the study period for whom the transplant type and the conditioning regimen were determinable: 398 patients had myeloablative allogeneic HSCT; 195 patients had nonmyeloablative/reduced-intensity allogeneic HSCT; and 969 patients had myeloablative autologous HSCT. The median total healthcare cost at 100 days was $289,283 for the myeloablative allogeneic regimen cohort compared with $253,467 for the nonmyeloablative/reduced-intensity allogeneic regimen cohort, and $140,792 for the myeloablative autologous regimen cohort. The mean hospital length of stay for the index (first claim of) HSCT was 35.6 days in the myeloablative allogeneic regimen cohort, 26.6 days in the nonmyeloablative/reduced-intensity allogeneic cohort, and 21.8 days in the myeloablative autologous regimen cohort.Allogeneic HSCT was more expensive than autologous HSCT, regardless of the regimen used. Myeloablative conditioning regimens led to higher overall costs than nonmyeloablative/reduced-intensity regimens in the allogeneic HSCT cohort, indicating a greater cost burden associated with inpatient services for higher-intensity preparative conditioning regimens. Pediatric patients had higher costs than adult patients. Future research should involve validating the algorithm for identifying conditioning regimens using clinical data.

  View details for PubMedID 29263771

• Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Veeraputhiran, M., Yang, L., Sundaram, V., Arai, S., Lowsky, R., Miklos, D., Meyer, E., Muffly, L., Negrin, R., Rezvani, A., Shizuru, J., Weng, W., Johnston, L. 2017; 23 (10): 1744–48

  Abstract

  The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.

  View details for PubMedID 28668491

• Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis BLOOD Kaufman, G. P., Schrier, S. L., Lafayette, R. A., Arai, S., Witteles, R. M., Liedtke, M. 2017; 130 (7): 900–902

  Abstract

  The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.

  View details for PubMedID 28615223

• An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease. Blood Martin, P. J., Storer, B. E., Inamoto, Y., Flowers, M. E., Carpenter, P. A., Pidala, J., Palmer, J., Arora, M., Jagasia, M., Arai, S., Cutler, C., Lee, S. J. 2017

  Abstract

  No gold standard has been established as a primary endpoint in trials of initial treatment for chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease and progressive disease were defined according to the 2014 NIH Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-versus-host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in less than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689.

  View details for DOI 10.1182/blood-2017-03-775767

  View details for PubMedID 28495794

• HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood advances Spinner, M. A., Fernández-Viña, M. n., Creary, L. E., Quinn, O. n., Elder, L. n., Arai, S. n., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Shizuru, J. A., Weng, W. K., Laport, G. G., Strober, S. n., Lowsky, R. n., Rezvani, A. R. 2017; 1 (17): 1347–57

  Abstract

  Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.

  View details for PubMedID 29296777

• Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors BLOOD Holtan, S. G., Khera, N., Levine, J. E., Chai, X., Storer, B., Liu, H. D., Inamoto, Y., Chen, G. L., Mayer, S., Arora, M., Palmer, J., Flowers, M. E., Cutler, C. S., Lukez, A., Arai, S., Lazaryan, A., Newell, L. F., Krupski, C., Jagasia, M. H., Pusic, I., Wood, W., Renteria, A. S., Yanik, G., Hogan, W. J., Hexner, E., Ayuk, F., Holler, E., Watanaboonyongcharoen, P., Efebera, Y. A., Ferrara, J. L., Panoskaltsis-Mortari, A., Weisdorf, D., Lee, S. J., Pidala, J. 2016; 128 (19): 2350-2358

  Abstract

  Late acute (LA) graft vs. host disease (GVHD) is persistent, recurrent, or new onset acute GVHD symptoms occurring after 100 days post-allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, mortality, and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n=909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, IQR 128-204) days after HCT. While 51/83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure free survival was only 7.1 months (95% confidence interval 3.4-19.1 months), and estimated overall survival (OS) at two years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n-55) and controls (n=50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG, an epidermal growth factor [EGF] receptor ligand) was elevated, and the AREG/EGF ratio ≥ median was associated with inferior OS and increased NRM in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD, and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.

  View details for DOI 10.1182/blood-2015-09-669846

  View details for PubMedID 27625357

• Clinicopathologic Threshold of Acute Colorectal Graft-versus-Host Disease ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Gomez, A. J., Arai, S., Higgins, J. P., Kambham, N. 2016; 140 (6): 570-577

  Abstract

  -Colon biopsies are often used to determine the presence and severity of acute gastrointestinal graft-versus-host disease following bone marrow transplant.-To establish a threshold consensus within our institution on the number of crypt apoptotic bodies (CAB) indicative of grade 1 acute colorectal graft-versus-host disease, we retrospectively reviewed colon biopsies from posttransplant patients and incorporated clinical and endoscopic findings to validate recently proposed minimum criteria for grade 1 graft-versus-host disease as 7 or more CAB per 10 contiguous crypts.-Eighty-one biopsies performed for suspected graft-versus-host disease from 74 individual patients were initially stratified based on their prior (prestudy) diagnoses: no significant abnormality, grade 1 graft-versus-host disease, and descriptive diagnoses mentioning increased apoptosis. A chart review was performed to assess the clinical and endoscopic impression at the time of biopsy and to determine the subsequent management and outcome.-Twenty-six biopsies with an average of 3 CAB were considered true-negative cases, and 32 biopsies with an average of 9.75 CAB were considered true-positive cases (t = 3.95999, P < .001). True-negative cases had an average density of 1.36 CAB per crypt, and true-positive cases had an average density of 2.97 CAB per crypt (t = 3.950178, P < .001).-A threshold of 7 or more CAB per 10 contiguous crypts promotes appropriate treatment of grade 1 acute graft-versus-host disease after other diagnostic entities are excluded. Although this threshold is 100% specific to grade 1 acute colorectal graft-versus-host disease after other histologic mimics are excluded, this threshold has a low sensitivity (59.4%) as patients with less than 7 CAB per 10 contiguous crypts constitute a heterogeneous group.

  View details for DOI 10.5858/arpa.2015-0187-OA

  View details for Web of Science ID 000377101500013

  View details for PubMedID 27232349

• Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia Khodadoust, M. S., Luo, B., Medeiros, B. C., Johnson, R. C., Ewalt, M. D., Schalkwyk, A. S., Bangs, C. D., Cherry, A. M., Arai, S., Arber, D. A., Zehnder, J. L., Gotlib, J. 2016; 30 (4): 947-950

  View details for DOI 10.1038/leu.2015.136

  View details for PubMedID 26055304

• Oral chronic GVHD outcomes and resource utilization: a subanalysis from the chronic GVHD consortium. Oral diseases Yuan, A., Chai, X., Martins, F., Arai, S., Arora, M., Correa, M. E., Pidala, J., Cutler, C. S., Lee, S. J., Treister, N. S. 2016; 22 (3): 235-240

  Abstract

  This study evaluated the extent to which oral chronic graft-versus-host disease (cGVHD) consensus assessments are predictive of management across institutions with and without oral medicine (OM) centers, and whether ancillary care guidelines are followed within clinical practice.Longitudinal oral cGVHD data were abstracted from the cGVHD Consortium, and additional mouth-specific management data were analyzed across five transplant centers.Seventy-nine patients with 656 visits were observed for a median of 7.1 months with one visit per follow-up month. Ancillary therapies for oral cGVHD were prescribed for 67% of patients for a median of 0.46 months (per follow-up month) at OM centers and 0.78 months at non-OM centers. Patients treated with ancillary therapy were more likely to have an National Institutes of Health (NIH) mouth score of ≥1 (P < 0.001, odds ratio: 5.1) and mouth pain (P = 0.01, odds ratio: 2.6). The odds ratios of receiving ancillary therapy from OM experts were higher than transplant physicians (53%; P = 0.03).Oral cGVHD consensus assessments corresponding with ancillary therapy use were mouth pain and NIH mouth score, with higher odds ratios of receiving therapy from OM experts. Ancillary care guidelines for oral cGVHD are reflected in academic clinical practice with respect to utilization of recommended prescriptions.

