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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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Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma
Kamdar, M., Li, H., Chen, R. W., Rimsza, L. M., Leblanc, M. L., Fenske, T. S., Shea, T. C., Barr, P. M., Phillips, T. J., Leonard, J. P., et al
Blood advances. 2019;3(20):3132-3135
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Autologous transplantation as consolidation for high risk aggressive T-cell non-Hodgkin lymphoma: a SWOG 9704 intergroup trial subgroup analysis
Al-Mansour, Z., Li, H., Cook, J. R., Constine, L. S., Couban, S., Stewart, D. A., Shea, T. C., Porcu, P., Winter, J. N., Kahl, B. S., et al
Leukemia & lymphoma. 2019;:1-8
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Editor's Choice
Abstract
Phase II data suggest a benefit to autotransplantation for aggressive T-cell non-Hodgkin lymphoma (T-NHL) in first remission; randomized trials have yet to validate this. We performed a retrospective analysis of aggressive T-NHL patients in the intergroup randomized consolidative autotransplant trial (SWOG 9704). Of the 370 enrolled, 40 had T-NHL: 12 were not randomized due to ineligibility (n = 1), choice (n = 2), or progression (n = 9), leaving 13 randomized to control and 15 to autologous stem cell transplantation (ASCT). Two ASCT patients refused transplant and one failed mobilization. The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38% (p = .56), and 40% vs. 45% (p = .98), respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI. Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. This and the 30% who dropped out pre-randomization mostly to progression, suggests that improved induction regimens be developed.
PICO Summary
Population
Aggressive T-cell non-Hodgkin lymphoma patients, treated with five cycles of CHOP/CHOP-R administered every three weeks; those who achieved at least a partial response were eligible for randomization (n=28).
Intervention
One further cycle of CHOP/CHOP-R followed by autologous stem cell transplantation
Comparison
Three further cycles of CHOP/CHOP-R
Outcome
Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. . The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38%, and 40% vs. 45%, respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI.
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RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106
Chen, R. W., Li, H., Bernstein, S. H., Kahwash, S., Rimsza, L. M., Forman, S. J., Constine, L., Shea, T. C., Cashen, A. F., Blum, K. A., et al
British Journal of Haematology. 2017;176(5):759-769
Abstract
Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto-HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre-transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto-HCT. Fifty-three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2-year progression-free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi-centre transplant trials in MCL. RB achieved a 2-year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL. Copyright © 2016 John Wiley & Sons Ltd.
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Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era
Hunter, B. D., Herr, M., Meacham, P. J., Barlaskar, F., Evans, A. G., Burack, W. R., Liesveld, J. L., Becker, M. W., Milner, L. A., Constine, L. S., et al
Clinical lymphoma, myeloma & leukemia. 2017;17(3):145-151
Abstract
BACKGROUND The standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (<= 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy. MATERIALS AND METHODS A retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (<= 1 year and > 1 year after ASCT). RESULTS The median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at <= 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years. CONCLUSION Patients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression. Copyright © 2016 Elsevier Inc. All rights reserved.
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Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: a NLCS and CIBMTR Analysis
Casulo, C., Friedberg, J. W., Ahn, K. W., Flowers, C., DiGilio, A., Smith, S. M., Ahmed, S., Inwards, D., Aljurf, M., Chen, A. I., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within two years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup.ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within two years of frontline chemoimmunotherapy. We identified two groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT); and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment. 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in five year OS between the two groups (60% vs 67% respectively; p=0.16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (<=1year of ETF; n=123) had higher five year OS than those without autoHCT (73% vs 60%, p=0.05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (HR=0.63, 95%CI:0.42-0.94, p=0.02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within one year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.
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Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma
Martin, P., Chen, Z., Cheson, B. D., Robinson, K. S., Williams, M., Rajguru, S. A., Friedberg, J. W., van der Jagt, R. H., LaCasce, A. S., Joyce, R., et al
British Journal of Haematology. 2017;178(2):250-256
Abstract
Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14.1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8.9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.
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Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704
Puvvada, S. D., Stiff, P. J., Leblanc, M., Cook, J. R., Couban, S., Leonard, J. P., Kahl, B., Marcellus, D., Shea, T. C., Winter, J. N., et al
British Journal of Haematology. 2016;174(5):686-91
Abstract
Double hit lymphoma (DHL) and double protein-expressing (MYC, BCL2) lymphomas (DPL) fare poorly with R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone); consolidative autologous stem cell transplant (ASCT) may improve outcomes. S9704, a phase III randomized study of CHOP +/-R with or without ASCT enabled evaluation of intensive consolidation. Immunohistochemistry (IHC) identified 27 of 198 patients (13.6%) with MYC overexpression; 20 (74%) harboured concurrent BCL2 overexpression. Four had DHL and 16 had DPL only. With median 127 months follow-up, there is a trend favouring outcomes after ASCT in DPL and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of ASCT. Copyright © 2016 John Wiley & Sons Ltd.
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Patterns and Timing of Failure for Diffuse Large B-Cell Lymphoma After Initial Therapy in a Cohort Who Underwent Autologous Bone Marrow Transplantation for Relapse
Dhakal, S., Bates, J. E., Casulo, C., Friedberg, J. W., Becker, M. W., Liesveld, J. L., Constine, L. S.
International Journal of Radiation Oncology, Biology, Physics. 2016;96(2):372-8
Abstract
PURPOSE To evaluate the location and timing of initial recurrence in patients with diffuse large B-cell lymphoma (DLBCL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT), to direct approaches for disease surveillance, elucidate the patterns of failure of contemporary treatment strategies, and guide adjuvant treatment decisions. METHODS AND MATERIALS We analyzed consecutive patients with DLBCL who underwent HDC/ASCT between May 1992 and March 2014 at our institution. Of the 187 evaluable patients, 8 had incomplete data, and 79 underwent HDC/ASCT as a component of initial treatment for de novo or refractory DLBCL and were excluded from further analysis. RESULTS The median age was 50.8 years; the median time to relapse was 1.3 years. Patients were segregated according to the initial stage at diagnosis, with early stage (ES) defined as stage I/II and advanced stage (AS) defined as stage III/IV. In total, 40.4% of the ES and 75.5% of the AS patients relapsed in sites of initial disease; 68.4% of those with ES disease and 75.0% of those with AS disease relapsed in sites of initial disease only. Extranodal relapses were common (44.7% in ES and 35.9% in AS) and occurred in a variety of organs, although gastrointestinal tract/liver (n=12) was most frequent. CONCLUSIONS Most patients with DLBCL who relapse and subsequently undergo HDC/ASCT initially recur in the previously involved disease site(s). Time to recurrence is brief, suggesting that frequency of screening is most justifiably greatest in the early posttherapy years. © 2016 Elsevier Inc.