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ASTCT Clinical practice recommendations for transplant and cellular therapies in diffuse large B-cell lymphoma
Epperla, N., Kumar, A., Abutalib, S. A., Awan, F. T., Chen, Y. B., Gopal, A. K., Holter-Chakrabarty, J., Kekre, N., Lee, C. J., Lekakis, L., et al
Transplantation and cellular therapy. 2023
Abstract
Autologous hematopoietic cell transplantation (auto-HCT) has long remained the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B-cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T-cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR T-cell therapy in the second line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking. Therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with a few key statements as follows: 1) in the first-line setting, there is no role of auto-HCT consolidation for those achieving complete remission (CR) following R-CHOP or similar therapy in non-double hit/triple hit cases (DHL/THL) and in DHL/THL cases receiving intensive induction therapies, but auto-HCT may be considered in eligible patients receiving R-CHOP or similar therapies in DHL/THL cases. 2) Auto-HCT consolidation with thiotepa-based conditioning is standard-of-care for eligible patients with primary central nervous system achieving CR with first-line therapy. 3) In the primary refractory and early relapse setting, the preferred option is CAR T-cell therapy, while in late relapse (>12 months), consolidation with auto-HCT is recommended in those achieving chemosensitivity to salvage therapy (CR or partial response), and CAR T-cell therapy is recommended in those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.
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Long-Term Outcomes and Safety Trends of Autologous Stem-Cell Transplantation in Non-Hodgkin Lymphoma: A Report From A Tertiary Care Center in India
Kumar, S., Sharma, A., Pramanik, R., Pathak, N., Gogia, A., Kumar, A., Kayal, S., Sharma, V., Sahoo, R. K., Thulkar, S., et al
JCO global oncology. 2022;8:e2100383
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Abstract
PURPOSE Published experience with autologous stem-cell transplantation (ASCT) in non-Hodgkin lymphoma (NHL) from the Indian subcontinent is extremely limited. Here, we describe the activity and outcomes of this treatment modality at a large tertiary care center in India. PATIENTS AND METHODS We retrospectively analyzed adult patients with NHL who were eligible for ASCT and autografted between January 1, 2002, and December 15, 2020, at our transplant unit. Toxicities, complications, and long-term outcomes were compared between patients who underwent transplant during 2002-2012 (group A) and 2013-2020 (group B). RESULTS Overall, 80 patients (group A, n = 37; group B, n = 43) underwent ASCT using peripheral blood stem cells. At a median follow-up of 57.6 months, the 5-year event-free survival (EFS) and overall survival (OS) were 43.5% and 47.6%, respectively, for all patients. More recently (group B), patients had reduced 100-day transplant-related mortality (2.3% v 21.6%, P < .01), improved 3-year EFS (52.9% v 37.3%, P = .04), and superior OS (at 3-year; 63.4% v 43.2%, P = .02). Patients in group B also tolerated the procedure better, with improved resource utilization. In multivariate analysis, an International Prognostic Index (IPI) ≥ 3 at diagnosis adversely affected EFS (hazard ratio [HR] = 2.82, P = .009) and OS (HR = 2.84, P = .01) after ASCT. Low pretransplant serum albumin levels were associated with inferior EFS (HR = 2.68, P = .02) and transplant-related mortality (odds ratio = 10.80, P = .02) after ASCT. CONCLUSION It is feasible to achieve comparable short- and long-term outcomes in patients with NHL undergoing ASCT in a resource-poor country with improved supportive care and expertise of the transplant team and center.