  View details for DOI 10.1111/odi.12429

  View details for PubMedID 26708609

• Long-awaited news for hepatic veno-occlusive disease. Blood Arai, S. 2016; 127 (13): 1630-1631

  View details for DOI 10.1182/blood-2016-02-694943

  View details for PubMedID 27034420

• Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood Richardson, P. G., Riches, M. L., Kernan, N. A., Brochstein, J. A., Mineishi, S., Termuhlen, A. M., Arai, S., Grupp, S. A., Guinan, E. C., Martin, P. L., Steinbach, G., Krishnan, A., Nemecek, E. R., Giralt, S., Rodriguez, T., Duerst, R., Doyle, J., Antin, J. H., Smith, A., Lehmann, L., Champlin, R., Gillio, A., Bajwa, R., D'Agostino, R. B., Massaro, J., Warren, D., Miloslavsky, M., Hume, R. L., Iacobelli, M., Nejadnik, B., Hannah, A. L., Soiffer, R. J. 2016; 127 (13): 1656-1665

  Abstract

  Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered atwww.clinicaltrials.govas #NCT00358501.

  View details for DOI 10.1182/blood-2015-10-676924

  View details for PubMedID 26825712

• Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation Arora, M., Cutler, C. S., Jagasia, M. H., Pidala, J., Chai, X., Martin, P. J., Flowers, M. E., Inamoto, Y., Chen, G. L., Wood, W. A., Khera, N., Palmer, J., Duong, H., Arai, S., Mayer, S., Pusic, I., Lee, S. J. 2016; 22 (3): 449-455

  Abstract

  Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.

  View details for DOI 10.1016/j.bbmt.2015.10.018

  View details for PubMedID 26541363

• A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation. Clinical cancer research Arai, S., Pidala, J., Pusic, I., Chai, X., Jaglowski, S., Khera, N., Palmer, J., Chen, G. L., Jagasia, M. H., Mayer, S. A., Wood, W. A., Green, M., Hyun, T. S., Inamoto, Y., Storer, B. E., Miklos, D. B., Shulman, H. M., Martin, P. J., Sarantopoulos, S., Lee, S. J., Flowers, M. E. 2016; 22 (2): 319-327

  Abstract

  Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.

  View details for DOI 10.1158/1078-0432.CCR-15-1443

  View details for PubMedID 26378033

• Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning BONE MARROW TRANSPLANTATION Rezvani, A. R., Kanate, A. S., Efron, B., Chhabra, S., Kohrt, H. E., Shizuru, J. A., Laport, G. G., Miklos, D. B., Benjamin, J. E., JOHNSTON, L. J., Arai, S., Weng, W., Negrin, R. S., Strober, S., Lowsky, R. 2015; 50 (10): 1286-1292

  Abstract

  We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n=19), T-cell NHL (n=6), mantle cell lymphoma (n=4) or other B-cell subtypes (n=3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute GvHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).

  View details for DOI 10.1038/bmt.2015.149

  View details for PubMedID 26146806

• Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study LANCET HAEMATOLOGY Anderlini, P., Wu, J., Gersten, I., Ewell, M., Tolar, J., Antin, J. H., Adams, R., Arai, S., Eames, G., Horwitz, M. E., McCarty, J., Nakamura, R., Pulsipher, M. A., Rowley, S., Leifer, E., Carter, S. L., DiFronzo, N. L., Horowitz, M. M., Confer, D., Deeg, H. J., Eapen, M. 2015; 2 (9): E367-E375

  Abstract

  The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts.In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417.96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively.Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies.US National Heart, Lung, and Blood Institute and National Cancer Institute.

  View details for Web of Science ID 000362075100007

  View details for PubMedCentralID PMC4861234

• Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease HAEMATOLOGICA Palmer, J., Chai, X., Martin, P. J., Weisdorf, D., Inamoto, Y., Pidala, J., Jagasia, M., Pavletic, S., Cutler, C., Vogelsang, G., Arai, S., Flowers, M. E., Lee, S. J. 2015; 100 (5): 690-695

  Abstract

  Failure-free survival, defined as the absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but its use has only been reported for single-center studies. We measured failure-free survival in a prospective observational cohort of patients (n=575) with both newly diagnosed and existing chronic graft-versus-host disease from nine centers. Failure was observed in 389 (68%) patients during the observation period. The median follow up of all patients was 30.9 months, and the median failure-free survival was 9.8 months (63% at 6 months, 45% at 1 year, and 29% at 2 years). Of the variables measured at enrollment, ten were associated with shorter failure-free survival: higher National Institutes of Health 0-3 skin score, higher National Institutes of Health 0-3 gastrointestinal score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor for male recipient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (hazard ratio=2.06, 95% confidence interval: 1.29-3.32; P<0.003) and decreased survival (hazard ratio=1.51, 95% confidence interval: 1.04-2.18; P<0.03). These results show that fewer than half of patients on systemic treatment will be failure-free survivors at 1 year, and fewer than a third will reach 2 years without experiencing failure. Better treatments are needed for chronic graft-versus-host disease. Clinicaltrials.gov identifier: NCT00637689.

  View details for DOI 10.3324/haematol.2014.117283

  View details for PubMedID 25715403

• Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

  Abstract

  We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

  View details for DOI 10.1111/ajt.13025

  View details for PubMedID 25648766

• National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biology of blood and marrow transplantation Jagasia, M. H., Greinix, H. T., Arora, M., Williams, K. M., Wolff, D., Cowen, E. W., Palmer, J., Weisdorf, D., Treister, N. S., Cheng, G., Kerr, H., Stratton, P., Duarte, R. F., McDonald, G. B., Inamoto, Y., Vigorito, A., Arai, S., Datiles, M. B., Jacobsohn, D., Heller, T., Kitko, C. L., Mitchell, S. A., Martin, P. J., Shulman, H., Wu, R. S., Cutler, C. S., Vogelsang, G. B., Lee, S. J., Pavletic, S. Z., Flowers, M. E. 2015; 21 (3): 389-401 e1

  Abstract

  The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

  View details for DOI 10.1016/j.bbmt.2014.12.001

  View details for PubMedID 25529383

  View details for PubMedCentralID PMC4329079

• National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biology of blood and marrow transplantation Jagasia, M. H., Greinix, H. T., Arora, M., Williams, K. M., Wolff, D., Cowen, E. W., Palmer, J., Weisdorf, D., Treister, N. S., Cheng, G., Kerr, H., Stratton, P., Duarte, R. F., McDonald, G. B., Inamoto, Y., Vigorito, A., Arai, S., Datiles, M. B., Jacobsohn, D., Heller, T., Kitko, C. L., Mitchell, S. A., Martin, P. J., Shulman, H., Wu, R. S., Cutler, C. S., Vogelsang, G. B., Lee, S. J., Pavletic, S. Z., Flowers, M. E. 2015; 21 (3): 389-401 e1

