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Allogeneic Blood or Marrow Transplantation with Post-transplantation Cyclophosphamide for Peripheral T-cell Lymphoma: The Importance of Graft Source
Sterling, C. H., Hughes, M. S., Tsai, H. L., Yarkony, K., Fuchs, E. J., Swinnen, L. J., Paul, S., Bolaños-Meade, J., Luznik, L., Imus, P. H., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T-cell lymphoma (PTCL). OBJECTIVES We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. STUDY DESIGN We reviewed the charts of all adult patients aged 18 years or older who underwent alloBMT with non-myeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. RESULTS Sixty-five patients were identified. The median age was 59 years (range, 24-75 years). Lymphoma histology included PTCL-not otherwise specified (n=24), ALK-negative anaplastic large cell lymphoma (n=14), angioimmunoblastic T-cell lymphoma (n=7), enteropathy-associated T-cell lymphoma (n=6), hepatosplenic T-cell lymphoma (n=4), and other (n=10). Eleven patients were in first complete remission (CR1, 17%). The remaining patients were in first partial remission (PR1) or underwent salvage therapy to at least PR prior to transplant. Forty-eight patients received an alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (mMUD, 11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most in the PB cohort (15/19) received 400 cGy TBI. GVHD prophylaxis was PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow up of 2.8 years (range, 290 days-14.2 years), the 2-year PFS for the entire cohort was 49% (95% confidence interval [CI] 38-64%), and the 2-year OS was 55% (95% CI 44-69%). Outcomes were significantly improved in those receiving PB compared to BM, including 2-year PFS of 79% (95% CI 63-100%) vs. 39% (95% CI 27-56%), 2-year OS of 84% (95% CI 69-100%) vs. 46% (95% CI 33-63%), and 1-year cumulative incidence of (CuI) relapse of 5% (95% CI 0-16%) vs. 33% (95% CI 19-46%), with no difference in GVHD or non-relapse mortality (NRM). CONCLUSIONS AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest increasing TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.
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Autologous stem cell transplantation in an older adult population
Fedorov, K., Jain, T., Pradhan, K., Mustafa, J., Lombardo, A., Khatun, F., Joseph, F., Gillick, K., Naik, A., Elkind, R., et al
Haematologica. 2022
Abstract
Not available.
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Allogeneic Blood or Marrow Transplantation with High-Dose Post-transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Aged ≥55
Webster, J. A., Reed, M., Tsai, H. L., Ambinder, A., Jain, T., Dezern, A. E., Levis, M. J., Showel, M. M., Prince, G. T., Hourigan, C. S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Patients ≥55 years-old with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy with 5-year overall survival of ∼20%. Tyrosine kinase inhibitors and novel B-cell targeted therapies improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (AlloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplants with low rates of non-relapse mortality (NRM) and graft-versus-host disease (GVHD). METHODS The transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received alloBMT for ALL using PTCy. FINDINGS The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% CI 34-57) and 49% (95% CI 37-60). Grade 3-4 acute GVHD occurred in only 3% of patients and chronic GVHD in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (HR 4.65, p=0.001); while transplant in CR1 (HR 0.30, p=0.004), and transplant for Ph+ ALL vs. T ALL (HR 0.29, p=0.03) improved RFS. Of the 54 patients who received RIC alloBMT in CR1 for B ALL, 5-year RFS and OS were 62% (95% CI 47-74) and 65% (95% CI 51-77), respectively, with a 5-year relapse incidence of 16% (95% CI 7-27) and NRM of 24% (95% CI 13-36). INTERPRETATION RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. FUNDING NIH grants P01 CA225618 and P30 CA06973.
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Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience
Ambinder, A., Smith, M., Tsai, H. L., Varadhan, R., DeZern, A., Dalton, W., Gocke, C., Webster, J., Gondek, L., Gojo, I., et al
Clinical lymphoma, myeloma & leukemia. 2021
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Abstract
INTRODUCTION Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. PATIENTS AND METHODS In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. RESULTS Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). CONCLUSION Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).
