David Miklos

All Publications

• Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-cell Lymphoma. Transplantation and cellular therapy Locke, F. L., Neelapu, S. S., Bartlett, N. L., Lekakis, L. J., Jacobson, C. A., Braunschweig, I., Oluwole, O. O., Siddiqi, T., Lin, Y., Timmerman, J. M., Kersten, M. J., Zheng, Y., Zhang, T., Nater, J., Shen, R., Miao, H., Kim, J. J., Miklos, D. B. 2024

  Abstract

  Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial.ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel.Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on Days -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on Day 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 hours after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines).Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-month minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 months (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid.Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.

  View details for DOI 10.1016/j.jtct.2024.08.018

  View details for PubMedID 39187161

• 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

• Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. The New England journal of medicine Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., Frank, M. J., Sahaf, B., Mackall, C. L., Gratzinger, D., Diehn, M., Alizadeh, A. A., Miklos, D. B. 2024; 390 (22): 2047-2060

  Abstract

  The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

  View details for DOI 10.1056/NEJMoa2401361

  View details for PubMedID 38865660

• 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

• 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

• CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias Hamilton, M. P., Sworder, B. J., Alig, S. K., Good, Z., Boegeholz, J., Schroers-Martin, J., Tamaresis, J., Esfahani, M., Lu, Y., Olsen, M., Liu, C., Ehlinger, Z., Desai, M., Liu-Fei, F., Muffly, L. S., Negrin, R. S., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Rezvani, A. R., Shizuru, J., Weng, W., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Diehn, M., Frank, M. J., Mackall, C. L., Kurtz, D. M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-182522

  View details for Web of Science ID 001159306701117

• Five Year Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axicabtagene Ciloleucel: Results from the US Lymphoma CAR-T Cell Consortium Spiegel, J. Y., Jain, M. D., Nastoupil, L. J., Tamaresis, J., Ghobadi, A., Lin, Y., Lekakis, L. J., Reagan, P. M., Oluwole, O. O., McGuirk, J. P., Deol, A., Dorritie, K., Sehgal, A. R., Goy, A., Hill, B. T., Andreadis, C., Munoz, J. L., Ulrickson, M. L., Westin, J., Chavez, J. C., Patel, D. A., Jacobs, M. T., Bansal, R., Bennani, N., Patel, V., Rapoport, A. P., Vose, J. M., Miklos, D. B., Neelapu, S. S., Locke, F. L., Lunning, M. A., Dahiya, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-179868

  View details for Web of Science ID 001159306704056

• Effective Prevention of Steroid-Requiring Chronic Graft-Vs.-Host Disease with B Cell Depletion: A Randomized, Placebo-Controlled Trial Cutler, C., Kim, H. T., El Banna, H., Halloran, E., Matozel, E., Ho, V., Koreth, J., Gooptu, M., Shapiro, R. M., Kelkar, A. H., Gibson, C., Reynolds, C., Ansuinelli, M., Tamada, R., Au, C., Defilipp, Z., El-Jawahri, A., Chen, Y., El Jurdi, N. H., Weisdorf, D., Couriel, D. R., Lee, C. J., Sahaf, B., Craig, J., Ji, K., Soiffer, R. J., Miklos, D. B., Antin, J., Ritz, J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-180142

  View details for Web of Science ID 001159306702162

• Post-CAR-T Minimal Residual Disease (MRD) Monitoring in Mantle Cell Lymphoma Enables Early Relapse Detection Ananth, S., Su, Y., Hamilton, M. P., Agarwal, N., Weng, W., Dahiya, S., Bharadwaj, S., Mallampet, J., Smith, M., Kong, K., Twoy, A., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-188338

  View details for Web of Science ID 001159306706144

• Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. Hematology/oncology clinics of North America Hamilton, M. P., Miklos, D. B. 2023

  Abstract

  Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary therapy increasingly used in the treatment of non-Hodgkin B-cell lymphoma. This review focuses on the use of CAR T-cell therapy in aggressive B-cell lymphoma including clinical indications, known short- and long-term toxicity, mechanisms of CAR T-cell efficacy and tumor resistance, and future directions in the treatment of aggressive lymphoma with CAR T-cell therapy.

  View details for DOI 10.1016/j.hoc.2023.05.007

  View details for PubMedID 37349153

• Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma. JOURNAL OF CLINICAL ONCOLOGY Westin, J., Oluwole, O. O., Kersten, M., Miklos, D., Perales, M., Ghobadi, A., Rapoport, A., Sureda, A., Jacobson, C., Farooq, U., van Meerten, T., Ulrickson, M. L., Elsawy, M., Leslie, L. A., Chaganti, S., Dickinson, M., Yang, Y., Schupp, M., To, C., Locke, F. L. 2023; 41 (17_SUPPL): LBA107

  View details for DOI 10.1200/JCO.2023.41.17_suppl.LBA107

  View details for Web of Science ID 001182783300022

• Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma. Westin, J., Oluwole, O. O., Kersten, M., Miklos, D., Perales, M., Ghobadi, A., Rapoport, A., Sureda, A., Jacobson, C., Farooq, U., van Meerten, T., Ulrickson, M. L., Elsawy, M., Leslie, L. A., Chaganti, S., Dickinson, M., Yang, Y., Schupp, M., To, C., Locke, F. L. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001043181100009

• Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

  Abstract

  Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

  View details for DOI 10.1016/j.ccell.2022.12.005

  View details for PubMedID 36584673

• Post-infusion CAR T-Reg cells identify patients resistant to CD19-CAR therapy NATURE MEDICINE Good, Z., Spiegel, J. Y., Sahaf, B., Malipatlolla, M. B., Ehlinger, Z. J., Kurra, S., Desai, M. H., Reynolds, W. D., Lin, A., Vandris, P., Wu, F., Prabhu, S., Hamilton, M. P., Tamaresis, J. S., Hanson, P. J., Patel, S., Feldman, S. A., Frank, M. J., Baird, J. H., Muffly, L., Claire, G. K., Craig, J., Kong, K. A., Wagh, D., Coller, J., Bendall, S. C., Tibshirani, R. J., Plevritis, S. K., Miklos, D. B., Mackall, C. L. 2022

  Abstract

  Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells. Validation cohort analysis upheld the link between higher CAR TReg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR TReg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.

  View details for DOI 10.1038/s41591-022-01960-7

  View details for Web of Science ID 000852940800007

  View details for PubMedID 36097223

• Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nature medicine Scholler, N., Perbost, R., Locke, F. L., Jain, M. D., Turcan, S., Danan, C., Chang, E. C., Neelapu, S. S., Miklos, D. B., Jacobson, C. A., Lekakis, L. J., Lin, Y., Ghobadi, A., Kim, J. J., Chou, J., Plaks, V., Wang, Z., Xue, A., Mattie, M., Rossi, J. M., Bot, A., Galon, J. 2022

  Abstract

  Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), gamma-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.

  View details for DOI 10.1038/s41591-022-01916-x

  View details for PubMedID 36038629

• Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. The New England journal of medicine Locke, F. L., Miklos, D. B., Jacobson, C. A., Perales, M., Kersten, M., Oluwole, O. O., Ghobadi, A., Rapoport, A. P., McGuirk, J., Pagel, J. M., Munoz, J., Farooq, U., van Meerten, T., Reagan, P. M., Sureda, A., Flinn, I. W., Vandenberghe, P., Song, K. W., Dickinson, M., Minnema, M. C., Riedell, P. A., Leslie, L. A., Chaganti, S., Yang, Y., Filosto, S., Shah, J., Schupp, M., To, C., Cheng, P., Gordon, L. I., Westin, J. R., All ZUMA-7 Investigators and Contributing Kite Members 2021

  Abstract

  BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred.CONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

  View details for DOI 10.1056/NEJMoa2116133

  View details for PubMedID 34891224

• 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

• Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Frank, M. J., Hossain, N. M., Bukhari, A., Dean, E., Spiegel, J. Y., Claire, G. K., Kirsch, I., Jacob, A. P., Mullins, C. D., Lee, L. W., Kong, K. A., Craig, J., Mackall, C. L., Rapoport, A. P., Jain, M. D., Dahiya, S., Locke, F. L., Miklos, D. B. 2021: JCO2100377

  Abstract

  PURPOSE: Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes.METHODS: Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity.RESULTS: A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion (P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached (P < .0001) and 19 months versus not reached (P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed (P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion.CONCLUSION: Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

  View details for DOI 10.1200/JCO.21.00377

  View details for PubMedID 34133196

• CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel. Blood Plaks, V., Rossi, J. M., Chou, J., Wang, L., Poddar, S., Han, G., Wang, Z., Kuang, S., Chu, F., Davis, R. E., Vega, F., Bashir, Z., Jacobson, C. A., Locke, F. L., Reagan, P., Rodig, S. J., Lekakis, L. J., Flinn, I. W., Miklos, D. B., Bot, A., Neelapu, S. S. 2021

  Abstract

  Although anti-CD19 chimeric antigen receptor (CAR) T-cell therapy produces high response rates and durable remissions in patients with large B-cell lymphoma (LBCL), relapses can still occur by mechanisms that are incompletely elucidated. We examined the CD19 antigen characteristics of pretreatment (n=100) and post-relapse (n=20) tumor biopsies from patients treated with axicabtagene ciloleucel (axi-cel) in the multicenter phase 1/2 ZUMA-1 study (NCT02899052). CD19 target antigen expression was variable at baseline and a subset of evaluable patients who relapsed after axi-cel CAR T-cell therapy (~30%) had CD19-low or negative tumors. By comparison CD20, CD22, and CD79a were mostly present at relapse, including in tumors with low CD19 levels. Transcriptomic analysis revealed that the observed impact to antigen levels in a subset of tumor biopsies at relapse was primarily attributed to low or absent CD19 protein expression that was unrelated to alternative splicing events and mutations in CD19, which were also observed. The emergence of tumor cells with low or no CD19 antigen expression are thought to drive the relapse process in some patients, in the context of targeted removal of antigen-positive tumor cells by the therapy. These findings support multi-antigen targeting CAR approaches to improve clinical outcomes in patients with LBCL.

  View details for DOI 10.1182/blood.2021010930

  View details for PubMedID 34041526

• 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

• Real-world evidence of axicabtagene ciloleucel (Axi-cel) for the treatment of large B-cell lymphoma (LBCL) in the United States (US). Jacobson, C. A., Locke, F., Hu, Z., Siddiqi, T., Ahmed, S., Ghobadi, A., Miklos, D., Lin, Y., Perales, M., Lunning, M., Herr, M., Hill, B. T., Ganguly, S., Dong, H., Nikiforow, S., Xie, J., Xu, H., Hooper, M., Kawashima, J., Pasquini, M. C. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.7552

  View details for Web of Science ID 000708120604149

• Safety and PK/PD of ALLO-647, an anti-CD52 antibody, with fludarabine (Flu)/cyclophosphamide (Cy) for lymphodepletion in the setting of allogeneic CAR-T cell therapy. Tees, M., Neelapu, S., Hari, P., Mailankody, S., Miklos, D., Locke, F., Nath, R., Prashad, S., Zhou, X., Demirhan, E., Nandakumar, S., Fisher, D., Opiteck, G., Wang, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.2527

  View details for Web of Science ID 000708120601049

• 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. W., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W. K., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143-155

  Abstract

  Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.