  Abstract

  The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

  View details for DOI 10.1016/j.bbmt.2014.12.001

  View details for PubMedID 25529383

• Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research. Biology of blood and marrow transplantation Arai, S., Arora, M., Wang, T., Spellman, S. R., He, W., Couriel, D. R., Urbano-Ispizua, A., Cutler, C. S., Bacigalupo, A. A., Battiwalla, M., Flowers, M. E., Juckett, M. B., Lee, S. J., Loren, A. W., Klumpp, T. R., Prockup, S. E., Ringdén, O. T., Savani, B. N., Socié, G., Schultz, K. R., Spitzer, T., Teshima, T., Bredeson, C. N., Jacobsohn, D. A., Hayashi, R. J., Drobyski, W. R., Frangoul, H. A., Akpek, G., Ho, V. T., Lewis, V. A., Gale, R. P., Koreth, J., Chao, N. J., AlJurf, M. D., Cooper, B. W., Laughlin, M. J., Hsu, J. W., Hematti, P., Verdonck, L. F., Solh, M. M., Norkin, M., Reddy, V., Martino, R., Gadalla, S., Goldberg, J. D., McCarthy, P. L., Pérez-Simón, J. A., Khera, N., Lewis, I. D., Atsuta, Y., Olsson, R. F., Saber, W., Waller, E. K., Blaise, D., Pidala, J. A., Martin, P. J., Satwani, P., Bornhäuser, M., Inamoto, Y., Weisdorf, D. J., Horowitz, M. M., Pavletic, S. Z. 2015; 21 (2): 266-274

  Abstract

  Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

  View details for DOI 10.1016/j.bbmt.2014.10.021

  View details for PubMedID 25445023

• Allogeneic hematopoietic cell transplant for normal karyotype AML: indirect evidence of selection for adverse molecular profile. Bone marrow transplantation Percival, M. M., Medeiros, B. C., Tian, L. n., Robeson, S. n., Laport, G. G., Johnston, L. J., Shizuru, J. A., Miklos, D. B., Arai, S. n., Weng, W. K., Negrin, R. S., Lowsky, R. n. 2015

  View details for PubMedID 25893457

• Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease HAEMATOLOGICA Inamoto, Y., Martin, P. J., Storer, B. E., Palmer, J., Weisdorf, D. J., Pidala, J., Flowers, M. E., Arora, M., Jagasia, M., Arai, S., Chai, X., Pavletic, S. Z., Vogelsang, G. B., Lee, S. J. 2014; 99 (10): 1618-1623

  Abstract

  The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of involvement of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of non-relapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to a moderate or mild global score, a severe global score was associated with increased risks of non-relapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts patients' mortality risk throughout the course of their chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.

  View details for DOI 10.3324/haematol.2014.109611

  View details for Web of Science ID 000343038500026

  View details for PubMedCentralID PMC4181259

• Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease. Haematologica Inamoto, Y., Martin, P. J., Storer, B. E., Palmer, J., Weisdorf, D. J., Pidala, J., Flowers, M. E., Arora, M., Jagasia, M., Arai, S., Chai, X., Pavletic, S. Z., Vogelsang, G. B., Lee, S. J. 2014; 99 (10): 1618-1623

  Abstract

  The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of involvement of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of non-relapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to a moderate or mild global score, a severe global score was associated with increased risks of non-relapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts patients' mortality risk throughout the course of their chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.

  View details for DOI 10.3324/haematol.2014.109611

  View details for PubMedID 24997150

• Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biology of blood and marrow transplantation Benjamin, J., Chhabra, S., Kohrt, H. E., Lavori, P., Laport, G. G., Arai, S., Johnston, L., Miklos, D. B., Shizuru, J. A., Weng, W., Negrin, R. S., Lowsky, R. 2014; 20 (6): 837-843

  Abstract

  Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.

  View details for DOI 10.1016/j.bbmt.2014.02.023

  View details for PubMedID 24607552

• Assessment of Joint and Fascia Manifestations in Chronic Graft-Versus-Host Disease ARTHRITIS & RHEUMATOLOGY Inamoto, Y., Pidala, J., Chai, X., Kurland, B. F., Weisdorf, D., Flowers, M. E., Palmer, J., Arai, S., Jacobsohn, D., Cutler, C., Jagasia, M., Goldberg, J. D., Martin, P. J., Pavletic, S. Z., Vogelsang, G. B., Lee, S. J., Carpenter, P. A. 2014; 66 (4): 1044-1052

  Abstract

  To investigate the usefulness of various scales for evaluating joint and fascia manifestations in patients with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, and to compare the scales in terms of simplicity of use and ability to yield reliable and clinically meaningful results.In a prospective, multicenter, longitudinal, observational cohort of patients with chronic GVHD (n = 567), we evaluated 3 scales proposed for assessing joint status: the National Institutes of Health (NIH) joint/fascia scale, the Hopkins fascia scale, and the Photographic Range of Motion (P-ROM) scale. Ten other scales were also tested for assessment of symptoms, quality of life, and physical functions.Joint and fascia manifestations were present at study enrollment in 164 (29%) of the patients. Limited range of motion was most frequent at the wrists or fingers. Among the 3 joint assessment scales, changes in the NIH scale correlated with both clinician- and patient-perceived improvement of joint and fascia manifestations, with higher sensitivity than the Hopkins fascia scale. Changes in all 3 scales correlated with clinician- and patient-perceived worsening, but the P-ROM scale was the most sensitive in this regard. Onset of joint and fascia manifestations was not associated with subsequent mortality.Joint and fascia manifestations are common in patients with chronic GVHD and should be assessed carefully in these patients. Our results support the use of the NIH joint/fascia scale and P-ROM scale to assess joint and fascia manifestations. The NIH scale better captures improvement, while the P-ROM scale better captures worsening. The utility of these scales could also be tested in the rheumatic diseases.

  View details for DOI 10.1002/art.38293

  View details for Web of Science ID 000337361000031

  View details for PubMedCentralID PMC4014356

• Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease. Biology of blood and marrow transplantation Palmer, J., Williams, K., Inamoto, Y., Chai, X., Martin, P. J., Tomas, L. S., Cutler, C., Weisdorf, D., Kurland, B. F., Carpenter, P. A., Pidala, J., Pavletic, S. Z., Wood, W., Jacobsohn, D., Arai, S., Arora, M., Jagasia, M., Vogelsang, G. B., Lee, S. J. 2014; 20 (3): 337-344

  Abstract

  The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality.

  View details for DOI 10.1016/j.bbmt.2013.11.025

  View details for PubMedID 24315845

• Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

  View details for DOI 10.1016/j.hrthm.2013.10.026

  View details for PubMedID 24121001

• Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma. Science translational medicine Weng, W., Armstrong, R., Arai, S., Desmarais, C., Hoppe, R., Kim, Y. H. 2013; 5 (214): 214ra171-?

  Abstract

  Mycosis fungoides (MF) and the leukemic presentation Sézary syndrome (SS) are clonal T cell lymphomas arising from the skin and are considered noncurable with standard therapies. To develop a specific and sensitive monitoring tool, we tested the ability of high-throughput sequencing (HTS) of T cell receptors (TCRB) to monitor minimal residual disease (MRD) after allogeneic hematopoietic cell transplantation. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) or skin samples. The rearranged TCRβ loci were amplified using Vβ- and Jβ-specific primers, followed by HTS, to generate up to 1,000,000 reads spanning the CDR3 region of individual cells. Malignant clones were identified in diagnostic samples in all cases by a dominant CDR3 sequence. Before transplant, four patients had circulating Sézary cells by the routine flow cytometry, which was confirmed by TCRB HTS. Although the flow cytometry found no detectable Sézary cells, malignant clones were detected by TCRB HTS in all other six cases. Five patients achieved "molecular remission" in blood between +30 and +540 days after transplant. Four of these patients also achieved molecular clearance in skin after transplant. Experiments using blood samples spiked with purified Sézary cells demonstrated that TCRB HTS can detect Sézary cells at the level of 1 in 50,000 PBMCs, which is more sensitive than standard diagnostics. We have thus demonstrated the utility of TCRB HTS to assess MRD with increased sensitivity and specificity compared to other current methodologies, and to monitor response to therapy in this MF/SS patient population.

