Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma

Abstract

The addition of high-dose cytarabine to rituximab/bendamustine (RB) induction could improve outcomes for transplant-eligible patients with mantle cell lymphoma (MCL). We conducted a pooled analysis of 2 phase 2 trials and an off-trial cohort each testing 3 cycles of RB and 3 cycles of rituximab/high-dose cytarabine (RC) followed by autologous stem cell transplantation (ASCT) among untreated, transplant-eligible patients with MCL. Dana-Farber Cancer Institute (DFCI) and Washington University in St. Louis (WUSTL) led separate phase 2 trials testing sequential and alternating cycles of RB/RC, respectively. Patients treated at DFCI with sequential RB/RC off trial were retrospectively identified. Minimal residual disease (MRD) was assessed in the DFCI trial. A total of 88 patients (23 DFCI trial, 18 WUSTL trial, and 47 off trial) received RB/RC; 92% of patients completed induction, and 84% underwent planned consolidative ASCT. Grade 3 or 4 adverse events among trial patients included lymphopenia (88%), thrombocytopenia (85%), neutropenia (83%), and febrile neutropenia (15%). There were no treatment-related deaths during induction and 2 following ASCT. Among 87 response-evaluable patients, the end-of-induction overall and complete response rates were 97% and 90%, respectively. After a median follow-up of 33 months, 3-year progression-free survival and overall survival were 83% and 92%, respectively. Patients undergoing MRD testing experienced prolonged MRD negativity after ASCT with emergence of MRD occurring in only 1 patient who subsequently relapsed. RB/RC followed by ASCT achieves high rates of durable remissions in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT01661881 (DFCI trial) and #NCT02728531 (WUSTL trial).

Conflict of interest statement

Conflict-of-interest disclosure: A.L. received consulting fees from Seattle Genetics, DSMB BMS, and Research to Practice for Speakers’ Bureau. J.R.B. has served as a consultant for Abbvie, Acerta, Astra-Zeneca, Beigene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Octapharma, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem; received honoraria from Janssen and Teva; received research funding from Gilead, Loxo, Sun, and Verastem; and served on data safety monitoring committees for Morphosys and Invectys. B.K. received consulting fees from Genetech and Roche and research support from Genentech. N.M-S. received consulting fees from Kiowa Hakka Kirin and institutional research funding from Genentech, BMS, Verastem, and Celgene. P.A. received consulting fees from Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, and Miltenyi; research funding (institutional) from Merck, BMS, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM; and honoraria from Merck and BMS. E.J. received consulting fees from Merck and Acerta; honoraria from Takeda, Astra-Zeneca, and Merck; and research funding from Novartis, Seattle Genetics, Celgene, Merck, Hoffmann-LaRoche, and Pharmacyclics. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment schema: a pooled analysis of 2 phase 2 clinical trials and a retrospectively identified nontrial cohort. In each cohort, patients received 3 cycles of RB and 3 cycles of RC. In the DFCI trial, the starting dose of cytarabine was reduced from 3 g/m2 to 2 g/m2 for patients >60 years with a further dose reduction to 1.5 g/m2 for patients >60 years with either renal dysfunction (creatinine, 1.3-2.0) or preexisting neurotoxicity or 1.0 g/m2 for patients >60 years with both renal dysfunction and preexisting neurotoxicity. In the WUSTL trial, the starting dose of cytarabine was reduced to 2 g/m2 for patients >60 years and/or with renal dysfunction (estimated glomerular filtration rate, 40-59). *The starting cytarabine dose was chosen by the treating physician for patients treated in the nontrial cohort. BID, twice a day.

Figure 2.

PFS and OS. PFS (A), PFS by cohort (B), OS (C), and OS by cohort (D).

Figure 3.

Univariate Cox regression for PFS.

Figure 4.

MRD analysis. When feasible, patients in the DFCI trial cohort had samples collected at baseline, after 3 cycles of induction therapy, after 6 cycles of induction therapy, and at various time points following ASCT for MRD analysis using Ig-NGS with ClonoSeq (Adaptive Biotechnologies). In this swimmer’s plot, each horizontal arrow represents an individual patient. Yellow lines denote patients who have relapsed, and the time of relapse is marked by a red x. Green patients are progression-free. Purple triangles represent the timing of ASCT, red circles are MRD-positive samples, and blue circles are MRD-negative samples.