  View details for DOI 10.1182/bloodadvances.2020002732

  View details for PubMedID 33570626

• Outcomes of Patients with Large B-cell Lymphoma Progressing after Axicabtagene Ciloleucel. Blood Spiegel, J. Y., Dahiya, S., Jain, M. D., Tamaresis, J. S., Nastoupil, L., Jacobs, M. T., Ghobadi, A., Lin, Y., Lunning, M., Lekakis, L. J., Reagan, P., Oluwole, O. O., McGuirk, J. P., Deol, A., Goy, A., Vu, K., Andreadis, C., Munoz, J., Bennani, N. N., Vose, J., Dorritie, K. A., Neelapu, S. S., Locke, F. L., Rapoport, A. P., Hill, B., Miklos, D. B. 2020

  View details for DOI 10.1182/blood.2020006245

  View details for PubMedID 33156925

• Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood advances Locke, F. L., Rossi, J. M., Neelapu, S. S., Jacobson, C. A., Miklos, D. B., Ghobadi, A., Oluwole, O. O., Reagan, P. M., Lekakis, L. J., Lin, Y., Sherman, M., Better, M., Go, W. Y., Wiezorek, J. S., Xue, A., Bot, A. 2020; 4 (19): 4898–4911

  Abstract

  ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

  View details for DOI 10.1182/bloodadvances.2020002394

  View details for PubMedID 33035333

• Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Nastoupil, L. J., Jain, M. D., Feng, L., Spiegel, J. Y., Ghobadi, A., Lin, Y., Dahiya, S., Lunning, M., Lekakis, L., Reagan, P., Oluwole, O., McGuirk, J., Deol, A., Sehgal, A. R., Goy, A., Hill, B. T., Vu, K., Andreadis, C., Munoz, J., Westin, J., Chavez, J. C., Cashen, A., Bennani, N. N., Rapoport, A. P., Vose, J. M., Miklos, D. B., Neelapu, S. S., Locke, F. L. 2020: JCO1902104

  Abstract

  PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.PATIENTS AND METHODS: Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.RESULTS: Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.CONCLUSION: The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

  View details for DOI 10.1200/JCO.19.02104

  View details for PubMedID 32401634

• 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

• Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR T-cell therapy LEUKEMIA & LYMPHOMA Hossain, N. M., Dahiya, S., Le, R., Abramian, A. M., Kong, K. A., Muffly, L. S., Miklos, D. B. 2019; 60 (2): 503-506

  View details for DOI 10.1080/10428194.2018.1474463

  View details for Web of Science ID 000463555600031

• A confirmation of chronic graft-versus-host disease prediction using allogeneic HY antibodies following sex-mismatched hematopoietic cell transplantation. Haematologica Paul, J., Nakasone, H., Sahaf, B., Wu, F., Wang, K., Ho, V., Wu, J., Kim, H., Blazar, B. R., Ritz, J., Howard, A., Cutler, C., Miklos, D. 2019

  View details for PubMedID 30655371

• Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial LANCET ONCOLOGY Locke, F. L., Ghobadi, A., Jacobson, C. A., Miklos, D. B., Lekakis, L. J., Oluwole, O. O., Lin, Y., Braunschweig, I., Hill, B. T., Timmerman, J. M., Deol, A., Reagan, P. M., Stiff, P., Flinn, I. W., Farooq, U., Goy, A., McSweeney, P. A., Munoz, J., Siddiqi, T., Chavez, J. C., Herrera, A. F., Bartlett, N. L., Wiezorek, J. S., Navale, L., Xue, A., Jiang, Y., Bot, A., Rossi, J. M., Kim, J. J., Go, W. Y., Neelapu, S. S. 2019; 20 (1): 31–42

  View details for DOI 10.1016/S1470-2045(18)30864-7

  View details for Web of Science ID 000454901700044

• Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. The Lancet. Oncology Locke, F. L., Ghobadi, A., Jacobson, C. A., Miklos, D. B., Lekakis, L. J., Oluwole, O. O., Lin, Y., Braunschweig, I., Hill, B. T., Timmerman, J. M., Deol, A., Reagan, P. M., Stiff, P., Flinn, I. W., Farooq, U., Goy, A., McSweeney, P. A., Munoz, J., Siddiqi, T., Chavez, J. C., Herrera, A. F., Bartlett, N. L., Wiezorek, J. S., Navale, L., Xue, A., Jiang, Y., Bot, A., Rossi, J. M., Kim, J. J., Go, W. Y., Neelapu, S. S. 2018

  Abstract

  BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.METHODS: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 * 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway.FINDINGS: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up.INTERPRETATION: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.FUNDING: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

  View details for PubMedID 30518502

• Updated Results of a Phase 1b/2 Study of Ibrutinib in Chronic Graft Versus Host Disease After Failure of Prior Therapy Waller, E. K., Miklos, D., Cutler, C. S., Arora, M., Jagasia, M., Pusic, I., Flowers, M. E., Logan, A. C., Nakamura, R., Dubovsky, J., Chang, S., Clow, F., Lal, I. D., Styles, L., Jaglowski, S. NATURE PUBLISHING GROUP. 2018: 71-73

  View details for Web of Science ID 000487702800056

• Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR T-cell therapy. Leukemia & lymphoma Hossain, N. M., Dahiya, S., Le, R., Abramian, A. M., Kong, K. A., Muffly, L. S., Miklos, D. B. 2018: 1–4

  View details for PubMedID 29966461

• Ibrutinib for chronic graft-versus-host disease after failure of prior therapy BLOOD Miklos, D., Cutler, C. S., Arora, M., Waller, E. K., Jagasia, M., Pusic, I., Flowers, M. E., Logan, A. C., Nakamura, R., Blazar, B. R., Li, Y., Chang, S., Lal, I., Dubovsky, J., James, D. F., Styles, L., Jaglowski, S. 2017; 130 (21): 2243–50

  Abstract

  Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.

  View details for PubMedID 28924018

• Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood Ryan, C. E., Sahaf, B., Logan, A. C., O'Brien, S., Byrd, J. C., Hillmen, P., Brown, J. R., Dyer, M. J., Mato, A. R., Keating, M. J., Jaglowski, S., Clow, F., Rezvani, A. R., Styles, L., Coutre, S. E., Miklos, D. B. 2016

  Abstract

  Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.

  View details for PubMedID 27802969

• Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans BLOOD Nakasone, H., Tian, L., Sahaf, B., Kawase, T., Schoenrock, K., Perloff, S., Ryan, C. E., Paul, J., Popli, R., Wu, F., Otani, J. M., Coller, J., Warren, E. H., Miklos, D. B. 2015; 125 (20): 3193-3201

  Abstract

  Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant: 78 (57%) of F→M patients were seropositive for at least 1 of the 6 HY-Abs, and 3-month seropositivity for each HY-Ab was associated with a persistent seropositive response throughout the posttransplant follow-up period (P < .001 in each). There were no associations between pretransplant features and 3-month overall HY-Ab development. Detection of multiple HY-Abs at 3 months (represented by HY score) was significantly associated with an increased risk of cGVHD (P < .0001) and nonrelapse mortality (P < .01). Compared to clinical factors alone, the addition of HY score to clinical factors improved the predictive potential of cGVHD (P < .01). Monitoring HY-Ab development thus stratifies cGVHD risk in F→M HCT patients and may support preemptive prophylaxis therapy for cGVHD beginning at 3 months posttransplant.

  View details for DOI 10.1182/blood-2014-11-613323

  View details for PubMedID 25766725

• Minimal residual disease quantification using consensus primers and high- throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia LEUKEMIA Logan, A. C., Zhang, B., Narasimhan, B., Carlton, V., Zheng, J., Moorhead, M., Krampf, M. R., Jones, C. D., Waqar, A. N., Faham, M., Zehnder, J. L., Miklos, D. B. 2013; 27 (8): 1659-1665

  Abstract

  Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifies immunoglobulin heavy chain (IGH) loci using consensus V and J segment primers followed by high-throughput sequencing (HTS), enabling quantification with a detection limit of one CLL cell per million mononuclear cells. Using this IGH-HTS approach, we analyzed MRD patterns in over 400 samples from 40 CLL patients who underwent reduced-intensity allo-HCT. Nine patients relapsed within 12 months post-HCT. Of the 31 patients in remission at 12 months post-HCT, disease-free survival was 86% in patients with MRD <10(-4) and 20% in those with MRD 10(-4) (relapse hazard ratio (HR) 9.0; 95% confidence interval (CI) 2.5-32; P<0.0001), with median follow-up of 36 months. Additionally, MRD predicted relapse at other time points, including 9, 18 and 24 months post-HCT. MRD doubling time <12 months with disease burden 10(-5) was associated with relapse within 12 months of MRD assessment in 50% of patients, and within 24 months in 90% of patients. This IGH-HTS method may facilitate routine MRD quantification in clinical trials.Leukemia advance online publication, 12 March 2013; doi:10.1038/leu.2013.52.

  View details for DOI 10.1038/leu.2013.52

  View details for Web of Science ID 000322823200006

  View details for PubMedID 23419792

• 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

• High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Logan, A. C., Gao, H., Wang, C., Sahaf, B., Jones, C. D., Marshall, E. L., Buno, I., Armstrong, R., Fire, A. Z., Weinberg, K. I., Mindrinos, M., Zehnder, J. L., Boyd, S. D., Xiao, W., Davis, R. W., Miklos, D. B. 2011; 108 (52): 21194-21199

  Abstract

  The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to aggregate cancer clone sequence variants arising from systematic and random artifacts occurring during IGH-HTS. We then compared the sensitivity of IGH-HTS, flow cytometry, and allele-specific oligonucleotide PCR for MRD quantification in 28 samples collected from 6 CLL patients following allogeneic HCT. Using amplimer libraries generated with consensus primers from patient blood samples, we demonstrate the sensitivity of IGH-HTS with 454 pyrosequencing to be 10(-5), with a high correlation between quantification by allele-specific oligonucleotide PCR and IGH-HTS (r = 0.85). From the same dataset used to quantify MRD, IGH-HTS also allowed us to profile IGH repertoire reconstitution after HCT-information not provided by the other MRD methods. IGH-HTS using consensus primers will broaden the availability of MRD quantification in CLL and other B cell malignancies, and this approach has potential for quantitative evaluation of immune diversification following transplant and nontransplant therapies.

  View details for DOI 10.1073/pnas.1118357109

  View details for Web of Science ID 000298479900065

  View details for PubMedID 22160699

  View details for PubMedCentralID PMC3248502

• Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission 45th Annual Meeting and Exhibition of the American-Society-of-Hematology Miklos, D. B., Kim, H. T., Miller, K. H., Guo, L. X., Zorn, E., Lee, S. J., Hochberg, E. P., Wu, C. J., Alyea, E. P., Cutler, C., Ho, V., Soiffer, R. J., Antin, J. H., Ritz, J. AMER SOC HEMATOLOGY. 2005: 2973–78

  Abstract

  Minor histocompatibility antigens (mHAs) are known targets of donor T cells after allogeneic hematopoietic stem cell transplantation (HSCT). In contrast, B-cell responses to mHAs have not been extensively characterized and the clinical significance of antibodies to mHAs is unknown. We tested 121 patients who underwent HSCT and 134 healthy donors for immunoglobulin G (IgG) antibodies against 5 mHAs encoded by genes on the Y chromosome (DBY, UTY, ZFY, RPS4Y, and EIF1AY). Antibodies to at least one H-Y protein developed in 52% of male patients with female donors compared with 8.7% of male patients with male donors (P < .0001), and in 41.4% of healthy females compared with 7.8% of healthy males (P < .0001). H-Y antibodies develop 4 to 12 months after transplantation and persist for long periods. The clinical significance of H-Y antibodies was characterized in 75 male patients with hematologic malignancies who received stem cells from female donors (F --> M HSCT). The presence of H-Y antibodies correlated with chronic graft-versus-host disease (GVHD) by univariate (odds ratio [OR] = 15.5; P < .0001) and multivariable logistic regression analysis (OR = 56.5; P < .0001). Antibody response to Y-chromosome encoded histocompatibility antigens (H-Y antigens) was also associated with maintenance of disease remission (P < .0001). B cells may provide a new target for immune intervention in chronic GVHD.

  View details for Web of Science ID 000228042900059

  View details for PubMedID 15613541

• Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor ECOG performance status with relapsed or refractory large B-cell lymphoma after 2 or more lines of prior therapy. American journal of hematology Lunning, M. A., Wang, H. L., Hu, Z. H., Locke, F. L., Siddiqi, T., Jacobson, C. A., Ahmed, S., Miklos, D. B., Lin, Y., Hill, B. T., Ghobadi, A., Neelapu, S. S., Westin, J., Dieyi, C., Field, P., Miao, H., Shahani, S. A., Patel, A., Spooner, C., Fu, C., Muramoto, D., Xu, H., Pasquini, M. C. 2024

  Abstract

  Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

  View details for DOI 10.1002/ajh.27283

  View details for PubMedID 38504387

• Axicabtagene Ciloleucel in Combination With the 4-1BB Agonist Utomilumab in Patients With Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results From ZUMA-11. Clinical cancer research : an official journal of the American Association for Cancer Research Jain, M. D., Miklos, D. B., Jacobson, C. A., Timmerman, J. M., Sun, J., Nater, J., Fang, X., Patel, A., Davis, M., Heeke, D., Trinh, T., Mattie, M., Neumann, F., Kim, J. J., To, C., Filosto, S., Reshef, R. 2023

  Abstract

  Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4-1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy.In Phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose: 2×106 cells/kg) plus utomilumab 10-200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLTs) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics.No DLTs were observed among patients treated with axi-cel and utomilumab (n=12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and 7 patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on Days 57-168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL-2, IFNγ, and IL-10.Utomilumab-mediated 4-1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.