  View details for DOI 10.1126/scitranslmed.3007420

  View details for PubMedID 24307695

• Minimal Residual Disease Monitoring with High-Throughput Sequencing of T Cell Receptors in Cutaneous T Cell Lymphoma SCIENCE TRANSLATIONAL MEDICINE Weng, W., Armstrong, R., Arai, S., Desmarais, C., Hoppe, R., Kim, Y. H. 2013; 5 (214)

  Abstract

  Mycosis fungoides (MF) and the leukemic presentation Sézary syndrome (SS) are clonal T cell lymphomas arising from the skin and are considered noncurable with standard therapies. To develop a specific and sensitive monitoring tool, we tested the ability of high-throughput sequencing (HTS) of T cell receptors (TCRB) to monitor minimal residual disease (MRD) after allogeneic hematopoietic cell transplantation. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) or skin samples. The rearranged TCRβ loci were amplified using Vβ- and Jβ-specific primers, followed by HTS, to generate up to 1,000,000 reads spanning the CDR3 region of individual cells. Malignant clones were identified in diagnostic samples in all cases by a dominant CDR3 sequence. Before transplant, four patients had circulating Sézary cells by the routine flow cytometry, which was confirmed by TCRB HTS. Although the flow cytometry found no detectable Sézary cells, malignant clones were detected by TCRB HTS in all other six cases. Five patients achieved "molecular remission" in blood between +30 and +540 days after transplant. Four of these patients also achieved molecular clearance in skin after transplant. Experiments using blood samples spiked with purified Sézary cells demonstrated that TCRB HTS can detect Sézary cells at the level of 1 in 50,000 PBMCs, which is more sensitive than standard diagnostics. We have thus demonstrated the utility of TCRB HTS to assess MRD with increased sensitivity and specificity compared to other current methodologies, and to monitor response to therapy in this MF/SS patient population.

  View details for Web of Science ID 000328057800011

  View details for PubMedID 24307695

• Comorbidity burden in patients with chronic GVHD BONE MARROW TRANSPLANTATION Wood, W. A., Chai, X., Weisdorf, D., Martin, P. J., Cutler, C., INAMOTO, Y., WOLFF, D., Pavletic, S. Z., Pidala, J., Palmer, J. M., Arora, M., Arai, S., Jagasia, M., Storer, B., Lee, S. J., Mitchell, S. 2013; 48 (11): 1429-1436

  Abstract

  Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n=239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non-relapse mortality (HR: 1.21:1.04-1.42, P=0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was ≤ 100,000/μL (HR: 2.01:1.20-3.35, P=0.01), but not when it was >100,000/μL (HR: 1.05:0.90-1.22, P=0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed.

  View details for DOI 10.1038/bmt.2013.70

  View details for Web of Science ID 000326887900010

  View details for PubMedID 23665819

  View details for PubMedCentralID PMC3937964

• Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

  Abstract

  Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

  View details for DOI 10.3324/haematol.2013.084574

  View details for PubMedID 23716538

• Measurement of oral chronic GVHD: results from the Chronic GVHD Consortium BONE MARROW TRANSPLANTATION Treister, N., Chai, X., Kurland, B., Pavletic, S., Weisdorf, D., Pidala, J., Palmer, J., Martin, P., INAMOTO, Y., Arora, M., Flowers, M., Jacobsohn, D., Jagasia, M., Arai, S., Lee, S. J., Cutler, C. 2013; 48 (8): 1123-1128

  Abstract

  Oral chronic GVHD (cGVHD) is a serious complication of alloSCT. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the National Institutes of Health (NIH) criteria, and patients completed symptom and quality-of-life measures at each visit. Both rated change on an eight-point scale. Of the 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4-5% for both the groups (weighted kappa=0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation.

  View details for DOI 10.1038/bmt.2012.285

  View details for Web of Science ID 000322819900018

  View details for PubMedID 23353804

• The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

  Abstract

  The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

  View details for DOI 10.1111/bjh.12269

  View details for PubMedID 23432783

• H-Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sahaf, B., Yang, Y., Arai, S., Herzenberg, L. A., Herzenberg, L. A., Miklos, D. B. 2013; 110 (8): 3005-3010

  Abstract

  B cells are known to play an important role in pathogenesis of human chronic graft vs. host disease (cGVHD). Our group has previously shown that IgG allo-antibodies recognize Y chromosome-encoded proteins (H-Y) and a dominant H-Y epitope, DEAD box protein (DBY-2) detectable 6-12 mo after transplant in male patients who receive grafts from female donors (F→M) hematopoietic cell transplantation (HCT). Here we present FACS studies of peripheral blood mononuclear cells collected 6 mo after transplant showing that 16 of 28 (57%) F→M HCT patients have circulating donor B cells that express B-cell receptor (mainly IgM and Igλ) specific for DBY-2. The detection of these DBY-2 B cells 6 mo after HCT are associated with cGVHD development (P = 0.004). Specifically, 15 of 16 F→M with DBY-2 B cells developed cGVHD. In contrast, cGVHD developed in only 5 of the 12 who did not have DBY-2 B cells detected. This demonstrates circulating human B cells binding an alloantigen (DBY-2) and that these DBY-2-specific B cells appear before development of cGVHD in roughly half of the F→M patients. Our study suggests that detection of anti-DBY-2 B cells may predict cGVHD and that this prediction may have clinical utility. Validation of this hypothesis will require larger prospective studies.

  View details for DOI 10.1073/pnas.1222900110

  View details for Web of Science ID 000315954400081

  View details for PubMedID 23382226

  View details for PubMedCentralID PMC3581974

• Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leukemia & lymphoma Arai, S. n., Fanale, M. n., DeVos, S. n., Engert, A. n., Illidge, T. n., Borchmann, P. n., Younes, A. n., Morschhauser, F. n., McMillan, A. n., Horning, S. J. 2013; 54 (11): 2531–33

  View details for PubMedID 23617324

• Successful Surgical and Medical Treatment of Rhizopus Osteomyelitis Following Hematopoietic Cell Transplantation ORTHOPEDICS Vashi, N., Avedian, R., Brown, J., Arai, S. 2012; 35 (10): E1556-E1561

  Abstract

  Mucormycosis has been reported in otherwise healthy individuals; however, it is primarily seen in immunocompromised patients, such as those with diabetes mellitus, malignancy, or chronic graft-versus-host disease, and has a high mortality rate. Because most cases of mucormycosis are associated with contiguous rhinocerebral infection, only 5 cases of isolated musculoskeletal Rhizopus infection have been reported in the literature. One patient underwent hematopoietic cell transplant, which resulted in a fatal outcome.This article describes the successful treatment of isolated Rhizopus osteomyelitis in a patient who underwent hematopoietic cell transplant using a combined surgical and medical approach. A 33-year-old woman with pre-B cell acute lymphoblastic leukemia underwent hematopoietic cell transplant with few complications but developed chronic graft-versus-host disease 8 months posttransplant. She was treated with high-dose steroids for 6 weeks before she was admitted for severe right tibial pain in the absence of trauma. Early detection, aggressive therapies, and a multidisciplinary surgical and medical team allowed for the microbiologically confirmed resolution of the infection. Treatment included multiagent antimicrobial therapy with amphotericin B, daptomycin, and ertapenem. Several surgical irrigation and debridement procedures were also performed, with the eventual placement of amphotericin-impregnated polymethylmethacrylate cement beads and small fragment titanium screws. The patient continued taking postoperative antifungal treatment for 7 months after discharge. Six months following the discontinuation of antifungal therapy, the team's multidisciplinary approach achieved a continued resolution of the patient's infection and a return to a fully ambulatory and radiographically proven recovery without limb loss.