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Efficacy of a second allogeneic hematopoietic cell transplant in relapsed acute myeloid leukemia: results of a systematic review and meta-analysis
Kharfan-Dabaja, M. A., Reljic, T., Yassine, F., Nishihori, T., Kumar, A., Tawk, M. M., Keller, K., Ayala, E., Savani, B., Mohty, M., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known treatment modality that can offer the possibility of cure for acute myeloid leukemia (AML). Unfortunately, relapse and/or disease progression still occurs in over one-third of cases even when patients are allografted in complete hematologic remission (CR). Treatment of AML relapsing after a first allo-HCT is particularly challenging. A second allo-HCT is offered to patients considered fit for the procedure, but reported outcomes have been conflicting. OBJECTIVES To perform a systematic review and meta-analysis to assess the totality of evidence on the role of a second allo-HCT in patients with AML. STUDY DESIGN AND METHODS We performed a comprehensive literature search using PUBMED/MEDLINE and EMBASE on August 25, 2021 and extracted clinical outcome data relating to benefits (CR, overall survival [OS], and progression-free/disease-survival [PFS/DFS]) and harms (acute and chronic graft-versus-host disease [GVHD], non-relapse mortality [NRM] and relapse). RESULTS The search identified 821 studies. Only 20 studies (n= 2,772 patients) met our inclusion criteria. A second allo-HCT resulted in pooled CR, OS, PFS/DFS, NRM and relapse rates of 67%, 34%, 30%, 27%, and 51%, respectively. OS was 2-fold higher when the second allo-HCT was performed in CR (38% vs. 17%) and 3-fold higher in patients who had a later relapse from the first allo-HCT (34% vs. 10%). There was no apparent difference in pooled OS (HR=1.01 (95%CI=0.78-1.31), p=0.94) whether the same original donor or a different one was used. CONCLUSION Notwithstanding several limitations apart from the high heterogeneity among included studies, this analysis shows that a second allo-HCT is a reasonable treatment option for relapsed AML. The procedure appears to be more effective when performed in CR and in patients who had a later relapse from the first allo-HCT. The high pooled relapse rates exceeding 50%, even when receiving the second allo-HCT in CR is worrisome and emphasizes the need to incorporate new therapies whether as post-transplant maintenance or consolidation, to mitigate relapse risk. This analysis was limited to patients receiving a second allo-HCT for the sole purpose of treating AML relapse. Accordingly, we caution against extrapolating these findings to other indications such as treatment of graft failure, poor graft function or mixed donor chimerism.
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Outcomes Following Intolerance to Tacrolimus/Sirolimus Graft-Versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation
Mirza, A. S., Tandon, A., Jenneman, D., Cao, S., Brimer, T., Kumar, A., Kidd, M., Khimani, F., Faramand, R., Mishra, A., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic cell transplant (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. OBJECTIVES To assess outcomes of patients with TAC/SIR intolerance and guide subsequent management after intolerance. STUDY DESIGN We retrospectively analyzed transplant outcomes of consecutive adult patients at Moffitt Cancer Center who received allogeneic HCT with TAC/SIR as GVHD prophylaxis from 2009 to 2018. TAC/SIR intolerance was defined as discontinuation due to toxicity of either TAC or SIR before post-transplant day 100. RESULTS 777 patients met the inclusion criteria. Median follow-up was 22 (0.2-125) months. Intolerance occurred in 13% (n = 104) of patients at a median of 30 (range 5-90) days. The most common causes of intolerance were acute kidney injury (n = 53 [51%]), thrombotic microangiopathy (n = 31 [28%]), and veno-occlusive disease (n = 23 [22%]). The cumulative incidence of grade 2 to 4 acute GVHD at 100 days in TAC/SIR-intolerant patients was 50% (95% CI, 39%-64%) and 25% (95% CI, 22%-29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, grade 2 to 4 acute GVHD was significantly higher in TAC/SIR-intolerant patients (HR 2.40; 95% CI, 1.59-3.61; P < .0001). Similarly, in multivariate analyses, TAC/SIR-intolerant patients had more chronic GVHD (HR 1.48, 95% CI, 1.03-2.12; P = .03). The non-relapse mortality (NRM) at 1 year in TAC/SIR-intolerant patients was 47% (95% CI, 38%-59%) and 12% (95% CI, 10%-15%) in those tolerant to the regimen (P < .0001). The 2-year relapse free survival of TAC/SIR-intolerant patients was 35% (95% CI, 25%-44%) and 60% (95% CI, 57%-65%) among TAC/SIR-tolerant patients, (HR 2.30; 95% CI, 1.61-3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31-100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early [95% CI, 59%-94%]) versus 33% ([late] 95% CI, 21%-50%) (P = .001) as well as the cumulative incidence of NRM at 61% ([early] 95% CI, 48%-77%) versus 35% ([late] 95% CI, 24%-51%) (P = .006). After developing TAC/SIR intolerance, most patients were switched to an alternative 2-drug regimen (71/104 [68%]), with the most common being mycophenolate mofetil in addition to continuing TAC or SIR (68/71 [96%]). CONCLUSIONS Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. Single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.
