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Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT
Kanate, A. S., Kumar, A., Dreger, P., Dreyling, M., Le Gouill, S., Corradini, P., Bredeson, C., Fenske, T. S., Smith, S. M., Sureda, A., et al
JAMA oncology. 2019
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Abstract
Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naive high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naive FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.
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Maintenance tyrosine kinase inhibitors following allo-HCT for chronic myeloid leukemia: A CIBMTR Study
DeFilipp, Z., Ancheta, R., Liu, Y., Hu, Z. H., Gale, R. P., Snyder, D., Schouten, H. C., Kalaycio, M., Hildebrandt, G. C., Ustun, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myeloid leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML transplanted from 2007-2014 who received maintenance TKI following HCT (n=89) as compared to no TKI maintenance (n=301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy prior to HCT. The majority of patients had disease beyond CP1 at HCT (n=240, 62%). The study was conducted as a landmark analysis, excluding patients that died, relapsed, had chronic graft-versus-host disease or were censored prior to Day 100 following HCT. Of the 89 patients receiving TKI maintenance, 77 (87%) received a single TKI while 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n=50), imatinib (n=27) and nilotinib (n=27). As measured from Day 100, the adjusted estimates for 5-year relapse (maintenance, 35% vs. no maintenance, 26%; p=0.11), leukemia-free survival (LFS, maintenance, 42% vs. no maintenance, 44%; p=0.65) or overall survival (OS, maintenance, 61% vs. no maintenance, 57%; p=0.61) did not significantly differ between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by the status of disease prior to transplant. In conclusion, our data did not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes in a Day 100 landmark analysis. The optimal approach to TKI administration in the post-transplant setting in CML remains undetermined.
PICO Summary
Population
Adult patients with CML transplanted from 2007-2014 (n=390)
Intervention
Maintenance TKI following HCT (n=89)
Comparison
no TKI maintenance (n=301)
Outcome
As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; ) or overall survival (maintenance, 61% versus no maintenance, 57%; ) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation.
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A Phase 2 Study of Pembrolizumab during Lymphodepletion after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma
D'Souza, A., Hari, P., Pasquini, M., Braun, T., Johnson, B., Lundy, S., Couriel, D., Hamadani, M., Magenau, J., Dhakal, B., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
The programmed death-1 (PD-1) axis can suppress immune surveillance against multiple myeloma (MM). We tested the safety and efficacy of pembrolizumab, an anti-PD-1 antibody, in MM after autologous hematopoietic cell transplantation (AHCT). We enrolled MM patients not achieving complete response (CR) to induction to receive 9 doses of 3- weekly IV pembrolizumab starting day 14 post-AHCT. The primary endpoint was CR rate at end-of-treatment (EOT) in patients receiving >2 pembrolizumab doses. Thirty-two patients were enrolled but 3 withdrew consent prior to receiving the first dose. The study was terminated early after failing to meet its interim analysis endpoint to detect a 20% difference in EOT CR rate conversion. The median age was 59 years. All except 1 received triplet induction for a median 4 cycles (range, 2-7), with 69% partial response (PR) and 31% very good PR (VGPR). No grade 4/5 toxicities or graft failures occurred. Among 26 evaluable patients, 23 had an EOT evaluation and 31% (7/23) achieved CR. Two had EOT serologic CR but no BM confirmation (CRu), while 1 had no EOT evaluation. Bone marrow was minimal residual disease-negative by flow cytometry in 75% (12/16) at day+180. With a median follow-up of 23.7 months (15.1-33.5), no patient achieving EOT CR/CRu had relapsed, while 3 progressed before EOT and one 8 months after EOT VGPR. Estimated 2-year progression-free rate was 83% (95% CI, 68-100). Early post-AHCT pembrolizumab with lenalidomide maintenance was feasible; however, the efficacy is uncertain and needs to be better studied. This trial was registered at www.clinicaltrials.gov as #NCT02331368.
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Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation
Knight, J. M., Kerswill, S. A., Hari, P., Cole, S. W., Logan, B. R., D'Souza, A., Shah, N. N., Horowitz, M. M., Stolley, M. R., Sloan, E. K., et al
BMC cancer. 2018;18(1):593
Abstract
BACKGROUND Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. METHODS We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18-75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. RESULTS One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. CONCLUSIONS Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. TRIAL REGISTRATION This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.