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Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report
Zhou, Z., Nath, R., Cerny, J., Wang, H. L., Zhang, M. J., Abdel-Azim, H., Agrawal, V., Ahmed, G., Al-Homsi, A. S., Aljurf, M., et al
Blood advances. 2020;4(13):3180-3190
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Editor's Choice
Abstract
There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
PICO Summary
Population
Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 (n=1413)
Intervention
Fludarabine/busulfan reduced intensity conditioning regimen (FB, n=791)
Comparison
Fludarabine/melphalan reduced intensity conditioning regimen (FM, n=622)
Outcome
Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82), but was marginally superior beyond 3 months (HR = 0.87). LFS was better with FM compared with FB (HR = 0.89). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85). Long-term relapse was lower with FM (HR = 0.65). Analysis restricted to patients with CR showed comparable results.
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Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy
Dholaria, B., Savani, B. N., Hamilton, B. K., Oran, B., Liu, H. D., Tallman, M. S., Ciurea, S. O., Holtzman, N. G., Ii, G. L. P., Devine, S. M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consistent of both transplant and non-transplant experts was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.
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Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Webster, J. A., Luznik, L., Tsai, H. L., Imus, P. H., DeZern, A. E., Pratz, K. W., Levis, M. J., Gojo, I., Showel, M. M., Prince, G., et al
Blood advances. 2020;4(20):5078-5088
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Editor's Choice
Abstract
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
PICO Summary
Population
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Intervention
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Comparison
Patients in second or subsequent remission (CR2+, n=12)
Outcome
For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%.
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Does early chimerism testing predict outcomes after allogeneic hematopoietic stem cell transplantation?
Mountjoy, L., Palmer, J., Kunze, K. L., Khera, N., Sproat, L. Z., Leis, J. F., Noel, P., Slack, J. L., Jain, T.
Leukemia & lymphoma. 2020;:1-3
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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
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., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Axicabtagene ciloleucel (YESCARTA(R), Kite Pharma, a Gilead Company) and tisagenlecleucel (KYMRIAH(R), 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.
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Rituximab Maintenance Therapy for Mantle Cell Lymphoma: A Systematic Review and Meta-Analysis
Hilal, T., Wang, Z., Almader-Douglas, D., Rosenthal, A., Reeder, C. B., Jain, T.
American journal of hematology. 2018
Abstract
Mantle cell lymphoma is characterized by relapse and progressive disease, despite initial response to chemoimmunotherapy. We conducted a systematic review and meta-analysis to determine the efficacy of rituximab maintenance (RM) therapy in patients with mantle cell lymphoma. We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from database inception through November 1st 2017. Only full-text articles were included. Prespecified data elements were extracted from each trial. Outcomes of interest included progression-free survival (PFS) and overall survival (OS). The overall effect was pooled using the DerSimonian-Laird random effects model. Three randomized controlled trials and four observational studies met our inclusion criteria and were identified in the analyses. Six studies compared RM therapy to observation, and one compared RM therapy to interferon alfa. Meta-analysis evaluating outcomes of patients treated after ASCT revealed that RM improved for both PFS (HR = 0.33, 95% CI = 0.23 to 0.49) and OS (HR of death = 0.35, 95% CI = 0.17 to 0.69). A second meta-analysis of studies evaluating outcomes of patients who are ASCT-ineligible treated with anthracycline-based induction therapy revealed that RM improved PFS (HR = 0.38, 95% CI = 0.25 to 0.58). There is a paucity of data on the role of RM in ASCT-ineligible patients and those with relapsed disease. Overall, RM therapy appears to improve PFS and OS in previously untreated patients with mantle cell lymphoma who undergo induction chemoimmunotherapy followed by ASCT. This article is protected by copyright. All rights reserved.