  View details for DOI 10.1158/1078-0432.CCR-23-0916

  View details for PubMedID 37527011

• Detection of Aberrant CD58 Expression in a Wide Spectrum of Lymphoma Subtypes: Implications for Treatment Resistance. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Younes, S., Zhao, S., Bharadwaj, S., Mosquera, A. P., Libert, D., Johnsrud, A., Majzner, R. G., Miklos, D. B., Frank, M. J., Natkunam, Y. 2023: 100256

  Abstract

  CD58 or lymphocyte function-associated antigen-3, is a ligand for CD2 receptors on T- and NK-cells and is required for their activation and target cell killing. We recently showed a trend towards higher frequency of CD58 aberrations in patients with diffuse large B-cell lymphoma (DLBCL) who progressed on CAR-T cell treatment compared to those who responded. Given that CD58 status may be an important measure of T-cell mediated therapy failure, we developed CD58 immunohistochemical assay and evaluated CD58 status in 748 lymphomas. Our results show that CD58 protein expression is downregulated in a significant proportion of all subtypes of B- T- and NK-cell lymphomas. CD58 loss is significantly related to poor prognostic indicators in DLBCL and to ALK and DUSP22 rearrangements in anaplastic large cell lymphoma. However, it is not associated with overall or progression free survival in any of the lymphoma subtypes. As eligibility for CAR-T therapy is being extended to a broader spectrum of lymphomas, mechanisms of resistance, such as target downregulation and CD58 loss, may limit therapeutic success. CD58 status is therefore an important biomarker in lymphoma patients who may benefit from next generation T-cell mediated therapies or other novel approaches that mitigate immune escape.

  View details for DOI 10.1016/j.modpat.2023.100256

  View details for PubMedID 37391168

• Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. The New England journal of medicine Westin, J. R., Oluwole, O. O., Kersten, M. J., Miklos, D. B., Perales, M. A., Ghobadi, A., Rapoport, A. P., Sureda, A., Jacobson, C. A., Farooq, U., van Meerten, T., Ulrickson, M., Elsawy, M., Leslie, L. A., Chaganti, S., Dickinson, M., Dorritie, K., Reagan, P. M., McGuirk, J., Song, K. W., Riedell, P. A., Minnema, M. C., Yang, Y., Vardhanabhuti, S., Filosto, S., Cheng, P., Shahani, S. A., Schupp, M., To, C., Locke, F. L. 2023

  Abstract

  In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes.In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization.A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival.At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

  View details for DOI 10.1056/NEJMoa2301665

  View details for PubMedID 37272527

• Circulating Tumor DNA Adds Specificity to PET following Axicabtagene Ciloleucel in Large B-cell Lymphoma. Blood advances Dean, E. A., Kimmel, G. J., Frank, M. J., Bukhari, A., Hossain, N. M., Jain, M. D., Dahiya, S., Miklos, D. B., Altrock, P. M., Locke, F. L. 2023

  Abstract

  We examined the meaning of metabolically active lesions on 1 month restaging nuclear imaging of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving axicabtagene ciloleucel (axi-cel) by assessing the relationship between total metabolic tumor volume (MTV) on positron emission tomography (PET) scans and circulating tumor DNA (ctDNA) in the plasma. In this prospective multicenter sample collection study, MTV was retrospectively calculated via commercial software at baseline, 1 and 3 months post chimeric antigen receptor (CAR) T-cell therapy; ctDNA was available pre and post axi-cel. Spearman correlation coefficient (rs) was used to study the relationship between the variables and a mathematical model was constructed to describe tumor dynamics 1 month post CAR T-cell therapy. The median time between baseline scan and axi-cel infusion was 33 (range, 1-137) days for all 57 patients. For 41 of the patients with imaging within 33 days of axi-cel or imaging before that time but no bridging therapy, the correlation at baseline became stronger (rs 0.61, P< 0.0001) compared to all patients (rs 0.38, P= 0.004). Excluding patients in complete remission with no measurable residual disease, ctDNA and MTV at 1 month did not correlate (rs 0.28, P= 0.11), but did correlate at 3 months (rs 0.79, P= 0.0007). Modeling of tumor dynamics, which incorporated ctDNA and inflammation as part of MTV, recapitulated outcomes of patients with positive radiologic 1-month scans. Our results suggested that non-progressing hypermetabolic lesions on 1 month PET represent ongoing treatment response and their composition may be elucidated by concurrent ctDNA.

  View details for DOI 10.1182/bloodadvances.2022009426

  View details for PubMedID 37126659

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

  Abstract

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

  View details for DOI 10.1182/blood.2022018827

  View details for PubMedID 36857637

• 5-Year Follow-Up Supports Curative Potential of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma (ZUMA-1). Blood Neelapu, S. S., Jacobson, C. A., Ghobadi, A., Miklos, D. B., Lekakis, L. J., Oluwole, O. O., Lin, Y., Braunschweig, I., Hill, B. T., Timmerman, J. M., Deol, A., Reagan, P. M., Stiff, P. J., Flinn, I. W., Farooq, U., Goy, A., McSweeney, P., Munoz, J., Siddiqi, T., Chavez, J. C., Herrera, A. F., Bartlett, N. L., Bot, A. A., Shen, R. R., Dong, J., Singh, K., Miao, H., Kim, J. J., Zheng, Y., Locke, F. L. 2023

  Abstract

  In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we aimed to assess survival and safety in ZUMA-1 after 5 years of follow-up. Eligible adults with refractory LBCL (diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma) received lymphodepleting chemotherapy followed by axi-cel infusion targeted at 2×106 cells/kg. Investigator-assessed response, updated survival, safety, and pharmacokinetic outcomes were assessed in treated patients. The objective response rate in the 101 treated patients was 83% (58% complete response rate), and with a median follow-up of 63.1 months, responses were ongoing at data cutoff in 31%. Median overall survival (OS) was 25.8 months and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91%. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. ClinicalTrials.gov, number NCT02348216.

  View details for DOI 10.1182/blood.2022018893

  View details for PubMedID 36821768

• Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wang, Y., Jain, P., Locke, F. L., Maurer, M. J., Frank, M. J., Munoz, J. L., Dahiya, S., Beitinjaneh, A. M., Jacobs, M. T., Mcguirk, J. P., Vose, J. M., Goy, A., Andreadis, C., Hill, B. T., Dorritie, K. A., Oluwole, O. O., Deol, A., Paludo, J., Shah, B., Wang, T., Banerjee, R., Miklos, D. B., Rapoport, A. P., Lekakis, L., Ghobadi, A., Neelapu, S. S., Lin, Y., Wang, M. L., Jain, M. D. 2023: JCO2201797

  Abstract

  Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines.Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis.In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

  View details for DOI 10.1200/JCO.22.01797

  View details for PubMedID 36753699

• Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Miklos, D. B., Abu Zaid, M., Cooney, J. P., Albring, J. C., Flowers, M., Skarbnik, A. P., Yakoub-Agha, I., Ko, B., Bruno, B., Waller, E. K., Yared, J., Sohn, S. K., Bulabois, C., Teshima, T., Jacobsohn, D., Greinix, H., Mokatrin, A., Lee, Y., Wahlstrom, J. T., Styles, L., Socie, G. 2023: JCO2200509

  Abstract

  PURPOSE: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD).METHODS: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety.RESULTS: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients.CONCLUSION: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.

  View details for DOI 10.1200/JCO.22.00509

  View details for PubMedID 36608310

• PROTEOMIC PROFILING IN BLOOD IDENTIFIES NOVEL PRETREATMENT AND MECHANISTIC MARKERS RELATED TO INFLAMMATORY ADVERSE EVENTS IN RELAPSED/ REFRACTORY LARGE B-CELL LYMPHOMA AFTER AXICABTAGENE CILOLEUCEL Speth, K., Tiwari, G., Adhikary, S., Song, Q., Chou, J., Locke, F., Jacobson, C., Miklos, D., Oluwole, O., Kersten, M., Topp, M., Kim, J., Bot, A. BMJ PUBLISHING GROUP. 2022: A717

  View details for DOI 10.1136/jitc-2022-SITC2022.0687

  View details for Web of Science ID 000919423400646

• BASECAMP-1: LEVERAGING HLA LOSS OF HETEROZYGOSITY IN SOLID TUMORS BY NGS TO IDENTIFY PATIENTS WITH RELAPSED SOLID TUMORS FOR FUTURE CEA AND MSLN LOGIC-GATED TMOD (TM) CAR T-CELL THERAPY Simeone, D., Morelli, M., Hecht, J., Patel, S., Fakih, M., Kirtane, K., Welling, T., Lau, S., Lin, Y., Borad, M., Garon, E., Larson, S., Kato, S., Vu, P., Locke, F., Kim, D., Sunwoo, J., Miklos, D., Frigault, M., Maus, M., Nikiforow, S., Jacobson, C., Liechty, K., Mardiros, A., Lozac'hmeur, A., Beutner, K., Welch, J., Ng, E., Go, W., Maloney, D., Kopetz, S., Molina, J. BMJ PUBLISHING GROUP. 2022: A670

  View details for DOI 10.1136/jitc-2022-SITC2022.0639

  View details for Web of Science ID 000919423400599

• MULTIOMICS AND MULTIMODAL ANALYSIS APPROACH TO CONSTRUCT A DIFFUSE LARGE B CELL LYMPHOMA ATLAS OF TUMOR MICROENVIRONMENT FOR PREDICTIVE MODELING Mattie, M., Perbost, R., Turcan, S., Danan, C., Locke, F., Neelapu, S., Miklos, D., Jacobson, C., Lekakis, L., Lin, Y., Ghobadi, A., Kim, J., Wang, Z., Xue, A., Filosto, S., Scholler, N., Galon, J. BMJ PUBLISHING GROUP. 2022: A1513

  View details for DOI 10.1136/jitc-2022-SITC2022.1454

  View details for Web of Science ID 000919423401558

• Recurrent Status Epilepticus in the Setting of Chimeric Antigen Receptor (CAR)-T Cell Therapy The Neurohospitalist Reveron-Thornton, R., Scott, B. J., Post, D., Finley Caulfield, A., Werbaneth, K., Hovsepian, D. A., Spiegel, J., Miklos, D., Thomas, R. P., Patel, C. B. 2021: 74-79

  Abstract

  Axicabtagene ciloleucel (AC) is an FDA-approved anti-CD19 autologous chimeric antigen receptor T-cell (CAR-T) therapy for refractory diffuse large B cell lymphoma (DLBCL). While its efficacy in DLBCL has been promising, neurotoxicity remains a significant concern. We present a case of a 22-year-old woman with chemotherapy-refractory DLBCL who exhibited Grade IV neurotoxicity in the setting of sepsis, after undergoing AC infusion. Despite prophylactic levetiracetam given per guidelines,1,2 she experienced a precipitous mental status decline on post-infusion day 8 (D8) followed by hypoxic respiratory failure in the setting of clinical status epilepticus on D11 and nonconvulsive status epilepticus (NCSE) on D18. While neuroimaging was unremarkable, EEG demonstrated diffuse slowing and 2.5-3 Hz generalized periodic discharges consistent with NCSE. Seizures were initially refractory to lorazepam, increasing doses of levetiracetam, and phenobarbital, requiring a midazolam drip titrated to 50-70% burst suppression for resolution. Methylprednisolone and tocilizumab were used to treat neurotoxicity and cytokine release syndrome, respectively. Empiric antibiotics were used for sepsis. After cessation of sedatives on D19, mental status improved to near baseline. PET/CT just prior to discharge showed a complete response of the DLBCL (Deauville 3). She was discharged on D37 with no further seizure activity. Unfortunately, a 3-month interval PET/CT demonstrated disease progression which continued through salvage pembrolizumab eventually leading to death 1.2 years post-CAR-T infusion. This case illustrates the clinical management challenges of a complex and rare neurotoxic side effect of CAR-T cell therapy, namely NCSE following status epilepticus.

