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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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Autologous hematopoietic cell transplantation versus whole-brain radiotherapy consolidation in primary central nervous system lymphoma: A systematic review and meta-analysis
Epperla, N., Reljic, T., Chowdhury, S. M., Ferreri, A. J. M., Kumar, A., Hamadani, M.
Hematological oncology. 2022
Abstract
The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I(2) = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I(2) = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.
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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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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, 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.
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Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome: A systematic review and meta-analysis
Aulakh, S., Reljic, T., Yassine, F., Ayala, E., Chavez, J. C., Chanan-Khan, A., Pinilla-Ibarz, J., Kumar, A., Kharfan-Dabaja, M. A.
Hematology/oncology and stem cell therapy. 2020
Abstract
Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n=72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.
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Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Waldenstrom Macroglobulinemia: A Systematic Review and Meta-analysis
Parrondo, R. D., Reljic, T., Iqbal, M., Ayala, E., Tun, H. W., Kharfan-Dabaja, M. A., Kumar, A., Murthy, H. S.
Clinical lymphoma, myeloma & leukemia. 2020
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Editor's Choice
Abstract
INTRODUCTION Waldenstrom macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies. MATERIALS AND METHODS We performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis. RESULTS Pooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively. CONCLUSIONS Our results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.
PICO Summary
Population
Systematic review of studies of Waldenstrom macroglobulinemia (WM) patients undergoing transplantation (15 studies, 589 patients)
Intervention
Autologous transplant (AHCT) (8 studies, 278 patients)
Comparison
Allogeneic transplant (allo-HCT) (7 studies, 311 patients)
Outcome
Pooled overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76%, 55%, and 4% respectively. Pooled OS, PFS, and NRM rates post allografting were 57%, 49%, and 29%, respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% and 81%, respectively. Pooled complete response rates post AHCT and allo-HCT were 22% and 26%, respectively. Relapse rates post AHCT and allo-HCT were 42% and 23%, respectively.
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Upfront autologous hematopoietic stem cell transplantation consolidation for patients with aggressive B-cell lymphomas in first remission in the rituximab era: A systematic review and meta-analysis
Epperla, N., Hamadani, M., Reljic, T., Kharfan-Dabaja, M. A., Savani, B. N., Kumar, A.
Cancer. 2019
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Editor's Choice
Abstract
BACKGROUND The outcomes for patients with diffuse large B-cell lymphoma (DLBCL) with adverse clinical prognostic factors such as a high age-adjusted International Prognostic Index (aaIPI) are not optimal. In the current study, the authors performed a systematic review and meta-analysis to assess the totality of evidence pertaining to the efficacy of autologous hematopoietic stem cell transplantation (auto-HCT) consolidation for patients with DLBCL in first remission. METHODS The authors searched the Cochrane and MEDLINE/PubMed databases through December 1, 2018, for studies comparing conventional chemotherapy with rituximab (R-chemo) versus R-chemo and auto-HCT. Two authors independently reviewed all references for study inclusion and extracted data related to benefits (overall survival, progression-free survival, and response rates) and harms (treatment-related mortality and adverse events). RESULTS Four studies (1173 patients) met the inclusion criteria and were included in the current analysis. The median duration of follow-up ranged from 42 to 76 months. There was no difference noted with regard to the overall survival (hazard ratio, 1.01; 95% CI, 0.74-1.37), progression-free survival (hazard ratio, 0.77; 95% CI, 0.58-1.04), or response rates (risk ratio, 0.98; 95% CI, 0.92-1.04) between patients who received R-chemo and auto-HCT and those who received R-chemo alone. The risk of mortality and therapy failure was not found to be different when the analysis was limited to high aaIPI between the 2 groups. Although there was no difference noted with regard to the risk of treatment-related mortality, there was a significantly higher incidence of CTCAE grade 3 or 4 adverse events in patients who received R-chemo and auto-HCT compared with patients treated with R-chemo alone. CONCLUSIONS The findings from what to the authors' knowledge is the first meta-analysis performed in the rituximab era demonstrated no beneficial effect of upfront auto-HCT consolidation in patients with aggressive B-cell non-Hodgkin lymphoma, including high-risk clinical groups (high aaIPI).