  View details for DOI 10.3928/01477447-20120919-30

  View details for Web of Science ID 000309814600019

  View details for PubMedID 23027498

• Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium BLOOD Jacobsohn, D. A., Kurland, B. F., Pidala, J., Inamoto, Y., Chai, X., Palmer, J. M., Arai, S., Arora, M., Jagasia, M., Cutler, C., Weisdorf, D., Martin, P. J., Pavletic, S. Z., Vogelsang, G., Lee, S. J., Flowers, M. E. 2012; 120 (13): 2545-2552

  Abstract

  There are no validated criteria to measure skin response in chronic GVHD. In a prospectively assembled, multicenter cohort of patients with chronic GVHD (N = 458), we looked for correlation of change in several different scales recommended by the National Institutes of Health (NIH) Consensus with clinician and patient perception of change and overall survival. Of the clinician scales, the NIH composite 0-3 skin score was the only one that correlated with both clinician and patient perception of improvement or worsening. Of the patient-reported scales, the skin subscale of the Lee Symptom Scale was the only one that correlated with both clinician and patient perception of improvement or worsening. At study entry, NIH skin score 3 and Lee skin symptom score > 15 were both associated with worse overall survival. Worsening of NIH skin score at 6 months was associated with worse overall survival. Improvement in the Lee skin symptom score at 6 months was associated with improved overall survival. Our findings support the use of the NIH composite 0-3 skin score and the Lee skin symptom score as simple and sensitive measures to evaluate skin involvement in clinical trials as well as in the clinical monitoring of patients with cutaneous chronic GVHD.

  View details for DOI 10.1182/blood-2012-04-424135

  View details for Web of Science ID 000311615800008

  View details for PubMedID 22773386

  View details for PubMedCentralID PMC3460679

• Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Tolar, J., Deeg, H. J., Arai, S., Horwitz, M., Antin, J. H., McCarty, J. M., Adams, R. H., Ewell, M., Leifer, E. S., Gersten, I. D., Carter, S. L., Horowitz, M. M., Nakamura, R., Pulsipher, M. A., DiFronzo, N. L., Confer, D. L., Eapen, M., Anderlini, P. 2012; 18 (7): 1007-1011

  Abstract

  Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m(2)), and antithymocyte globulin was associated with excessive organ toxicity.

  View details for DOI 10.1016/j.bbmt.2012.04.014

  View details for Web of Science ID 000305667900005

  View details for PubMedID 22546497

  View details for PubMedCentralID PMC3677744

• Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence BLOOD Arai, S., Sahaf, B., Narasimhan, B., Chen, G. L., Jones, C. D., Lowsky, R., Shizuru, J. A., Johnston, L. J., Laport, G. G., Weng, W., Benjamin, J. E., Schaenman, J., Brown, J., Ramirez, J., Zehnder, J. L., Negrin, R. S., Miklos, D. B. 2012; 119 (25): 6145-6154

  Abstract

  B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.

  View details for DOI 10.1182/blood-2011-12-395970

  View details for PubMedID 22563089

• More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

  View details for PubMedID 22652951

• Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation BONE MARROW TRANSPLANTATION Johnston, L., Florek, M., Armstrong, R., McCune, J. S., Arai, S., Brown, J., Laport, G., Lowsky, R., Miklos, D., Shizuru, J., Sheehan, K., Lavori, P., Negrin, R. 2012; 47 (4): 581-588

  Abstract

  We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

  View details for DOI 10.1038/bmt.2011.104

  View details for Web of Science ID 000302576700018

  View details for PubMedID 21552302

  View details for PubMedCentralID PMC3163055

• Tandem chemo-mobilization followed by high-dose melphalan and carmustine with single autologous hematopoietic cell transplantation for multiple myeloma BONE MARROW TRANSPLANTATION Chen, A. I., Negrin, R. S., McMillan, A., Shizuru, J. A., JOHNSTON, L. J., Lowsky, R., Miklos, D. B., Arai, S., Weng, W., Laport, G. G., Stockerl-Goldstein, K. 2012; 47 (4): 516-521

  Abstract

  Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemo-mobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m(2) plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR)+CR pre-mobilization to 76% VGPR+CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P=0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P=0.80). The 100-day non-relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates.

  View details for DOI 10.1038/bmt.2011.106

  View details for PubMedID 21602899

• Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a Chronic Graft-versus-Host Disease Consortium study HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Pidala, J., Vogelsang, G., Martin, P., Chai, X., Storer, B., Pavletic, S., Weisdorf, D. J., Jagasia, M., Cutler, C., Palmer, J., Jacobsohn, D., Arai, S., Lee, S. J. 2012; 97 (3): 451-458

  Abstract

  The National Institutes of Health Consensus Conference proposed the term "overlap" graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present.We examined whether the overlap subtype of graft-versus-host disease was associated with a different prognosis, functional limitations, or patient-reported outcomes compared to "classic" chronic graft-versus-host disease without any acute features.Prospective data were collected from 427 patients from nine centers. Patients were classified as having overlap (n=352) or classic chronic (n=75) graft-versus-host disease based on reported organ involvement. Overlap cases had a significantly shorter median time from transplantation to cohort enrollment (P=0.01), were more likely to be incident cases (P<0.001), and had a lower platelet count at onset of the graft-versus-host disease (P<0.001). Patients with overlap graft-versus-host disease had significantly greater functional impairment measured by a 2-minute walk test, higher symptom burden and lower Human Activity Profile scores. Quality of life was similar, except patients with overlap graft-versus-host disease had worse social functioning, assessed by the Short Form-36. Multivariable analysis utilizing time-varying covariates demonstrated that the overlap subtype of graft-versus-host disease was associated with worse overall survival (HR 2.1, 95% CI 1.1-4.7; P=0.03) and higher non-relapse mortality (HR 2.8, 95% CI 1.2-8.3; P=0.02) than classic chronic graft-versus-host disease.These findings suggest that the presence of acute features in patients with chronic graft-versus-host disease is a marker of adverse prognosis, greater functional impairment, and higher symptom burden.

  View details for DOI 10.3324/haematol.2011.055186

  View details for Web of Science ID 000301975700024

  View details for PubMedID 22058206

  View details for PubMedCentralID PMC3291602

• Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

  Abstract

  Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

  View details for DOI 10.1016/j.healun.2011.09.010

  View details for PubMedID 22051505

• Adoptive Immunotherapy with Cytokine-Induced Killer Cells for Patients with Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Laport, G. G., Sheehan, K., Baker, J., Armstrong, R., Wong, R. M., Lowsky, R., Johnston, L. J., Shizuru, J. A., Miklos, D., Arai, S., Benjamin, J. E., Weng, W., Negrin, R. S. 2011; 17 (11): 1679-1687

  Abstract

  Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.

  View details for DOI 10.1016/j.bbmt.2011.05.012

  View details for PubMedID 21664472

• A phase 1 study of imatinib for corticosteroid-dependent/refractory chronic graft-versus-host disease: response does not correlate with anti-PDGFRA antibodies BLOOD Chen, G. L., Arai, S., Flowers, M. E., Otani, J. M., Qiu, J., Cheng, E. C., McMillan, A., Johnston, L. J., Shizuru, J. A., Miklos, D. B. 2011; 118 (15): 4070-4078

  Abstract

  Stimulatory antiplatelet derived growth factor receptor α (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid-dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti-PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981.

  View details for DOI 10.1182/blood-2011-03-341693

  View details for Web of Science ID 000296282200013

  View details for PubMedID 21828142

• Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria BLOOD Arai, S., Jagasia, M., Storer, B., Chai, X., Pidala, J., Cutler, C., Arora, M., Weisdorf, D. J., Flowers, M. E., Martin, P. J., Palmer, J., Jacobsohn, D., Pavletic, S. Z., Vogelsang, G. B., Lee, S. J. 2011; 118 (15): 4242-4249

  Abstract

  In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.

