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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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Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma
Rath, C., Yoo, C., Cheplowitz, H., Lo, M., Young, R., Guglielmo, J., Saunders, I. M., Banerjee, R., Young, R., Kumar, A., et al
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552221150935
Abstract
BACKGROUND For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. OBJECTIVES The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. STUDY DESIGN This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. RESULTS Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30-77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3-8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5-25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. CONCLUSION This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance.
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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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4.
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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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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Efficacy of allogeneic hematopoietic cell transplantation in patients with chronic phase CML resistant or intolerant to tyrosine kinase inhibitors
Yassine, F., Reljic, T., Moustafa, M. A., Iqbal, M., Murthy, H. S., Kumar, A., Kharfan-Dabaja, M. A.
Hematology/oncology and stem cell therapy. 2021
Abstract
Approximately 15-20% of chronic myeloid leukemia (CML) patients fail tyrosine kinase inhibitor (TKI) therapy secondary to resistance or intolerance. In the pre-TKI era, front-line allogeneic hematopoietic cell transplantation (allo-HCT) represented the standard approach for patients with chronic phase-CML (CP-CML) who were deemed fit to tolerate the procedure and had a human leukocyte antigen compatible donor available. Currently, CP-CML patients are eligible for allo-HCT only if they fail more than one TKI and/or are intolerant to the drug. We performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease), and stratified by age into adult and pediatric groups. For adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84% [95% confidence interval (CI) 59-99%], 66% (95% CI 59-73%), 56% (95% CI 30-60%), and 88% (95% CI 62-98%), respectively. Pooled NRM and relapse were 20% (95% CI 15-26%) and 19% (95% CI 10-28%), respectively. For the pediatric group, the OS rate was reported in one study and was 91% (95% CI 72-99%). Our results suggest that allo-HCT is an effective treatment for TKI-resistant or TKI-intolerant CP-CML. Post-transplant strategies are needed to further mitigate the risk of relapse.
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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.