PICO Summary
Population
Patients with diffuse large B-cell lymphoma (4 studies, 1173 pts)
Intervention
Chemotherapy with rituximab + autologous stem cell transplantation. (R-chemo and auto-HCT)
Comparison
Chemotherapy with rituximab (R-chemo)
Outcome
There was no difference noted with regard to the overall survival, progression-free survival, or response rates between patients who received R-chemo and auto-HCT and those who received R-chemo alone. The risk of mortality and therapy failure was not found to be different when the analysis was limited to high aaIPI between the 2 groups. Although there was no difference noted with regard to the risk of treatment-related mortality, there was a significantly higher incidence of CTCAE grade 3 or 4 adverse events in patients who received R-chemo and auto-HCT compared with patients treated with R-chemo alone.
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Efficacy of allogeneic hematopoietic cell transplantation in cutaneous T-cell lymphoma: results of a systematic review/meta-analysis
Iqbal, M., Reljic, T., Ayala, E., Sher, T., Murthy, H., Roy, V., Foran, J., Tun, H., Kumar, A., Kharfan-Dabaja, M. A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
INTRODUCTION Mycosis Fungoides (MF) and Sezary Syndrome (SS) are the most common types of primary cutaneous T cell lymphomas (CTCL). The clinical presentation of MF is generally indolent whereas SS represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early stage disease, those who develop progressive disease or have an advance stage represent a therapeutic challenge due to lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. There remains however a lack of randomized controlled data and the published literature is limited to mostly retrospective studies. METHODS We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and non-relapse mortality [NRM]) independently by two authors. Our search strategy identified a total of 289 references. Five studies (n= 266 patients) were included in this systematic review and the meta-analysis. RESULTS Reduced intensity (RIC) and non-myeloablative (NMA) regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells (PBSC) were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95%CI=50-69%) and 36% (95%CI=27-45%), respectively. Pooled relapse rate was 47% (95%CI=41-53%) and pooled NRM rate was 19% (95%CI=13-27%). CONCLUSIONS Results of this systematic review/meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT prior to development of resistant disease, and reducing relapse by incorporating post-transplant maintenance therapies.
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Efficacy of allogeneic HCT in HTLV-1 associated adult T-cell leukemia/lymphoma: results of a systematic review/meta-analysis
Iqbal, M., Reljic, T., Klocksieben, F., Sher, T., Ayala, E., Murthy, H., Bazarbachi, A., Kumar, A., Kharfan-Dabaja, M. A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
INTRODUCTION HTLV-1 associated adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disorder associated with the Human T-cell Lymphotropic Virus Type-1 (HTLV1). Intensive conventional chemotherapy regimens and autologous hematopoietic cell transplantation (auto-HCT) have failed to improve outcomes in ATLL. Allogeneic HCT (allo-HCT) is commonly offered as front-line consolidation despite lack of randomized controlled studies (RCT). METHODS We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane reviews on September 10, 2018. We extracted data on clinical outcomes related to benefits (complete response [CR], overall [OS] and progression-free [PFS] survival) and harms (relapse and non-relapse mortality [NRM]), independently by two authors. Our search strategy identified a total of 801 references. Nineteen studies (n= 2446 patients) were included in the systematic review; however, only 18 studies (n=1767 patients) were included in the meta-analysis. RESULTS Reduced intensity conditioning (RIC) regimens were more commonly prescribed (52%). Bone marrow (50%) and peripheral blood (40%) were more frequently used as stem cell source. The pooled post-allografting CR, OS, and PFS rates were 73% (95%CI=57-87%), 40 % (95%CI=33-46%), and 37% (95%CI=27-48%), respectively. Pooled relapse and NRM rates were 36% (95%CI=28-43%) and 29% (95%CI=21-37%), respectively. The heterogeneity among the included studies was generally high. CONCLUSIONS These results support the use of allo-HCT as an effective treatment for patients with ATLL, yielding pooled OS rates of 40%, but relapse still occurs in over one-third of cases. Future studies should evaluate strategies to help reduce relapse in patients with ATLL undergoing allo-HCT.