  View details for DOI 10.1182/blood-2011-03-344390

  View details for PubMedID 21791424

• Rationale and Design of the Chronic GVHD Cohort Study: Improving Outcomes Assessment in Chronic GVHD BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Lee, S. J., Flowers, M. E., Martin, P. J., Carpenter, P., Hansen, J., Chai, X., Kurland, B., Storer, B., Arai, S., Johnston, L., Miklos, D., Weisdorf, D., Arora, M., Majhail, N., Cutler, C., Jagasia, M., Palmer, J., Pidala, J., Westervelt, P., Pusic, I., Giralt, S., Goldberg, J., Couriel, D., Kitko, C., Pavletic, S. Z., Vogelsang, G. B., Gilman, A., Schultz, K. 2011; 17 (8): 1114-1120

  Abstract

  In 2005, the National Institutes of Health sponsored a Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host (cGVHD) to achieve consensus about key elements of cGVHD research, including definitions for diagnosis, severity scoring, and response measures. To test these proposed definitions, a multicenter prospective cohort study of people with cGVHD is ongoing. This study will evaluate the performance of proposed prognostic factors, measures of disease activity, and surrogate endpoints for therapeutic response. Data are collected at 6-month intervals in a heterogeneous population of patients reflecting modern transplant techniques and posttransplantation clinical management (target enrollment 672 with cGVHD from 10 transplantation centers). This report describes the rationale, design, and methods of the cGVHD cohort study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.

  View details for DOI 10.1016/j.bbmt.2011.05.007

  View details for Web of Science ID 000293429600003

  View details for PubMedID 21664473

• Short tandem repeat and human leukocyte antigen mutations or losses confound engraftment and typing analysis in hematopoietic stem cell transplants HUMAN IMMUNOLOGY Pereira, S., Vayntrub, T., Hiraki, D. D., Cherry, A. M., Arai, S., Dvorak, C. C., Grumet, F. C. 2011; 72 (6): 503-509

  Abstract

  Clonal chromosomal abnormalities are often found in the tumor cells of patients with malignancies. These abnormalities can cause downregulation of human leukocyte antigen (HLA) and instability of short tandem repeat (STR) DNA sequences, confounding HLA typing and/or engraftment analysis in hematopoietic stem cell transplants (HSCT). We describe here the abnormalities observed during testing of 600 HSCT patients. HLA molecular typing was performed by reference strand conformational analyses and/or sequence-based typing. STR testing was performed with 10 to 16 STR primer sets, following 1 to 4 informative loci in each patient. Eight patients exhibited either loss of heterozygosity (4 STR, 3 HLA) or STR length mutation (n = 1), and 5 of the 8 exhibited correlative cytogenetic abnormalities. Diagnoses were acute myelogenous leukemia (AML; n = 7) or myelofibrosis (MFIB: n = 1), yielding an 11% incidence of these chromosomal abnormalities among the subset of 72 AML/MFIB HSCT patients. These results highlight some of the problems encountered and the possibility for interpretive errors that can arise when analyzing molecular typing and engraftment data, particularly among AML/MFIB patients.

  View details for DOI 10.1016/j.humimm.2011.03.003

  View details for Web of Science ID 000291138900007

  View details for PubMedID 21463659

• Early CMV Viremia Is Associated with Impaired Viral Control following Nonmyeloablative Hematopoietic Cell Transplantation with a Total Lymphoid Irradiation and Antithymocyte Globulin Preparative Regimen BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Schaenman, J. M., Shashidhar, S., Rhee, C., Wong, J., Navato, S., Wong, R. M., Ho, D. Y., Arai, S., Johnston, L., Brown, J. M. 2011; 17 (5): 693-702

  Abstract

  The reconstitution of immune function after hematopoietic cell transplant (HCT) plays an important role in the control of viral infections. Both donor and recipient cytomegalovirus (CMV) serostatus has been shown to contribute to effective immune function; however, the influence of a nonmyeloablative preparative (NMA) regimen using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) on antiviral immune reconstitution has not yet been described. In 117 recipients of NMA HCT patients following ATG and TLI, not unexpectedly, CMV viremia was seen in approximately 60% of the seropositive patients regardless of donor serostatus, and recipient seropositivity significantly increased the odds of CMV viremia after transplant in a multivariate analysis. The administration of ATG and TLI resulted in a strikingly earlier viremia in the posttransplant period when compared to the previously reported timing of viremia following myeloablative preparative regimens, especially for transplant recipients who were seropositive for CMV with seronegative donors. Furthermore, early viremia in the setting of a CMV naïve donor was associated with a delay in functional antiviral control. These observations demonstrate the dynamic nature of immunity in relation to CMV antigen exposure in the complex environment resulting from NMA conditions where both donor and residual recipient immune response affect viral control.

  View details for DOI 10.1016/j.bbmt.2010.08.010

  View details for Web of Science ID 000290061500012

  View details for PubMedID 20736077

• Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium BLOOD Pidala, J., Kurland, B., Chai, X., Majhail, N., Weisdorf, D. J., Pavletic, S., Cutler, C., Jacobsohn, D., Palmer, J., Arai, S., Jagasia, M., Lee, S. J. 2011; 117 (17): 4651-4657

  Abstract

  Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.

  View details for DOI 10.1182/blood-2010-11-319509

  View details for Web of Science ID 000289984800031

  View details for PubMedID 21355084

  View details for PubMedCentralID PMC3099579

• Long-term outcomes in patients with high-risk myeloid malignancies following matched related donor hematopoietic cell transplantation with myeloablative conditioning of BU, etoposide and CY BONE MARROW TRANSPLANTATION Naik, S., Wong, R., Arai, S., Brown, J., Laport, G., Lowsky, R., Miklos, D., Shizuru, J., Blume, K., Negrin, R., Johnston, L. 2011; 46 (2): 192-199

  Abstract

  Patients with high-risk or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single-institution, long-term follow-up of 96 patients, median age 50 (range, 20-60) years, who received HLA-matched related HCT between 1992 and 2007. All patients were treated with a uniform preparatory regimen intended to enhance the widely used regimen of BU and CY that included: BU 16.0 mg/kg (days -8 to -5), etoposide 60 mg/kg (day -4), CY 60 mg/kg (day -2) with GVHD prophylaxis of CsA or FK506 and prednisone. Disease status at transplantation was high-risk AML (n=41), CML in second chronic phase or blast crisis (n=8), myelofibrosis and myeloproliferative disorders (n=8), and myelodysplasia (n=39). Thirty-six percent (n=35) of patients received BM whereas 64% (n=61) received G-CSF-mobilized PBPC. With a median follow-up of 5.6 years (range, 1.6-14.6 years) actuarial 5-year OS was 32% (95% CI 22-42) and 5-year EFS was 31% (95% CI 21-41). Relapse rate was 24% (95% CI 15-33) at 2 and 5 years. Nonrelapse mortality was 29% (95% CI 20-38) at day 100 and 38% (95% CI 29-47) at 1 year. Cumulative incidence of acute (grade II-IV) and extensive chronic GVHD was 27% (95% CI 18-36) and 29% (95% CI 18-40), respectively. There was no statistically significant difference in OS (31 vs 32%, P=0.89) or relapse rates (17 vs 28%, P=0.22) for recipients of BM vs PBPC, respectively. These results confirm that patients with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning.