  View details for DOI 10.1177/19418744211000980

  View details for PubMedCentralID PMC8689529

• KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients with Relapsed/refractory (R/R) Mantle Cell Lymphoma (MCL): Results from Phase 2 of ZUMA-2 Wang, M., Munoz, J., Goy, A., Locke, F., Jacobson, C., Hill, B., Timmerman, J., Holmes, H., Jaglowski, S., Flinn, I., McSweeney, P., Miklos, D., Pagel, J., Kersten, M., Peng, W., Zheng, L., Rossi, J., Jain, R., Rao, A., Reagan, P. SPRINGERNATURE. 2020: 41–43

  View details for Web of Science ID 000600556200033

• A Comparison of 2-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel; Axi-Cel) and SCHOLAR-1 in Patients (Pts) with Refractory Large B Cell Lymphoma (LBCL) Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Reagan, P., Miklos, D. B., Jacobson, C. A., Braunschweig, I., Oluwole, O., Siddiqi, T., Lin, Y., Crump, M., Kuruvilla, J., Van den Neste, E., Farooq, U., Navale, L., DePuy, V., Kim, J., Gisselbrecht, C. CELL PRESS. 2020: 575–76

  View details for Web of Science ID 000530089302417

• Outcomes of older patients in ZUMA-1, a pivotal study of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood Neelapu, S. S., Jacobson, C. A., Oluwole, O. O., Munoz, J., Deol, A., Miklos, D., Bartlett, N. L., Braunschweig, I., Jiang, Y., Kim, J. J., Zheng, L., Rossi, J. M., Locke, F. L. 2020

  View details for DOI 10.1182/blood.2019004162

  View details for PubMedID 32181801

• 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

• A Comparison of 2-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel [Axi-Cel]) and SCHOLAR-1 in Patients (Pts) with Refractory Large B Cell Lymphoma (LBCL) Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Reagan, P. M., Miklos, D. B., Jacobson, C. A., Braunschweig, I., Oluwole, O. O., Siddiqi, T., Lin, Y., Crump, M., Kuruvilla, J., Van Den Neste, E., Farooq, U., Navale, L., DePuy, V., Kim, J. J., Gisselbrecht, C. ELSEVIER SCIENCE INC. 2020: S232

  View details for Web of Science ID 000516887900345

• KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL): Results of the Phase 2 ZUMA-2 Study Wang, M., Munoz, J., Goy, A., Locke, F. L., Jacobson, C. A., Hill, B. T., Timmerman, J. M., Holmes, H., Jaglowski, S., Flinn, I. W., McSweeney, P. A., Miklos, D. B., Pagel, J. M., Kersten, M., Peng, W., Zheng, L., Rossi, J. M., Jain, R. K., Rao, A. V., Reagan, P. M. ELSEVIER SCIENCE INC. 2020: S1

  View details for Web of Science ID 000516887900002

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

  Abstract

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

  View details for DOI 10.1084/jem.20191712

  View details for PubMedID 32558897

• Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET Clinical cancer research: an official journal of the American Association for Cancer Research Alam*, I. S., Simonetta*, F. 2020: 1058–68

  Abstract

  Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Noninvasive molecular imaging of CAR T cells by PET is a promising approach with the ability to provide spatial, temporal, and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T-cell molecular imaging. In this study, we assessed the ability of antibody-based PET (immunoPET) to noninvasively visualize CAR T cells.After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer, which we have previously reported.Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow-containing skeletal sites of CAR T-cell-treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T-cell persistence and function.This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T-cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.See related commentary by Volpe et al., p. 911.

  View details for DOI 10.1158/1078-0432.CCR-20-2770

  View details for PubMedCentralID PMC7887027

• KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. The New England journal of medicine Wang, M. n., Munoz, J. n., Goy, A. n., Locke, F. L., Jacobson, C. A., Hill, B. T., Timmerman, J. M., Holmes, H. n., Jaglowski, S. n., Flinn, I. W., McSweeney, P. A., Miklos, D. B., Pagel, J. M., Kersten, M. J., Milpied, N. n., Fung, H. n., Topp, M. S., Houot, R. n., Beitinjaneh, A. n., Peng, W. n., Zheng, L. n., Rossi, J. M., Jain, R. K., Rao, A. V., Reagan, P. M. 2020; 382 (14): 1331–42

  Abstract

  Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).

  View details for DOI 10.1056/NEJMoa1914347

  View details for PubMedID 32242358

• Utilization of Chimeric Antigen Receptor (CAR) T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B cell non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Jain, T., Bar, M., Kansagra, A. J., Chong, E. A., Hashmi, S. K., Neelapu, S. S., Byrne, M., Jacoby, E., Lazaryan, A., Jacobson, C. A., Ansell, S. M., Awan, F. T., Burns, L., Bachanova, V., Bollard, C. M., Carpenter, P. A., DiPersio, J. F., Hamadani, M., Heslop, H. E., Hill, J. A., Komanduri, K. V., Kovitz, C. A., Lazarus, H. M., Serrette, J. M., Mohty, M., Miklos, D., Nagler, A., Pavletic, S. Z., Savani, B. N., Schuster, S. J., Kharfan-Dabaja, M. A., Perales, M., Lin, Y. 2019

  Abstract

  Axicabtagene ciloleucel (YESCARTA, Kite Pharma, a Gilead Company) and tisagenlecleucel (KYMRIAH, Novartis Pharmaceuticals Corp.) are two CD19-directed chimeric antigen receptor T cell (CD19 CAR T) products that are currently approved by the U.S. Food and Drug Administration, the European Medicines Agency, Health Canada, Ministry of Health, Labor and Welfare (Japan) and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/ refractory aggressive B cell non-Hodgkin lymphoma (NHL). While this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate utilization of this novel therapy, as well as short- and long-term toxicities. To address these issues, representatives of American Society of Transplantation and Cellular Therapy (ASTCT) convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts and members of International Society of Cell and Gene Therapy (ISCT), American Society of Hematology (ASH), Foundation for the Accreditation of Cellular Therapy (FACT) and European Society for Blood and Marrow Transplantation (EBMT). The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the utilization of CD19 CAR T for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.

  View details for DOI 10.1016/j.bbmt.2019.08.015

  View details for PubMedID 31446199

• Ibrutinib for Chronic Graft-Versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Waller, E. K., Miklos, D., Cutler, C., Arora, M., Jagasia, M. H., Pusic, I., Flowers, M. E., Logan, A. C., Nakamura, R., Chang, S., Clow, F., Lal, I. D., Styles, L., Jaglowski, S. 2019

  Abstract

  Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a phase 1b/2, open-label study (PCYC-1129; NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here, we describe extended follow-up for patients in this study. After a median (range) follow-up of 26 months (0.53‒36.7), best overall response rate (ORR) in the all treated population was 69% (29/42) with 13 (31%) patients who achieved a complete response and 16 (38%) patients who achieved a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs; 6 of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. A total of 11 of 18 (61%) patients who had sclerosis at baseline showed a sclerotic response (39% complete response, 22% partial response). A total of 27 of 42 (64%) patients reached a corticosteroid dose of <0.15 mg/kg/day during the study; 8 responders discontinued corticosteroid treatment and remained off corticosteroid as of study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n=12). AEs leading to discontinuation occurred in 18 (43%) patients. At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD that had failed prior systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile was observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

  View details for DOI 10.1016/j.bbmt.2019.06.023

  View details for PubMedID 31260802

• Inhibition of Inositol kinase B controls acute and chronic graft-versus-host disease. Blood Thangavelu, G. n., Du, J. n., Paz, K. G., Loschi, M. n., Zaiken, M. C., Flynn, R. n., Taylor, P. A., Kirchmeier, A. K., Panoskaltsis-Mortari, A. n., Luznik, L. n., MacDonald, K. P., Hill, G. R., Maillard, I. n., Munn, D. H., Serody, J. S., Murphy, W. J., Miklos, D. n., Cutler, C. S., Koreth, J. n., Antin, J. H., Soiffer, R. J., Ritz, J. n., Dahlberg, C. n., Miller, A. T., Blazar, B. R. 2019

  Abstract

  T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation, differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T-cells, and can control T-cell mediated autoimmunity. Here, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine induced Itpkb deleted (Itpkb-/-) T-cells had attenuated acute GVHD in two models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against two acute myeloid leukemia lines (MLL-AF9-eGFP; C1498-luciferase). Compared to FK506, GNF362 more selectively deleted donor alloreactive versus nominal antigen responsive T-cells. Consistent with these data and as compared to FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a distinct pathophysiology from acute GVHD, Itpkb-/- donor T-cells reduced active chronic GVHD in a multi-organ system model with bronchiolitis obliterans (BO) driven by germinal center reactions, resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is required to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.

  View details for DOI 10.1182/blood.2019000032

  View details for PubMedID 31697815

• Circulating DNA for Molecular Response Prediction, Characterization of Resistance Mechanisms and Quantification of CAR T-Cells during Axicabtagene Ciloleucel Therapy American Society of Hematology Sworder, B., Kurtz, D. M., Macaulay, C., Frank, M. J., Alig, S., Garofalo, A., Sahaf, B., Esfahani, M. S., Spiegel, J. Y., Oak, J., Beygi, S., Jin, M. C., Chabon, J. J., Khodadoust, M. S., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2019

  View details for DOI 10.1182/blood-2019-129015

• 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

• 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

• Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience Nastoupil, L. J., Jain, M. D., Spiegel, J. Y., Ghobadi, A., Lin, Y., Dahiya, S., Lunning, M. A., Lekakis, L. J., Reagan, P. M., Oluwole, O. O., McGuirk, J. P., Deol, A., Sehgal, A. R., Goy, A., Hill, B. T., Andreadis, C., Munoz, J., Westin, J. R., Chavez, J. C., Cashen, A. F., Bennani, N. N., Rapoport, A. P., Vose, J. M., Miklos, D. B., Neelapu, S. S., Locke, F. L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-114152

  View details for Web of Science ID 000454837600145

• 1 Study of CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR) Therapy in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia (ALL) Schultz, L. M., Davis, K. L., Baggott, C., Chaudry, C., Marcy, A., Mavroukakis, S., Sahaf, B., Kong, K. A., Muffly, L. S., Kim, S., Meyer, E. H., Fry, T. J., Qin, H., Miklos, D. B., Mackall, C. L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117445

  View details for Web of Science ID 000454837602274

• Phase I Experience with a Bi-Specific CAR Targeting CD19 and CD22 in Adults with B-Cell Malignancies Hossain, N., Sahaf, B., Abramian, M., Spiegel, J. Y., Kong, K., Kim, S., Mavroukakis, S., Oak, J., Natkunam, Y., Meyer, E. H., Frank, M. J., Feldman, S. A., Long, S. R., Qin, H., Fry, T. J., Muffly, L. S., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110142

  View details for Web of Science ID 000454837601199

• 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

• 2-Year Follow-up and High-Risk Subset Analysis of Zuma-1, the Pivotal Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory Large B Cell Lymphoma Neelapu, S. S., Ghobadi, A., Jacobson, C. A., Miklos, D. B., Lekakis, L. J., Oluwole, O. O., Lin, Y., Braunschweig, I., Hill, B. T., Timmerman, J. M., Deol, A., Reagan, P. M., Stiff, P. J., Flinn, I. W., Farooq, U., Goy, A., McSweeney, P. A., Munoz, J., Siddiqi, T., Chavez, J. C., Herrera, A. F., Xue, A., Jiang, Y., Bot, A., Rossi, J. M., Kim, J. J., Go, W. Y., Locke, F. L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-111368

  View details for Web of Science ID 000454842800151

• End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma Jacobson, C. A., Locke, F. L., Miklos, D. B., Herrera, A. F., Westin, J. R., Lee, J., Rossi, J. M., Zheng, L., Avanzi, M. P., Roberts, Z. J., Sun, J. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-111523

  View details for Web of Science ID 000454842803214

• Target Antigen Downregulation and Other Mechanisms of Failure after Axicabtagene Ciloleucel (CAR19) Therapy Oak, J., Spiegel, J. Y., Sahaf, B., Natkunam, Y., Long, S. R., Hossain, N., Mackall, C. L., Kong, K. A., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-120206

  View details for Web of Science ID 000454842804282

• Small-molecule BCL6 inhibitor effectively treats mice with non-sclerodermatous chronic graft-versus-host disease. Blood Paz, K., Flynn, R., Du, J., Qi, J., Luznik, L., Maillard, I., MacDonald, K. P., Hill, G. R., Serody, J. S., Murphy, W. J., Sage, P. T., Sharpe, A. H., Miklos, D., Culter, C. S., Koreth, J., Antin, J. H., Soiffer, R. J., Ritz, J., Bradner, J. E., Melnick, A. M., Blazar, B. 2018

  Abstract

  Patient outcomes for steroid-dependent or -refractory cGVHD are poor and only ibrutinib has been FDA approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B-cells to produce antibodies that are associated with disease pathogenesis. The transcriptional co-repressor BCL6 is a member of the BTB/POZ transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T-cells and B-cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multi-organ system injury with bronchiolitis obliterans associated with a robust GC reaction but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.