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ASTCT Committee on Practice Guidelines Survey on Evaluation & Management of Diffuse Large B-cell Lymphoma after failure of Chimeric antigen receptor T cell therapy (CAR-T) therapy
Ahmed, N., Kumar, A., Kharfan-Dabaja, M. A., DeFilipp, Z., Herrera, A., Hashmi, S., Dholaria, B., Perales, M. A., Carpenter, P. A., Hamadani, M.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Chimeric antigen receptor T cell therapy (CAR-T) is a major advance in managing aggressive relapsed and/or refractory B-cell lymphomas; however, relapses are frequent and pose a major therapeutic challenge. There is substantial variability across transplant and cellular therapy programs in assessing and managing post-CAR-T failures. METHODS The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between August 2021 and October 2021, to determine the U.S. lymphoma and transplant and cellular therapy physicians' practice patterns for the detection and diagnosis of CAR-T failure, and management strategies for diffuse large B cell lymphoma (DLBCL) in this particular setting. RESULTS Email surveys were sent to 901 potential participants, of which 174 (19%) completed the survey. Responders were mainly White (51.2%), male (70.7%), and with >10 years of practice experience (51.2%). 87% of the responders were affiliated with university/teaching centers; 54.6% had general oncology practices and 45.4% had lymphoma-focused transplant/cellular therapy practices. The most common periods to perform surveillance scans were at 3 months and 12 months after CAR-T infusion. 88.5% of responders would often or always consider a biopsy to confirm relapse and 89% would routinely check for the persistence of the antigen targeted by the CAR (e.g. CD19 in the case of CD19 CAR-T). The most popular first salvage regimen for relapse or progression was an alternate CAR-T therapy (dual or alternate target) regardless of CD19 positivity. 27% of responders chose this regimen for CD19 positive relapse, while 31% of responders did so for CD19 negative relapse. 88.5% of responders favored consolidative allogeneic hematopoietic cell transplantation (alloHCT) after response to salvage, whereas 51.2% of physicians would consider autologous hematopoietic cell transplant (AHCT) in transplant naïve patients. CONCLUSIONS There is substantial cross-center variation in surveillance, diagnosis, and management of CAR-T failure. Prospective clinical trials evaluating novel agents in this setting are urgently needed to identify best management strategies.
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ASTCT Clinical Practice recommendations for transplant and cellular therapies in multiple myeloma
Dhakal, B., Shah, N., Kansagra, A., Kumar, A., Lonial, S., Garfall, A., Cowan, A., Poudyal, B. S., Costello, C., Gay, F., et al
Transplantation and cellular therapy. 2022
Abstract
Over the past decade, therapeutic options in multiple myeloma (MM) have changed dramatically. Given the unprecedented efficacy of novel agents, the role of hematopoietic cell transplantation (HCT) in MM remains under scrutiny. Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape. The American Society for Transplantation and Cellular Therapy (ASTCT) convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of autologous (auto-HCT), allogeneic (allo-HCT) and CAR T-cell therapy for patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). The RAND-modified Delphi method was used to generate consensus statements. Twenty consensus statements were generated. The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial. For patients not undergoing auto-HCT upfront, the panel recommended its use in first relapse. Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients. In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy. The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial. The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.
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Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma
Moskowitz, A. J., Shah, G., Schöder, H., Ganesan, N., Drill, E., Hancock, H., Davey, T., Perez, L., Ryu, S., Sohail, S., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;39(28):3109-3117
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Abstract
PURPOSE We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550). METHODS Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m(2) IV, days 1 and 8), vinorelbine (20 mg/m(2) IV, days 1 and 8), and liposomal doxorubicin (15 mg/m(2), days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT. RESULTS Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months). CONCLUSION Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.
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Systematic Review/Meta-Analysis on Efficacy of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium
Iqbal, M., Reljic, T., Corbacioglu, S., de la Fuente, J., Gluckman, E., Kumar, A., Yassine, F., Ayala, E., El-Jawahri, A., Murthy, H., et al
Transplantation and cellular therapy. 2021;27(2):167.e1-167.e12
Abstract
Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.
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Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD
Arnold, D. E., Nofal, R., Wakefield, C., Lehmberg, K., Wustrau, K., Albert, M. H., Morris, E. C., Heimall, J. R., Bunin, N. J., Kumar, A., et al
Journal of clinical immunology. 2021;:1-10
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n?=?30, 75%) and HLA-mismatched (n?=?10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p?=?0.01) and 8.2 (CI 2.1-32.7, p?0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.
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ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma
Munshi, P. N., Hamadani, M., Kumar, A., Dreger, P., Friedberg, J. W., Dreyling, M., Kahl, B., Jerkeman, M., Kharfan-Dabaja, M. A., Locke, F. L., et al
Bone marrow transplantation. 2021
Abstract
Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.