  View details for DOI 10.1038/bmt.2010.114

  View details for PubMedID 20498648

• Complete donor T-cell engraftment 30 days after allogeneic transplantation predicts molecular remission in high-risk chronic lymphocytic leukaemia BRITISH JOURNAL OF HAEMATOLOGY Jones, C. D., Arai, S., Lowsky, R., Tyan, D. B., Zehnder, J. L., Miklos, D. B. 2010; 150 (5): 637-639

  View details for DOI 10.1111/j.1365-2141.2010.08252.x

  View details for Web of Science ID 000281060700020

  View details for PubMedID 20528878

  View details for PubMedCentralID PMC2935248

• Phase I/II Trial of GN-BVC, a Gemcitabine and Vinorelbine-Containing Conditioning Regimen for Autologous Hematopoietic Cell Transplantation in Recurrent and Refractory Hodgkin Lymphoma BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Arai, S., Letsinger, R., Wong, R. M., Johnston, L. J., Laport, G. G., Lowsky, R., Miklos, D. B., Shizuru, J. A., Weng, W., Lavori, P. W., Blume, K. G., Negrin, R. S., Horning, S. J. 2010; 16 (8): 1145-1154

  Abstract

  Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

  View details for DOI 10.1016/j.bbmt.2010.02.022

  View details for PubMedID 20197102

• Rituximab in hematopoietic cell transplantation EXPERT OPINION ON BIOLOGICAL THERAPY Arai, S., Miklos, D. B. 2010; 10 (6): 971-982

  Abstract

  The success of rituximab therapy in managing B cell malignancies supports its widespread application in both autologous and allogeneic hematopoietic cell transplantation.We searched the PubMed database using the terms rituximab, stem cell transplant, autologous, or allogeneic and limited the search to clinical trials in English. In total, 92 trials were identified and 16 were reviewed in detail for significance of rituximab intervention. In this review, we will examine rituximab's emerging roles in: i) in vivo graft purging; ii) maintenance following autologous transplantation; iii) allogeneic transplant conditioning; and iv) the rationale for its use in the treatment/prevention of chronic graft-versus-host disease and post-transplant lymphoproliferative disorder.The reader will gain an understanding of the use of rituximab not only in transplants for B cell malignancies, but also its extension to other diseases where we are learning that B cells are involved in the pathogenesis.With rituximab firmly established in the non-transplant therapy of B cell malignancies, the new challenge in transplantation is how to incorporate the drug for optimum efficacy in those patients coming to transplant with relapse after rituximab-containing therapy.

  View details for DOI 10.1517/14712598.2010.485982

  View details for Web of Science ID 000277392300011

  View details for PubMedID 20420511

• TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors BLOOD Kohrt, H. E., Turnbull, B. B., Heydari, K., Shizuru, J. A., Laport, G. G., Miklos, D. B., Johnston, L. J., Arai, S., Weng, W., Hoppe, R. T., Lavori, P. W., Blume, K. G., Negrin, R. S., Strober, S., Lowsky, R. 2009; 114 (5): 1099-1109

  Abstract

  A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

  View details for DOI 10.1182/blood-2009-03-211441

  View details for PubMedID 19423725

• High prevalence of metabolic syndrome after allogeneic hematopoietic cell transplantation BONE MARROW TRANSPLANTATION Majhail, N. S., Flowers, M. E., Ness, K. K., Jagasia, M., Carpenter, P. A., Arora, M., Arai, S., Johnston, L., Martin, P. J., Baker, K. S., Lee, S. J., Burns, L. J. 2009; 43 (1): 49-54

  Abstract

  We conducted a cross-sectional study to estimate the prevalence of metabolic syndrome, a clustering of risk factors associated with cardiovascular disease, among 86 adults who had allogeneic hematopoietic-cell transplant (HCT) as compared with 258 age- and gender-matched US population controls selected from the 2005-2006 National Health and Nutrition Examination Survey database. The median age at study enrollment was 50 years (range, 21-71), and patients were at a median of 3 years (range, 1-21) from HCT. The prevalence of metabolic syndrome was 49% (95% confidence intervals (CI), 38-60%) among HCT recipients, a 2.2-fold (95% CI, 1.3-3.6, P=0.002) increase compared with controls. The prevalence rates of elevated blood pressure and hypertriglyceridemia were significantly higher among HCT recipients than among controls, but the prevalence rates of abdominal obesity, elevated blood glucose and low high-density lipoprotein cholesterol were not. HCT survivors with metabolic syndrome were more likely to have microalbuminuria (43 vs 10%) and elevated creatinine (31 vs 11%). No patient, donor or transplant characteristics were associated with the diagnosis of metabolic syndrome. We conclude that metabolic syndrome occurs frequently among allogeneic HCT survivors who are seen by transplant physicians. Approaches to screening, prevention and management of metabolic syndrome should be developed for HCT recipients.

  View details for DOI 10.1038/bmt.2008.263

  View details for Web of Science ID 000262489800007

  View details for PubMedID 18724397

  View details for PubMedCentralID PMC2628412

• Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial CYTOTHERAPY Arai, S., Meagher, R., Swearingen, M., Myint, H., Rich, E., Martinson, J., Klingemann, H. 2008; 10 (6): 625-632

  Abstract

  Renal cell cancer and malignant melanoma are two types of cancer that are responsive to immunotherapy. In this phase I dose-escalation study, the feasibility of large-scale expansion and safety of administering ex vivo-expanded NK-92 cells as allogeneic cellular immunotherapy in patients with refractory renal cell cancer and melanoma were determined.Twelve patients (aged 31-74 years) were enrolled, three per cohort at cell dose levels of 1x10(8)/m(2), 3x10(8)/m(2), 1x10(9)/m(2) and 3x10(9)/m(2). One treatment course consisted of three infusions. Eleven patients had refractory metastatic renal cell cancer; one patient had refractory metastatic melanoma.The NK-92 cells were expanded in X-Vivo 10 serum-free media supplemented with 500 U/mL Proleukin recombinant human interleukin-2 (rhIL-2), amino acids and 2.5% human AB plasma. Final yields of approximately 1x10(9) cells/culture bag (218-250xexpansion) over 15-17 days were achievable with >or=80% viability. Infusional toxicities of NK-92 were generally mild, with only one grade 3 fever and one grade 4 hypoglycemic episode. All toxicities were transient, resolved and did not require discontinuation of treatment. One patient was alive with disease at 4 years post-NK-92 infusion. The one metastatic melanoma patient had a minor response during the study period. One other patient exhibited a mixed response.This study establishes the feasibility of large-scale expansion and safety of administering NK-92 cells as allogeneic cellular immunotherapy in advanced cancer patients and serves as a platform for future study of this novel natural killer (NK)-cell based therapy.

  View details for DOI 10.1080/14653240802301872

  View details for Web of Science ID 000259762000009

  View details for PubMedID 18836917

• A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu-positive breast cancer JOURNAL OF CLINICAL ONCOLOGY Kurian, A. W., Newton Thompson, R., Gaw, A. F., Arai, S., Ortiz, R., Garber, A. M. 2007; 25 (6): 634-641

  Abstract

  One-year adjuvant trastuzumab (AT) therapy, with or without anthracyclines, increases disease-free and overall survival in early-stage HER2/neu-positive breast cancer. We sought to evaluate the cost effectiveness of these regimens, which are expensive and potentially toxic.We used a Markov health-state transition model to simulate three adjuvant therapy options for a cohort of 49-year-old women with HER2/neu-positive early-stage breast cancer: conventional chemotherapy without trastuzumab; anthracycline-based AT regimens used in the National Surgical Adjuvant Breast and Bowel Project B-31 and North Central Cancer Treatment Group N9831 trials; and the nonanthracycline AT regimen used in the Breast Cancer International Research group 006 trial. The base case used treatment efficacy measures reported in the randomized clinical trials of AT. We measured health outcomes in quality-adjusted life-years (QALYs) and costs in 2005 United States dollars (US dollars) and subjected results to probabilistic sensitivity analysis.In the base case, the anthracycline-based AT arm has an incremental cost-effectiveness ratio (ICER) of 39,982 dollars/QALY, whereas the nonanthracycline AT arm is more expensive and less effective; this result is insensitive to changes in recurrence rates, but if there is no benefit after 4 years, ICERs exceed 100,000 dollars/QALY for both AT arms. Results are moderately sensitive to variation in breast cancer survival rates and trastuzumab cost, and less sensitive to variations in cardiac toxicity.AT has an ICER comparable to those for other widely used interventions. Longer clinical follow-up is warranted to evaluate the long-term efficacy and toxicity of different AT regimens.