  View details for PubMedID 30279226

• Axicabtagene Ciloleucel in Patients with Refractory Large B Cell Lymphoma: Outcomes by Prior Lines of Therapy in the Pivotal Phase 2 Study, ZUMA-1 Locke, F. L., Ghobadi, A., Lekakis, L. J., Miklos, D. B., Jacobson, C. A., Jacobsen, E., Braunschweig, I., Oluwole, O. O., Siddiqi, T., Lin, Y., Reagan, P. M., Farooq, U., Deol, A., Bot, A., Rossi, J. M., Jiang, Y., Xue, A., Go, W. Y., Neelapu, S. S. CIG MEDIA GROUP, LP. 2018: S276

  View details for Web of Science ID 000444343400251

• Detection of Measurable Residual Disease by Next-Generation Sequencing in Paired Blood and Bone Marrow Samples from Patients with Lymphoid Malignancies Miklos, D., Muffly, L., Lee, L., Crossley, B. CIG MEDIA GROUP, LP. 2018: S295–S296

  View details for Web of Science ID 000444343400290

• Durability of Response in Patients with Refractory Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel in the Pivotal Phase 2 Study, ZUMA-1 Locke, F. L., Ghobadi, A., Jacobson, C. A., Jacobsen, E., Miklos, D. B., Lekakis, L. J., Braunschweig, I., Oluwole, O. O., Lin, Y., Siddiqi, T., Deol, A., Reagan, P. M., Farooq, U., Bot, A., Jiang, Y., Rossi, J. M., Xue, A., Go, W. Y., Neelapu, S. S. CIG MEDIA GROUP, LP. 2018: S277–S278

  View details for Web of Science ID 000444343400254

• Characteristics of the pretreatment tumor microenvironment may influence clinical response in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel) in the pivotal ZUMA-1 Rossi, J. M., Galon, J., Turcan, S., Danan, C., Locke, F. L., Neelapu, S. S., Miklos, D. B., Jacobson, C. A., Lekakis, L. J., Lin, Y., Ghobadi, A., Go, W. Y., Bot, A. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-LB-016

  View details for Web of Science ID 000468818900188

• 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

• 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

• The Biology of Chronic Graft-Versus-Host Disease: a Task Force Report From the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Biology of blood and marrow transplantation Cooke, K. R., Luznik, L., Sarantopoulos, S., Hakim, F. T., Jagasia, M., Fowler, D. H., van den Brink, M. R., Hansen, J. A., Parkman, R., Miklos, D. B., Martin, P. J., paczesny, s., Vogelsang, G., Pavletic, S., Ritz, J., Schultz, K. R., Blazar, B. R. 2016

  Abstract

  Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.

  View details for DOI 10.1016/j.bbmt.2016.09.023

  View details for PubMedID 27713092

• Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes HAEMATOLOGICA Nakasone, H., Sahaf, B., Tian, L., Wang, T., Haagenson, M. D., Schoenrock, K., Perloff, S., Ryan, C. E., Wu, F., Spellman, S. R., Lee, S. J., Ritz, J., Miklos, D. B., Ctr Int Blood Marrow 2016; 101 (1): E30–E33

  View details for PubMedID 26494841

• Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy. Haematologica Nakasone, H., Remberger, M., Tian, L., Brodin, P., Sahaf, B., Wu, F., Mattsson, J., Lowsky, R., Negrin, R., Miklos, D. B., Meyer, E. 2015; 100 (11): 1477-1485

  Abstract

  Sex-mismatched hematopoietic cell transplantation is linked to increased graft-versus-host disease and mortality in myeloablative conditioning. Here we evaluated outcomes of 1,041 adult transplant recipients at two centers between 2006 and 2013 and investigated how the effect of sex-mismatching differed in myeloablative, reduced-intensity, and non-myeloablative total lymphoid irradiation with anti-thymocyte globulin conditioning. Among patients who underwent myeloablative conditioning, male recipients with female donors had increased chronic graft-versus-host disease (hazard ratio 1.83, P<0.01), increased non-relapse mortality (hazard ratio 1.84, P=0.022) and inferior overall survival (hazard ratio 1.59, P=0.018). In contrast, among patients who received reduced-intensity conditioning, male recipients with female donors had increased acute graft-versus-host disease (hazard ratio 1.96, P<0.01) but no difference in non-relapse mortality or overall survival. Among the patients who underwent total lymphoid irradiation with anti-thymocyte globulin, male recipients with female donors showed no increase in graft-versus-host disease or non-relapse mortality. Notably, only in the cohort receiving total lymphoid irradiation with anti-thymocyte globulin were male recipients with female donors significantly associated with reduced relapse (hazard ratio 0.64, P<0.01), and allo-antibody responses against H-Y antigens were predictive of reduced relapse. In the cohort given total lymphoid irradiation with anti-thymocyte globulin, the graft-versus-leukemia effect resulted in superior overall survival in recipients of sex-mismatched grafts (HR 0.69, P=0.037). In addition, only in the cohort treated with total lymphoid irradiation with anti-thymocyte globulin were female recipients with male donors associated with reduced relapse (hazard ratio 0.59, P<0.01) and superior survival (hazard ratio 0.61, P=0.014) compared with sex-matched pairs. We conclude that the risks and benefits of sex-mismatched transplants appear to differ according to conditioning strategy and this could affect donor selection.

  View details for DOI 10.3324/haematol.2015.125294

  View details for PubMedID 26250581

• 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

• Red blood cell transfusions are associated with HLA class I but not H-Y alloantibodies in children with sickle cell disease. British journal of haematology Nickel, R. S., Hendrickson, J. E., Yee, M. M., Bray, R. A., Gebel, H. M., Kean, L. S., Miklos, D. B., Horan, J. T. 2015; 170 (2): 247-256

  Abstract

  Blood transfusions can induce alloantibodies to antigens on red blood cells (RBCs), white blood cells and platelets, with these alloantibodies affecting transfusion and transplantation. While transfusion-related alloimmunization against RBC antigens and human leucocyte antigens (HLA) have been studied, transfusion-related alloimmunization to minor histocompatibility antigens (mHA), such as H-Y antigens, has not been clinically characterized. We conducted a cross-sectional study of 114 children with sickle cell disease (SCD) and tested for antibodies to 5 H-Y antigens and to HLA class I and class II. Few patients had H-Y antibodies, with no significant differences in the prevalence of any H-Y antibody observed among transfused females (7%), transfused males (6%) and never transfused females (4%). In contrast, HLA class I, but not HLA class II, antibodies were more prevalent among transfused than never transfused patients (class I: 33% vs. 13%, P = 0·046; class II: 7% vs. 8%, P = 0·67). Among transfused patients, RBC alloantibody history but not amount of transfusion exposure was associated with a high (>25%) HLA class I panel reactive antibody (Odds ratio 6·8, 95% confidence interval 2·1-22·3). These results are consistent with immunological responder and non-responder phenotypes, wherein a subset of patients with SCD may be at higher risk for transfusion-related alloimmunization.

  View details for DOI 10.1111/bjh.13424

  View details for PubMedID 25891976

  View details for PubMedCentralID PMC4490004

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

  Abstract

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

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

  View details for PubMedID 25887775

• Therapeutic benefits targeting B-cells in chronic graft-versus-host disease INTERNATIONAL JOURNAL OF HEMATOLOGY Nakasone, H., Sahaf, B., Miklos, D. B. 2015; 101 (5): 438-451

  Abstract

  Allogeneic hematopoietic cell transplantation (allo-HCT) can be a curative strategy for hematological diseases, and the indications for allo-HCT have broadened widely due to recent progress in supportive strategies. However, patients must overcome various complications and chronic graft-versus-host disease (cGVHD) remains the most common allo-HCT cause of long-term morbidity and mortality. cGVHD is difficult to biologically assess due to the heterogeneity of cGVHD symptoms, and the pathogenesis of cGVHD has yet to be established. Recent experimental model progress has suggested that B-cells play a critical role in cGVHD development. Consistent with these experimental results, some clinical studies investigating B-cell depletion and modulation of B-cell signaling pathways have decreased cGVHD incidence and provided some therapeutic benefit. However, randomized control studies are necessary to confirm the efficacy of B-cell targeting drugs for cGVHD. Here, we review the pathophysiology of cGVHD, especially focusing on the role of B-cell immunity, and discuss the efficacy of both B-cell depletion and modulation of B-cell signaling pathways in human cGVHD prevention, initial treatment, and salvage treatment.

  View details for DOI 10.1007/s12185-015-1782-4

  View details for Web of Science ID 000354213800004

  View details for PubMedID 25812839

• National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Paczesny, S., Hakim, F. T., Pidala, J., Cooke, K. R., Lathrop, J., Griffith, L. M., Hansen, J., Jagasia, M., Miklos, D., Pavletic, S., Parkman, R., Russek-Cohen, E., Flowers, M. E., Lee, S., Martin, P., Vogelsang, G., Walton, M., Schultz, K. R. 2015; 21 (5): 780-792

  Abstract

  Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, or of a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include the following: (1) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity; (2) prognostic risk to develop chronic GVHD; and (3) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well documented following established quality control guidelines for sample acquisition, processing, preservation, and testing, at intervals that are both calendar and event driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for use in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a 4-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines.

  View details for DOI 10.1016/j.bbna.2015.01.003

  View details for PubMedID 25644957

• ABO Mismatch Is Associated with Increased Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Logan, A. C., Wang, Z., Alimoghaddam, K., Wong, R. M., Lai, T., Negrin, R. S., Grumet, C., Logan, B. R., Zhang, M., Spellman, S. R., Lee, S. J., Miklos, D. B. 2015; 21 (4): 746-754

  Abstract

  We evaluated ABO associated outcomes in 1737 patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT) at Stanford University between January 1986 and July 2011. Grafts were 61% ABO matched, 18% major mismatched (MM), 17% minor MM, and 4% bidirectional MM. Median follow-up was 6 years. In multivariate analysis, overall survival (OS) was inferior in minor MM hematopoietic cell transplantations (median 2.1 versus 6.3 years; hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.19 to 2.05; P = .001) in comparison with ABO-matched grafts. ABO minor MM was associated with an increase in early nonrelapse mortality (NRM) (18% versus 13%; HR, 1.48; 95% CI, 1.06 to 2.06; P = .02). In an independent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts, impairment of OS (HR, 1.55; 95% CI, 1.07 to 2.25; P = .021) and increased NRM (HR, 1.72; 95% CI, 1.11 to 2.68; P = .03) were observed in recipients of ABO minor-MM grafts. A second independent analysis of a CIBMTR data set including 5179 patients with acute myeloid leukemia and myelodysplastic syndrome identified a nonsignificant trend toward decreased OS in recipients of ABO minor-MM grafts and also found ABO major MM to be significantly associated with decreased OS (HR, 1.19; 95% CI, 1.08 to 1.31; P < .001) and increased NRM (HR, 1.23; 95% CI, 1.08 to 1.4; P = .002). ABO minor and major MM are risk factors for worse transplantation outcomes, although the associated hazards may not be uniform across different transplantation populations. Further study is warranted to determine which patient populations are at greatest risk, and whether this risk can be modified by anti-B cell therapy or other peri-transplantation treatments.

