Bendamustine Plus Rituximab (BR) in the Treatment of Relapsed/Refractory Mantle Cell Lymphoma of a Phase 2 Study: Multivariate Analysis and Updated Final Results By Subgroup

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma that usually presents as advanced-stage disease. Relapse is common, and management of relapsed/refractory MCL is difficult due to a limited number of approved agents and numerous comorbidities seen in this typically elderly patient population. We conducted a study of bendamustine plus rituximab (BR) in patients with relapsed/refractory MCL and presented preliminary results (Czuczman et al, ASH 2012, Abstract 3662). Final data are being analyzed in a multivariate analysis of baseline demographic and disease factors affecting outcomes for this study, and we present below the final data for individual subgroups for best overall response, DOR, and progression free survival (PFS). Patients and Methods: This multicenter, open-label, single-arm, phase 2 study was conducted to evaluate the efficacy, tolerability, and safety of BR in adults with relapsed or refractory CD20-positive B-cell MCL. Relapsed disease was defined as having achieved CR with a previous therapy but demonstrating recurrent disease >6 mo after the last dose. Refractory disease was defined as either a lack of CR while undergoing previous therapy or the loss of CR <6 mo after the last dose. Bendamustine 90 mg/m2 was administered on days 1 and 2; rituximab 375 mg/m2 was administered on day 1 of a 28-day cycle. The treatment period was 6 cycles, but patients without disease progression and without a documented CR could receive up to 8 cycles. Results of a univariate analysis will be conducted, and variables with a P value ≤0.1 will be included in a multivariate analysis. For the multivariate analysis, logistical regression will be used to examine the predictive value of baseline variables associated with response in categorical analyses. Results: Forty-five patients received ≥1 dose of BR. Median age was 70 years, 71% were male, and 82% had stage IV disease. Median treatment duration was 6 cycles. For the entire cohort, the overall response rate (ORR) was 82%. Results of a multivariate analysis, which is designed to identify baseline characteristics predictive of response to BR study treatment and to examine the association of response with survival in patients, will be presented. Final data among patients with relapsed (n=21) and refractory (n=24) MCL show overall response rates (ORRs) of 90% (n=19; CR 16 [76%], PR 3 [14%], 2 not calculable [NC]); and 75% (n=18; CR 5 [21%], PR 13 [54%], 1 NC), respectively. Median DOR (95% CI) was 19.7 mo (11.1, 38.8) and 15.3 mo (7.9, 35.3), and median PFS was 23.1 mo (13.2, 41.5) and 17.1 (8.3, 24.0), for relapsed and refractory patients, respectively. ORRs based on patients’ response to most recent prior rituximab treatment were CR, 95% (n=18; CR 15, PR 3); PR, 89% (n=8; CR 3, PR 5); stable disease (SD), 56% (n=5; CR 1, PR 4); progressive disease (PD), 71% (n=5; CR 1, PR 4); unknown, 100% (n=1; CR 1). DORs based on response to prior rituximab: CR, 17.0 mo (10.7, 38.8); PR, 17.9 mo (4.9, 35.9); SD, 35.3 mo (7.9, 35.3); PD, 14.3 mo (3.9, NC); unknown was NC. PFS results were: CR, 22.1 mo (13.2, 41.5); PR, 18.1 mo (4.7, 38.7); SD, 17.9 mo (2.4, 40.4); PD, 13.8 mo (5.4, NC); unknown was NC. In subgroups based on MIPI category, the ORR of patients in categories ≤3 was 92% (n=22; CR 14, PR 8); in 4–5 was 92% (n=11; CR 5, PR 6); in >5 was 44% (n=4; CR 2, PR 2). DORs based on risk category: ≤3, 20.6 mo (14.3, 35.5); 4–5, 11.1 mo (5.1, 21.3); >5, NC (5.1, NC). PFS results were: ≤3, 23.2 mo (16.2, 40.4); 4–5, 12.8 mo (8.3, 24.0); >5, 7.9 mo (2.0, NC). Main treatment-emergent grade 3/4 adverse events (>10%) were hematologic: neutropenia (n=15), lymphopenia (n=6), and leukopenia (n=5). Conclusion: The multivariate analysis is intended to indicate which patient characteristics are most closely associated with efficacy endpoints such as durability of response to BR. BR showed efficacy across a wide range of patient subgroups with relapsed/refractory MCL. In the subgroup of patients with relapsed MCL, CR was more common than PR, while patients with refractory MCL were more likely to achieve PR than CR. This information may be used to help guide treatment decisions when considering BR in heavily treated MCL patients. The BR regimen is generally well-tolerated and may serve as the backbone to which other active agents can be added in the study regimens to further improve anti-lymphoma activity. Support: Teva BPP R&D, Inc. Disclosures Czuczman: Teva: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.. Goy:JNJ: Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution, Research funding for clinical trials through institution Other, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution, Research funding for clinical trials through institution Other; Millennium: Membership on an entity's Board of Directors or advisory committees, Research fundiing for clinical trials through institution, Research fundiing for clinical trials through institution Other, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution Other, Speakers Bureau. Munteanu:Teva: Employment, Equity Ownership. van der Jagt:Teva: Consultancy, Honoraria, Research Funding, Speakers Bureau; Lundbeck: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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