  View details for DOI 10.1200/JCO.2006.06.3081

  View details for Web of Science ID 000244384000006

  View details for PubMedID 17308268

• Natural killer cells: can they be useful as adoptive immunotherapy for cancer? Expert Opin Biol Ther Arai S, Klingemann H-G 2005; 5: 163-172
• Regulation of OX40 gene expression in graft-versus- host disease 20th International Congress of the Transplantation-Society Miura, Y., Thoburn, C. J., Bright, E. C., Arai, S., Hess, A. D. ELSEVIER SCIENCE INC. 2005: 57–61

  Abstract

  OX40 (CD134), a member of the tumor necrosis factor receptor superfamily, is expressed on activated T cells, including CD4(+)CD25(+) T regulatory (Treg) cells. To investigate the kinetics of OX40-OX40L in graft-versus-host disease (GVHD), OX40 mRNA transcript levels were temporally examined in peripheral blood mononuclear cells (PBMCs) from patients undergoing either allogeneic (allo) bone marrow transplantation (alloBMT) or autologous (auto) BMT with the induction of autoGVHD by cyclosporine (CsA) treatment posttransplant. Real-time quantitative PCR analysis revealed that OX40 mRNA expression decreased significantly in PBMCs from patients with either alloGVHD or autoGVHD compared with healthy individuals. No differences were detected between patients developing alloGVHD and those who did not develop this posttransplant complication. On the other hand, a decrease in OX40 mRNA levels correlated directly with the development of autoGVHD. Moreover, the upregulation of OX40 gene expression coincided with the resolution of autoGVHD. Interestingly, expression of OX40 by CD4(+) T lymphocytes after stimulation with autoantigen (Ag) was significantly (>700-fold) increased with a concomitant increase in expression of the Foxp3 regulatory gene. Expression of OX40 was increased (maximum 11-fold) after allo-Ag via mixed-lymphocyte reaction response. CsA suppressed the upregulation of OX40 expression after allo-Ag in a dose-dependent manner. Taken together, these results suggest that the decrease in OX40 expression posttransplant includes the defective reconstitution of Treg cells, and the active inhibition of gene transcription by CsA.

  View details for DOI 10.1016/j.transproceed.2005.01.014

  View details for Web of Science ID 000228091300022

  View details for PubMedID 15808546

• Association of Foxp3 regulatory gene expression and graft-versus-host disease Blood Miura Y, Thoburn CJ, Bright EC, Phelps ML, Shin T, Matsui EC, Matsui WH, Arai S, Fuchs EJ, Vogelsang GB, Jones RJ, Hess AD 2004; 104: 2187-93
• Role of immunotherapy in stem cell transplantation INTERNATIONAL JOURNAL OF HEMATOLOGY Arai, S., Klingemann, H. G. 2003; 77 (1): 22-28

  Abstract

  Relapse of the underlying malignancy continues to be a major problem after both autologous and allogeneic stem cell transplantation. Over the years, it has been recognized that immune-mediated graft-versus-tumor effects are crucially involved in eliminating minimal disease and controlling its recurrence after stem cell transplantation. This recognition has led to a number of studies that have attempted to stimulate a cellular immune response in the recipient, especially after allogeneic transplantation. Immunotherapy after autologous transplantation has to take into consideration the fact that patients' immune cells frequently are compromised and tolerance to the host tumor may have developed. Hence, trials involving the administration of cytokines (such as with interleukin and interferon) have shown limited benefits. This situation is different for allogeneic transplantation for which the infusion of donor lymphocytes has shown disease regression, especially in patients with chronic leukemias. However, such treatment is effective only if the patient has limited disease, and severe graft-versus-host disease frequently has to be accepted as a complication. This fact has led investigators to pursue the generation of specific lymphocytes that can recognize tumor antigens but not necessarily induce graft-versus-host disease. Such studies are in the early stages, and although some promising results have been observed, it is unclear at this point if the antitumor effect can be separated sufficiently from the graft-versus-host disease mediated by allogeneic lymphocytes. More recently, it has been shown that natural killer (NK) cells can have an antitumor effect in myeloid malignancies, particularly if the cells are allogeneic and do not recognize self-HLA antigens. At this point, it appears that engineered T-lymphocytes and allogeneic NK cells may be useful in preventing or treating relapse after allogeneic transplantation. It remains to be seen if such novel cellular therapies can also be implemented after autologous transplantation via the use of engineered allogeneic immune cells.

  View details for Web of Science ID 000180669400004

  View details for PubMedID 12568296

• Poor outcome in steroid refractory GVHD with ATG treatment Biol Blood Marrow Transplant Arai S, Margolis J, Zahurak M, Anders V, Vogelsang GB 2002; 8: 155-60
• Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings BONE MARROW TRANSPLANTATION Vogelsang, G. B., Arai, S. 2001; 27 (12): 1255-1262

  Abstract

  The therapeutic benefits of allogeneic stem cell transplantation in patients with hematologic disorders are limited by the significant morbidity and mortality of graft-versus-host disease (GVHD). Current agents for the prevention and treatment of GVHD have limited efficacy and often result in toxic side-effects. Mycophenolate mofetil (MMF) is a new immunosuppressant with a selective mechanism of action. When employed following solid organ transplantation, MMF reduces the incidence and severity of acute rejection episodes. By selectively targeting activated lymphocytes, the active metabolite of MMF, mycophenolic acid (MPA), appears to augment the actions of standard immunosuppressant agents without adding overlapping toxicities. Studies of combination regimens that include MMF report that this agent permits a dose reduction of cyclosporine, tacrolimus, or corticosteroid, without increasing the incidence of acute rejection in solid organ transplants. Reports on the efficacy of MMF following stem cell transplantation in animal studies were mixed. However, the use of a non-myeloablative conditioning regimen with a post-graft immunosuppressive regimen of MMF and cyclosporine was able to sustain stable mixed chimeras in 60% to 80% of dogs who received hematopoietic grafts from DLA-identical littermates. MMF has demonstrated activity in preliminary clinical trials for GVHD prophylaxis, and treatment of acute or chronic GVHD. Larger clinical trials are warranted to determine the optimum dose and route of MMF administration for GVHD, as well as the comparative safety and efficacy of MMF-containing regimens.

  View details for Web of Science ID 000169873200005

  View details for PubMedID 11548843

• von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy The Hematology Journal Arai S, Allan C, Streiff M, Hutchins GM, Vogelsang GB, Tsai HM 2001; 2: 292-299
• Management of graft-versus-host disease BLOOD REVIEWS Arai, S., Vogelsang, G. B. 2000; 14 (4): 190-204

  Abstract

  The increasing number of allogeneic stem cell transplants, particularly those involving donors other than HLA-identical siblings, has made the management of acute and chronic graft-versus-host disease (GVHD) a continuing problem for transplant experts. There have been improvements in the prevention of acute GVHD with cyclosporine- and FK506-based combination therapies, as well as lymphocyte depletion. However, fewer than 50% of patients have durable improvement after initial treatment. FK506 and mycophenolate mofetil (MMF) are promising salvage therapies in steroid-resistant GVHD, as are the anti-cytokine antibodies and the purine nucleoside analog, pentostatin. The incidence of chronic GVHD has unfortunately not decreased, despite advances in treatment of acute GVHD. Treatment of chronic GVHD involves treatment of the underlying immunologic process and supportive therapies. Initial therapy has tended to be cyclosporine and prednisone. Refractory patients have hope with combination MMF and FK506, etretinate, plaquenil, and nonpharmacologic approaches, such as PUVA. Supportive care is an integral part of chronic GVHD management with emphasis on infection control and symptom control. Death in chronic GVHD is still largely attributable to infection. The progress in therapies for GVHD has been encouraging, but the future of GVHD management lies in a better understanding of its pathogenesis.

  View details for DOI 10.1054/blre.2000.0137

  View details for Web of Science ID 000166387000003

  View details for PubMedID 11124107