  View details for DOI 10.1016/j.bbmt.2014.12.036

  View details for PubMedID 25572032

• A Reduced-Toxicity Regimen Is Associated with Durable Engraftment and Clinical Cure of Nonmalignant Genetic Diseases among Children Undergoing Blood and Marrow Transplantation with an HLA-Matched Related Donor. Biology of blood and marrow transplantation Mahadeo, K. M., Weinberg, K. I., Abdel-Azim, H., Miklos, D. B., Killen, R., Kohn, D., Crooks, G. M., Shah, A. J., Kharbanda, S., Agarwal, R., Kapoor, N. 2015; 21 (3): 440-444

  Abstract

  Blood and marrow transplantation (BMT) is a standard curative therapy for patients with nonmalignant genetic diseases. Myeloablative conditioning has been associated with significant regimen-related toxicity (RRT), whereas reduced-intensity conditioning regimens have been associated with graft failure. In this prospective pilot trial conducted at 2 centers between 2006 and 2013, we report the outcome of 22 patients with nonmalignant genetic diseases who were conditioned with a novel reduced-toxicity regimen: i.v. busulfan (16 mg/kg), alemtuzumab (52 mg/m(2)), fludarabine (140 mg/m(2)), and cyclophosphamide (105 mg/kg). The median age of the study population was 3.5 years (range, 5 months to 26 years). No cases of sinusoidal obstruction syndrome, severe or chronic graft-versus-host disease (GVHD), or primary graft failure were reported. Median time to neutrophil engraftment (>500 cells/μL) and platelet engraftment (>20K cells/μL) were 19 (range, 12 to 50) and 23.5 (range, 14 to 134) days, respectively. The median length of follow-up was 3 years (range, .2 to 6.3). The overall survival rates were 95% at 100 days (95% confidence interval, .72 to .99) and 90% at 6 years (95% confidence interval, .68 to .98). RRT and chronic GVHD are significant barriers to BMT for patients with nonmalignant genetic diseases. This alemtuzumab-based reduced-toxicity regimen appears to be promising with durable engraftment, effective cure of clinical disease, low rates of RRT, and no observed chronic GVHD.

  View details for DOI 10.1016/j.bbmt.2014.11.005

  View details for PubMedID 25459642

• 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

• Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biology of blood and marrow transplantation Logan, A. C., Vashi, N., Faham, M., Carlton, V., Kong, K., Buño, I., Zheng, J., Moorhead, M., Klinger, M., Zhang, B., Waqar, A., Zehnder, J. L., Miklos, D. B. 2014; 20 (9): 1307-1313

  Abstract

  Minimal residual disease (MRD) quantification is an important predictor of outcome after treatment for acute lymphoblastic leukemia (ALL). Bone marrow ALL burden ≥ 10(-4) after induction predicts subsequent relapse. Likewise, MRD ≥ 10(-4) in bone marrow before initiation of conditioning for allogeneic (allo) hematopoietic cell transplantation (HCT) predicts transplantation failure. Current methods for MRD quantification in ALL are not sufficiently sensitive for use with peripheral blood specimens and have not been broadly implemented in the management of adults with ALL. Consensus-primed immunoglobulin (Ig), T cell receptor (TCR) amplification and high-throughput sequencing (HTS) permit use of a standardized algorithm for all patients and can detect leukemia at 10(-6) or lower. We applied the LymphoSIGHT HTS platform (Sequenta Inc., South San Francisco, CA) to quantification of MRD in 237 samples from 29 adult B cell ALL patients before and after allo-HCT. Using primers for the IGH-VDJ, IGH-DJ, IGK, TCRB, TCRD, and TCRG loci, MRD could be quantified in 93% of patients. Leukemia-associated clonotypes at these loci were identified in 52%, 28%, 10%, 35%, 28%, and 41% of patients, respectively. MRD ≥ 10(-4) before HCT conditioning predicted post-HCT relapse (hazard ratio [HR], 7.7; 95% confidence interval [CI], 2.0 to 30; P = .003). In post-HCT blood samples, MRD ≥10(-6) had 100% positive predictive value for relapse with median lead time of 89 days (HR, 14; 95% CI, 4.7 to 44, P < .0001). The use of HTS-based MRD quantification in adults with ALL offers a standardized approach with sufficient sensitivity to quantify leukemia MRD in peripheral blood. Use of this approach may identify a window for clinical intervention before overt relapse.

  View details for DOI 10.1016/j.bbmt.2014.04.018

  View details for PubMedID 24769317

• Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1. Bone marrow transplantation Fleischhauer, K., Fernandez-Viña, M. A., Wang, T., Haagenson, M., Battiwalla, M., Baxter-Lowe, L. A., Ciceri, F., Dehn, J., Gajewski, J., Hale, G. A., Heemskerk, M. B., Marino, S. R., McCarthy, P. L., Miklos, D., Oudshoorn, M., Pollack, M. S., Reddy, V., Senitzer, D., Shaw, B. E., Waller, E. K., Lee, S. J., Spellman, S. R. 2014; 49 (9): 1176-1183

  Abstract

  HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence.

  View details for DOI 10.1038/bmt.2014.122

  View details for PubMedID 24955785

• 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

• Clinical impact of H-Y alloimmunity. Immunologic research Popli, R., Sahaf, B., Nakasone, H., Lee, J. Y., Miklos, D. B. 2014; 58 (2-3): 249-258

  Abstract

  H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.

  View details for DOI 10.1007/s12026-014-8514-3

  View details for PubMedID 24781195

• A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease. Blood Meyer, E. H., Hsu, A. R., Liliental, J., Löhr, A., Florek, M., Zehnder, J. L., Strober, S., Lavori, P., Miklos, D. B., Johnson, D. S., Negrin, R. S. 2013; 121 (24): 4955-4962

  Abstract

  Steroid refractory gastrointestinal (GI) acute graft versus host disease (aGVHD) is a major cause of mortality in hematopoietic stem cell transplantation (HCT) without immune markers to establish a diagnosis or guide therapy. We found that T cell receptor β (TCRβ) CDR3 repertoire sequencing reveals patterns that could eventually serve as a disease biomarker of T cell alloreactivity in aGVHD. We identified T cell clones in GI biopsies in a heterogeneous group of 15 allogeneic HCT patients with GI aGVHD symptoms. Seven steroid-refractory aGVHD patients showed a more conserved TCRβ clonal structure between different biopsy sites in the GI tract than eight primary-therapy responsive patients. Tracking GI clones identified at endoscopy longitudinally in the blood also revealed an increased clonal expansion in patients with steroid-refractory disease. Immune repertoire sequencing-based methods could enable a novel personalized way to guide diagnosis and therapy in diseases where T cell activity is a major determinant.

  View details for DOI 10.1182/blood-2013-03-489757

  View details for PubMedID 23652802

• A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease BLOOD Meyer, E. H., Hsu, A. R., Liliental, J., Loehr, A., Florek, M., Zehnder, J. L., Strober, S., Lavori, P., Miklos, D. B., Johnson, D. S., Negrin, R. S. 2013; 121 (24): 4955-4962

  Abstract

  Steroid refractory gastrointestinal (GI) acute graft versus host disease (aGVHD) is a major cause of mortality in hematopoietic stem cell transplantation (HCT) without immune markers to establish a diagnosis or guide therapy. We found that T cell receptor β (TCRβ) CDR3 repertoire sequencing reveals patterns that could eventually serve as a disease biomarker of T cell alloreactivity in aGVHD. We identified T cell clones in GI biopsies in a heterogeneous group of 15 allogeneic HCT patients with GI aGVHD symptoms. Seven steroid-refractory aGVHD patients showed a more conserved TCRβ clonal structure between different biopsy sites in the GI tract than eight primary-therapy responsive patients. Tracking GI clones identified at endoscopy longitudinally in the blood also revealed an increased clonal expansion in patients with steroid-refractory disease. Immune repertoire sequencing-based methods could enable a novel personalized way to guide diagnosis and therapy in diseases where T cell activity is a major determinant.

  View details for DOI 10.1182/blood-2013-03-489757

  View details for Web of Science ID 000321896300024

• Birth Order and Transplantation Outcome in HLA-Identical Sibling Stem Cell Transplantation: An Analysis on Behalf of the Center for International Blood and Marrow Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Dobbelstein, C., Ahn, K. W., Haagenson, M., Hale, G. A., Van Rood, J. J., Miklos, D., Waller, E. K., Spellman, S. R., Fernandez-Vina, M., Ganser, A., Aljurf, M., Bornhaeuser, M., Gupta, V., Marino, S. R., Pollack, M. S., Reddy, V., Eder, M., Lee, S. J. 2013; 19 (5): 741-745

  Abstract

  Allogeneic stem cell transplantation (SCT) is the most effective treatment option for many hematologic malignancies, but graft-versus-host disease (GVHD) remains a major cause of treatment failure. Along with well-established risk factors for transplantation outcomes, recent single-center studies have identified a birth order effect in HLA-identical sibling SCT, with lower rates of acute and chronic GVHD and improved overall survival when the donor is younger than the recipient. One hypothesized mechanism for this effect is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. The aim of the present study was to validate previously reported single-center data in a large, multicenter cohort provided by the Center for International Blood and Marrow Transplantation. All adult and pediatric patients (n = 11,365) with a hematologic malignancy who underwent allogeneic SCT with a graft from an HLA-identical sibling donor between 1990 and 2007 were included. When donors were younger than recipients, there was a significantly lower rate of acute GVHD grade II-IV and chronic GVHD in children, as well as a lower rate of chronic GVHD in adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed. Our data suggest that if otherwise equally matched, a graft from a younger sibling may be superior to a graft from an older sibling for children and adolescents undergoing SCT.

  View details for DOI 10.1016/j.bbmt.2013.01.020

  View details for Web of Science ID 000318132500010

  View details for PubMedID 23380341

• Humoral Immunity to Cytomegalovirus and Chronic Graft-Versus-Host Disease VIRAL IMMUNOLOGY Namboodiri, A. M., Nietert, P. J., Wadia, P. P., Miklos, D. B., Pandey, J. P. 2012; 25 (4): 338-340

  Abstract

  Human cytomegalovirus (HCMV) is an important cause of morbidity and mortality in patients with chronic graft-versus-host disease (cGVHD), but the underlying mechanisms are not understood. The aim of this investigation was to determine whether humoral immune responses to the HCMV antigens were quantitatively different in hematopoietic cell transplant (HCT) recipients who developed cGVHD from those who did not. Antibodies to HCMV and its proteins UL94 and UL70 were quantitated in 79 cGVHD and 30 non-cGVHD patients by enzyme-linked immunosorbent assays (ELISAs). Mean levels of antibodies to the whole HCMV and to its protein UL94 were not significantly different between the cGVHD and the non-cGVHD subjects. However, the levels of antibodies to HCMV UL70 were significantly higher in non-cGVHD subjects than in those with cGVHD (20.91±15.63 versus 15.00±10.35 ng/mL; p=0.03). This suggests that anti-UL70 antibodies might play a protective role in the development of cGVHD.

  View details for DOI 10.1089/vim.2012.0013

  View details for Web of Science ID 000307729400014

  View details for PubMedID 22803743

  View details for PubMedCentralID PMC3413074

• 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

• Clonally identical Hodgkin's disease develops after allogeneic hematopoietic cell transplant for CLL BONE MARROW TRANSPLANTATION Tseng, D., Jones, C. D., Anderson, M., Warnke, R., Zehnder, J. L., Miklos, D. B. 2011; 46 (12): 1576-1578

  View details for DOI 10.1038/bmt.2010.340

  View details for Web of Science ID 000298326500015

  View details for PubMedID 21258419

• 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

• Combined CD4 T-Cell and Antibody Response to Human Minor Histocompatibility Antigen DBY After Allogeneic Stem-Cell Transplantation TRANSPLANTATION Porcheray, F., Miklos, D. B., Floyd, B. H., Sarantopoulos, S., Bellucci, R., Soiffer, R. J., Antin, J. H., Alyea, E. P., Ritz, J., Zorn, E. 2011; 92 (3): 359-365

  Abstract

  Antibody responses to HY antigens in male recipients are frequent after transplantation of stem cells from female donors (Miklos et al., Blood 2005; 105: 2973; Miklos et al., Blood 2004; 103: 353). However, evidence that this B-cell immunity is accompanied by T-cell responses to the cognate antigens is scarce. Here, we examined T- and B-cell responses to DBY antigen in a male patient who received hematopoietic stem cells from a human leukocyte antigen-identical female sibling.We used 93 overlapping peptides representing the entire DBY protein to detect and characterize T-cell and antibody responses to DBY by enzyme-linked immunosorbent spot (ELISPOT) and enzyme-linked immunosorbent assay.High frequency CD4+ T cells specific for a unique DBY peptide were detected in the patient blood. We isolated the corresponding T-cell clone and characterized the recognized epitope as an 18-mer peptide restricted by human leukocyte antigen-DRB1*0101. Upon stimulation, this clone produced cytokines with no evidence of Th1 or Th2 polarization. Remarkably, this clone also recognized the DBX homologue peptide and responded to female donor dendritic cells stimulated with poly I/C or lipopolysaccharide, indicating that the peptide was endogenously processed in these cells. High titer DBY-specific antibodies were also found in the patient serum which, in contrast to the T-cell response, did not cross-react with DBX.We show here the development of a coordinated B and T-cell response to DBY in a recipient of sex mismatched allogeneic hematopoietic stem-cell transplantation. Our findings support a role for CD4+ T cells in the development of humoral immunity to minor histocompatibility antigens.

  View details for DOI 10.1097/TP.0b013e3182244cc3

  View details for Web of Science ID 000293176300021

  View details for PubMedID 21709606

  View details for PubMedCentralID PMC3263512

• The Outcomes of Family Haploidentical Hematopoietic Stem Cell Transplantation in Hematologic Malignancies Are Not Associated with Patient Age BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Dong, L., Wu, T., Gao, Z., Zhang, M., Kan, F., Spellman, S. R., Tan, X., Zhao, Y., Wang, J., Lu, D., Miklos, D., Petersdorf, E., Fernandez-Vina, M., Lee, S. J. 2011; 17 (8): 1205-1213

  Abstract

  Haploidentical hematopoietic cell transplantation (HCT) has been used to treat hematologic malignancies, but it is unknown whether the procedure is more effective in adults or children. To address this question, we analyzed patients aged 1 to 65 years old receiving myeloablative conditioning regimens followed by family 2 to 3 antigen HLA-mismatched HCT and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR; n = 137) or performed in Dao-Pei Hospital in China, China (n = 181). The Dao-Pei cohort had more acute and chronic graft-versus-host disease (GVHD), less relapse, lower transplant-related mortality (TRM), and better leukemia-free survival (LFS) than the CIBMTR cohort. Overall survival (OS) and outcomes were similar between adults and children. In the CIBMTR cohort receiving ex vivo T cell depletion (TCD), adults had higher TRM (relative risk [RR] 2.71, 95% confidence interval [CI] 1.29-5.69, P = .008) and lower OS (RR 1.75, 95% CI 1.08-2.84, P = .023) than children. In the CIBMTR subset that did not receive ex vivo TCD, relapse was lower in adults compared to children (RR 0.24, 95% CI 0.07-0.80, P = .020), but TRM, LFS, and OS were similar. We conclude that outcomes in adults and children are similar overall, although children have better survival than adults if ex vivo TCD is used.

  View details for DOI 10.1016/j.bbmt.2010.12.703

  View details for Web of Science ID 000293429600013

  View details for PubMedID 21193055

  View details for PubMedCentralID PMC3113644

• B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies NATURE MEDICINE Winer, D. A., Winer, S., Shen, L., Wadia, P. P., Yantha, J., Paltser, G., Tsui, H., Wu, P., Davidson, M. G., Alonso, M. N., Leong, H. X., Glassford, A., Caimol, M., Kenkel, J. A., Tedder, T. F., McLaughlin, T., Miklos, D. B., Dosch, H., Engleman, E. G. 2011; 17 (5): 610-U134

  Abstract

  Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

  View details for DOI 10.1038/nm.2353

  View details for Web of Science ID 000290250400038

  View details for PubMedID 21499269

  View details for PubMedCentralID PMC3270885

• Protein Microarrays Discover Angiotensinogen and PRKRIP1 as Novel Targets for Autoantibodies in Chronic Renal Disease MOLECULAR & CELLULAR PROTEOMICS Butte, A. J., Sigdel, T. K., Wadia, P. P., Miklos, D. B., Sarwal, M. M. 2011; 10 (3)

  Abstract

  Biomarkers for early detection of chronic kidney disease are needed, as millions of patients suffer from chronic diseases predisposing them to kidney failure. Protein microarrays may also hold utility in the discovery of auto-antibodies in other conditions not commonly considered auto-immune diseases. We hypothesized that proteins are released as a consequence of damage at a cellular level during end-organ damage from renal injury, not otherwise recognized as self-antigens, and an adaptive humoral immune response to these proteins might be detected in the blood, as a noninvasive tracker of this injury. The resultant antibodies (Ab) detected in the blood would serve as effective biomarkers for occult renal injury, enabling earlier clinical detection of chronic kidney disease than currently possible, because of the redundancy of the serum creatinine as a biomarker for early kidney injury. To screen for novel autoantibodies in chronic kidney disease, 24 protein microarrays were used to compare serum Ab from patients with chronic kidney disease against matched controls. From a panel of 38 antigens with increased Ab binding, four were validated in 71 individuals, with (n=50) and without (n=21) renal insufficiency. Significant elevations in the titer of novel auto-Ab were noted against angiotensinogen and PRKRIP1 in renal insufficiency. Current validation is underway to evaluate if these auto-Ab can provide means to follow the evolution of chronic kidney disease in patients with early stages of renal insufficiency, and if these rising titers of these auto-Ab correlate with the rate of progression of chronic kidney disease.

  View details for DOI 10.1074/mcp.M110.000497

  View details for Web of Science ID 000287847200001

  View details for PubMedID 21183621

  View details for PubMedCentralID PMC3047141

• 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

• Recombinant antigen microarrays for serum/plasma antibody detection. Methods in molecular biology (Clifton, N.J.) Wadia, P. P., Sahaf, B., Miklos, D. B. 2011; 723: 81-104

  Abstract

  Recombinant antigen arrays represent a new frontier in parallel analysis of multiple immune response profiles requiring only minute blood samples. In this article, we review the benefits and pitfalls of recombinant antigen microarrays developed for multiplexed antibody quantification. In particular, we describe the development of antigen arrays presenting a set of Y chromosome-encoded antigens, called H-Y antigens. These H-Y antigens are immunologically recognized as minor histocompatibility antigens (mHA) following allogeneic blood and organ transplantation. Clinically relevant B-cell responses against H-Y antigens have been demonstrated in male patients receiving female hematopoietic stem cell grafts and are associated with chronic graft versus host development. This chapter discusses our recombinant antigen microarray methods to measure these clinically relevant allo-antibodies.

  View details for DOI 10.1007/978-1-61779-043-0_7

  View details for PubMedID 21370061

• Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors BLOOD Shaw, P. J., Kan, F., Ahn, K. W., Spellman, S. R., Aljurf, M., Ayas, M., Burke, M., Cairo, M. S., Chen, A. R., Davies, S. M., Frangoul, H., Gajewski, J., Gale, R. P., Godder, K., Hale, G. A., Heemskerk, M. B., Horan, J., Kamani, N., Kasow, K. A., Chan, K. W., Lee, S. J., Leung, W. H., Lewis, V. A., Miklos, D., Oudshoorn, M., Petersdorf, E. W., Ringden, O., Sanders, J., Schultz, K. R., Seber, A., Setterholm, M., Wall, D. A., Yu, L., Pulsipher, M. A. 2010; 116 (19): 4007-4015

  Abstract

  Although some trials have allowed matched or single human leukocyte antigen (HLA)-mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.

  View details for DOI 10.1182/blood-2010-01-261958

  View details for Web of Science ID 000284110400040

  View details for PubMedID 20671124

  View details for PubMedCentralID PMC2981549

• H-Y antibody titers are increased in unexplained secondary recurrent miscarriage patients and associated with low male : female ratio in subsequent live births HUMAN REPRODUCTION Nielsen, H. S., Wu, F., Aghai, Z., Steffensen, R., van Halteren, A. G., Spierings, E., Christiansen, O. B., Miklos, D., Goulmy, E. 2010; 25 (11): 2745-2752

  Abstract

  The birth of a boy is significantly more common than a girl prior to secondary recurrent miscarriage (SRM) and is associated with a poorer chance of a subsequent live birth. Children born after SRM are more likely to be girls. High-titer antisera specific for male antigens (H-Y) have been shown to arrest development of male bovine embryos efficiently. We consequently questioned the role of H-Y antibodies in women with SRM.Serum samples from patients with unexplained SRM (n = 84), unexplained primary recurrent miscarriage (PRM) (n = 12) and healthy women (n = 37) were obtained. The samples were taken during pregnancy (gestational weeks 4-5) for 77 (80%) of the patients. Enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies that specifically recognized any of the five recombinant H-Y proteins (EIF1AY, RPS4Y1, ZFY, DDX3Y and UTY) and their H-X homologs.H-Y-specific antibodies were more frequent in SRM patients (46%) compared with female controls (19%, P = 0.004) and PRM patients (8%, P = 0.01). The presence of H-Y antibodies in early pregnancy was associated with a low male: female birth ratio among the subsequent live births, as only 12% of children born to H-Y antibody-positive patients were boys compared with 44% boys born to H-Y antibody negative patients (P = 0.03).The high frequency of H-Y antibody-positive SRM patients and the association between the presence of these antibodies in early pregnancy and the low number of male offspring, suggest that maternal immune responses against H-Y antigens can cause pregnancy losses. Further exploring these mechanisms may increase our understanding of unexplained SRM.

  View details for DOI 10.1093/humrep/deq242

  View details for Web of Science ID 000283124000007

  View details for PubMedID 20823116

• 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

• Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation. Proceedings of the National Academy of Sciences of the United States of America Müller, A. M., Linderman, J. A., Florek, M., Miklos, D., Shizuru, J. A. 2010; 107 (33): 14721-14726

  Abstract

  Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.

  View details for DOI 10.1073/pnas.1009220107

  View details for PubMedID 20679222

  View details for PubMedCentralID PMC2930440

• Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mueller, A. M., Linderman, J. A., Florek, M., Miklos, D., Shizuru, J. A. 2010; 107 (33): 14721-14726

  Abstract

  Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.

  View details for DOI 10.1073/pnas.1009220107

  View details for Web of Science ID 000281287600038

  View details for PubMedCentralID PMC2930440

• 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

• Individual Variation in the Germline Ig Gene Repertoire Inferred from Variable Region Gene Rearrangements JOURNAL OF IMMUNOLOGY Boyd, S. D., Gaeta, B. A., Jackson, K. J., Fire, A. Z., Marshall, E. L., Merker, J. D., Maniar, J. M., Zhang, L. N., Sahaf, B., Jones, C. D., Simen, B. B., Hanczaruk, B., Nguyen, K. D., Nadeau, K. C., Egholm, M., Miklos, D. B., Zehnder, J. L., Collins, A. M. 2010; 184 (12): 6986-6992

  Abstract

  Individual variation in the Ig germline gene repertoire leads to individual differences in the combinatorial diversity of the Ab repertoire, but the study of such variation has been problematic. The application of high-throughput DNA sequencing to the study of rearranged Ig genes now makes this possible. The sequencing of thousands of VDJ rearrangements from an individual, either from genomic DNA or expressed mRNA, should allow their germline IGHV, IGHD, and IGHJ repertoires to be inferred. In addition, where previously mere glimpses of diversity could be gained from sequencing studies, new large data sets should allow the rearrangement frequency of different genes and alleles to be seen with clarity. We analyzed the DNA of 108,210 human IgH chain rearrangements from 12 individuals and determined their individual IGH genotypes. The number of reportedly functional IGHV genes and allelic variants ranged from 45 to 60, principally because of variable levels of gene heterozygosity, and included 14 previously unreported IGHV polymorphisms. New polymorphisms of the IGHD3-16 and IGHJ6 genes were also seen. At heterozygous loci, remarkably different rearrangement frequencies were seen for the various IGHV alleles, and these frequencies were consistent between individuals. The specific alleles that make up an individual's Ig genotype may therefore be critical in shaping the combinatorial repertoire. The extent of genotypic variation between individuals is highlighted by an individual with aplastic anemia who appears to lack six contiguous IGHD genes on both chromosomes. These deletions significantly alter the potential expressed IGH repertoire, and possibly immune function, in this individual.

  View details for DOI 10.4049/jimmunol.1000445

  View details for Web of Science ID 000278516700047

  View details for PubMedID 20495067

• 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

• Antibodies specifically target AML antigen NuSAP1 after allogeneic bone marrow transplantation BLOOD Wadia, P. P., Coram, M., Armstrong, R. J., Mindrinos, M., Butte, A. J., Miklos, D. B. 2010; 115 (10): 2077-2087

  Abstract

  Identifying the targets of immune response after allogeneic hematopoietic cell transplantation (HCT) promises to provide relevant immune therapy candidate proteins. We used protein microarrays to serologically identify nucleolar and spindle-associated protein 1 (NuSAP1) and chromatin assembly factor 1, subunit B (p60; CHAF1b) as targets of new antibody responses that developed after allogeneic HCT. Western blots and enzyme-linked immunosorbent assays (ELISA) validated their post-HCT recognition and enabled ELISA testing of 120 other patients with various malignancies who underwent allo-HCT. CHAF1b-specific antibodies were predominantly detected in patients with acute myeloid leukemia (AML), whereas NuSAP1-specific antibodies were exclusively detected in patients with AML 1 year after transplantation (P < .001). Complete genomic exon sequencing failed to identify a nonsynonymous single nucleotide polymorphism (SNP) for NuSAP1 and CHAF1b between the donor and recipient cells. Expression profiles and reverse transcriptase-polymerase chain reaction (RT-PCR) showed NuSAP1 was predominately expressed in the bone marrow CD34(+)CD90(+) hematopoietic stem cells, leukemic cell lines, and B lymphoblasts compared with other tissues or cells. Thus, NuSAP1 is recognized as an immunogenic antigen in 65% of patients with AML following allogeneic HCT and suggests a tumor antigen role.

  View details for DOI 10.1182/blood-2009-03-211375

  View details for Web of Science ID 000275751300033

  View details for PubMedID 20053754

  View details for PubMedCentralID PMC2837325

• 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

• Identifying compartment-specific non-HLA targets after renal transplantation by integrating transcriptome and "antibodyome'' measures PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Li, L., Wadia, P., Chen, R., Kambham, N., Naesens, M., Sigdel, T. K., Miklos, D. B., Sarwal, M. M., Butte, A. J. 2009; 106 (11): 4148-4153

  Abstract

  We have conducted an integrative genomics analysis of serological responses to non-HLA targets after renal transplantation, with the aim of identifying the tissue specificity and types of immunogenic non-HLA antigenic targets after transplantation. Posttransplant antibody responses were measured by paired comparative analysis of pretransplant and posttransplant serum samples from 18 pediatric renal transplant recipients, measured against 5,056 unique protein targets on the ProtoArray platform. The specificity of antibody responses were measured against gene expression levels specific to the kidney, and 2 other randomly selected organs (heart and pancreas), by integrated genomics, employing the mapping of transcription and ProtoArray platform measures, using AILUN. The likelihood of posttransplant non-HLA targets being recognized preferentially in any of 7 microdissected kidney compartments was also examined. In addition to HLA targets, non-HLA immune responses, including anti-MICA antibodies, were detected against kidney compartment-specific antigens, with highest posttransplant recognition for renal pelvis and cortex specific antigens. The compartment specificity of selected antibodies was confirmed by IHC. In conclusion, this study provides an immunogenic and anatomic roadmap of the most likely non-HLA antigens that can generate serological responses after renal transplantation. Correlation of the most significant non-HLA antibody responses with transplant health and dysfunction are currently underway.

  View details for DOI 10.1073/pnas.0900563106

  View details for Web of Science ID 000264278800020

  View details for PubMedID 19251643

  View details for PubMedCentralID PMC2657434

• B Cells and Transplantation: An Educational Resource Tandem Meeting on Biology of Blood and Marrow Transplantation Small, T. N., Robinson, W. H., Miklos, D. B. ELSEVIER SCIENCE INC. 2009: 104–13

  View details for DOI 10.1016/j.bbmt.2008.10.016

  View details for Web of Science ID 000263034300022

  View details for PubMedID 19147088

  View details for PubMedCentralID PMC2944827

• H-Y antibody development associates with acute rejection in female patients with male kidney transplants TRANSPLANTATION Tan, J. C., Wadia, P. P., Coram, M., Grumet, F. C., Kambham, N., Miller, K., Pereira, S., Vayntrub, T., Miklos, D. B. 2008; 86 (1): 75-81

  Abstract

  Human minor histocompatibility antigens (mHA) and clinically relevant immune responses to them have not been well defined in organ transplantation. We hypothesized that women with male kidney transplants would develop antibodies against H-Y, the mHA encoded on the Y-chromosome, in association with graft rejection.We tested sera from 118 consecutive transplant recipients with kidney biopsies. Antibodies that specifically recognized the recombinant H-Y antigens RPS4Y1 or DDX3Y were detected by IgG enzyme-linked immunosorbent assay and western blotting. Immunogenic epitopes were further identified using overlapping H-Y antigen peptides for both the H-Y proteins.In the 26 female recipients of male kidneys, H-Y antibody development posttransplant (1) was more frequent (46%) than in other gender combinations (P<0.001), (2) showed strong correlation with acute rejection (P=0.00048), (3) correlated with plasma cell infiltrates in biopsied kidneys (P=0.04), and (4) did not correlate with C4d deposition or donor-specific anti-human leukocyte antigen (HLA) antibodies. Of the two H-Y antigens, RPS4Y1 was more frequently recognized (P=0.005).This first demonstration of a strong association between H-Y antibody development and acute rejection in kidney transplant recipients shows that in solid organ allografts, humoral immune responses against well defined mHA have clear clinical correlates, can be easily monitored, and warrant study for possible effects on long-term graft function.

  View details for DOI 10.1097/TP.0b013e31817352b9

  View details for Web of Science ID 000257790400014

  View details for PubMedID 18622281

  View details for PubMedCentralID PMC2943873

• Renal pathology in hematopoietic cell transplantation recipients 96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Troxell, M. L., Pilapil, M., Miklos, D. B., Higgins, J. P., Kambham, N. NATURE PUBLISHING GROUP. 2008: 396–406

  Abstract

  Hematopoietic cell transplantation-associated renal injury may be related to a combination of factors including chemotherapy, radiation, infection, immunosuppressive agents, ischemia, and graft-versus-host disease. Renal biopsy specimens from hematopoietic cell transplant recipients at two institutions (Stanford University Medical Center and Oregon Health & Science University) were reviewed in correlation with clinical data. Fifteen cases were identified (post hematopoietic cell transplant time 0.7-14.5 years), including six with autologous hematopoietic cell transplant. Indications for renal biopsy included proteinuria (n=13; nephrotic range in 8), increased serum creatinine (n=10), or both (n=6). Many patients had multiple pathologic findings on renal biopsy. Membranous glomerulonephritis was the most common diagnosis (n=7), including two patients with autologous hematopoietic cell transplant and five with evidence of chronic graft-versus-host disease elsewhere. Four membranous glomerulonephritis patients achieved sustained remission with rituximab therapy. Other glomerular pathology included focal segmental glomerulosclerosis (n=1) and minimal change disease (n=1). Evidence of thrombotic microangiopathy was common (in isolation or combined with other pathology), as was acute tubular necrosis and tubulointerstitial nephritis. Of 14 patients with follow-up (2-64 months, mean 19 months), 6 had chronic renal insufficiency (serum creatinine >1.5 mg/dl), 2 had end stage renal disease, and 6 had essentially normal renal function. Our retrospective study shows that renal dysfunction in hematopoietic cell transplant recipients is often multifactorial, and biopsy may reveal treatable causes. Membranous glomerulonephritis is seen in autologous and allogeneic hematopoietic cell transplant recipients, and may respond to anti-B-cell therapy, which has implications regarding pathogenesis and relationship to graft-versus-host disease.

  View details for DOI 10.1038/modpathol.3801011

  View details for PubMedID 18223556

• Rituximab for steroid-refractory chronic graft-versus-host disease Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-International-Blood-and-Marrow-Transplant-Research Cutler, C., Miklos, D., Kim, H. T., Treister, N., Woo, S., Bienfang, D., Klickstein, L. B., Levin, J., Miller, K., Reynolds, C., Macdonell, R., Pasek, M., Lee, S. J., Ho, V., Soiffer, R., Antin, J. H., Ritz, J., Alyea, E. AMER SOC HEMATOLOGY. 2006: 756–62

  Abstract

  B cells may be implicated in the pathophysiology of chronic graft-versus-host disease (GVHD), as evidenced by antibody production against sex-mismatched, Y chromosome-encoded minor HLA antigens in association with chronic GVHD. We therefore designed a phase 1/2 study of anti-B-cell therapy with rituximab in steroid-refractory chronic GVHD. Twenty-one patients were treated with 38 cycles of rituximab. Rituximab was tolerated well, and toxicity was limited to infectious events. The clinical response rate was 70%, including 2 patients with complete responses. Responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy. The median dose of prednisone among treated subjects fell from 40 mg/day to 10 mg/day, 1 year after rituximab therapy (P < .001). A chronic GVHD symptom score improved in the majority of treated patients. Antibody titers against Y chromosome-encoded minor HLA antigens fell and remained low, whereas titers against infectious antigens (EBV, tetanus) remained stable or rose during the treatment period. We conclude that specific anti-B-cell therapy with rituximab may be beneficial for patients with steroidrefractory chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00136396.

  View details for DOI 10.1182/blood-2006-01-0233

  View details for Web of Science ID 000239129500057

  View details for PubMedID 16551963

  View details for PubMedCentralID PMC1895490

• Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker working group report BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Schultz, K. R., Miklos, D. B., Fowler, D., Cooke, K., Shizuru, J., Zorn, E., Holler, E., Ferrara, Y., Shulman, H., Lee, S. Y., Martin, P., Filipovich, A. H., Flowers, M. E., Weisdorf, D., Couriel, D., Lachenbruch, P. A., Mittleman, B., Vogelsang, G. B., Pavletic, S. Z. 2006; 12 (2): 126-137

  Abstract

  Biology-based markers that can be used to confirm the diagnosis of chronic graft-versus-host disease (GVHD) or monitor progression of the disease could help in the evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biologic or pathogenic process, a pharmacologic response to a therapeutic intervention, or a surrogate end point intended to substitute for a clinical end point. The following applications of biomarkers could be useful in chronic GVHD clinical trials or management: (1) predicting response to therapy; (2) measuring disease activity and distinguishing irreversible damage from continued disease activity; (3) predicting the risk of developing chronic GVHD; (4) diagnosing chronic GVHD: (5) predicting the prognosis of chronic GVHD; (6) evaluating the balance between GVHD and graft-versus-leukemia effects (graft-versus-leukemia or GVT); and (7) serving as a surrogate end point for therapeutic response. Such biomarkers can be identified by either hypothesis-driven testing or by high-throughput discovery-based methods. To date, no validated biomarkers have been established for chronic GVHD, although several candidate biomarkers have been identified from limited hypothesis-driven studies. Both approaches have merit and should be pursued. The consistent treatment and standardized documentation needed to support biomarker studies are most likely to be satisfied in prospective clinical trials.

  View details for DOI 10.1016/j.bbmt.2005.11.010

  View details for Web of Science ID 000235284900002

  View details for PubMedID 16443511

• Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors 44th Annual Meeting of the American-Society-of-Hematology Miklos, D. B., Kim, H. T., Zorn, E., Hochberg, E. P., Guo, L. X., Mattes-Ritz, A., Viatte, S., Soiffer, R. J., Antin, J. H., Ritz, J. AMER SOC HEMATOLOGY. 2004: 353–59

  Abstract

  Minor histocompatibility antigens (mHAs) recognized by donor T cells play a central role as immunologic targets of graft-versus-host disease (GVHD) and graft versus leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Men who have undergone sex-mismatched allogeneic HSCT are at high risk for GVHD because of immune responses directed against mHAs encoded by genes on the Y chromosome (termed H-Y antigens). We hypothesized that the immunogenicity of mHAs results in a coordinated response involving B cells as well as T cells. To test this, we measured antibody responses to a well-characterized H-Y antigen, dead box RNA helicase Y (DBY), and its homolog, DBX, in 150 HSCT patients. Using Western blot and enzyme-linked immunosorbent assay (ELISA), we found that 50% of male patients who received stem cell grafts from female donors developed antibody responses to recombinant DBY protein. Antibodies to DBY were also detected in 17% of healthy women, but not in healthy men. Antibody responses were directed primarily against areas of amino acid disparity between DBY and DBX. These studies demonstrate that the immune response to mHA includes the generation of specific antibodies and suggests that the serologic response to these antigens may also be useful in the identification of new mHAs.

  View details for DOI 10.1182/blood-2003-03-0984

  View details for Web of Science ID 000187573000060

  View details for PubMedID 14512314