Bortezomib plus DA-EPOCH-rituximab followed by bortezomib maintenance versus observation in previously untreated mantle cell lymphoma (MCL).

Abstract

8022 Background: Bortezomib (B) is a proteasome inhibitor that appears to work in MCL by causing cell cycle arrest and induction of apoptosis through oxidative and ER stress-mediated up-regulation of NOX. Phase II clinical trials of B in relapsed/refractory MCL have shown durable responses in up to 58% of patients. DA-EPOCH-R is an effective platform regimen in MCL and we set out to investigate the efficacy of DA-EPOCH-RB and maintenance B in newly diagnosed MCL. Methods: All patients received Part A and Part B. Part A was B alone (1.5 or 1.3mg/m2) for 1 cycle on d 1, 4, 8, 11 and Part B was DA-EPOCH-R for 6 cycles with B on d 1, 4. Due to excessive neurotoxicity in the first 5 patients on study (all required reduction or discontinuation of B), the dose of B with DA-EPOCH-R was reduced from 1.5 to 1.3 mg/m2. Patients with a CR or PR to Part B (and without significant neurotoxicity) were randomized to maintenance B (1.3mg/m2 d 1, 4, 8 and 11 q 8 wks for 18 mos) or observation (Part C). Results: Patient (n=38) characteristics: median (range) age 58 (41-73); male sex 29 (76%); stage IV disease 100%. Responses: Part A: PR in 4 (11%) and NR in 34 (89%); Part B: CR in 24 (63%), PR in 11 (29%) and NR in 3 (8%). PFS and OS at 36-month follow-up are 47% and 84% respectively. For 11 patients randomized to B maintenance, PFS at 36 months is 48% compared to 63% for patients (10) randomized to observation (2-tailed log-rank p-value=0.66). 50% of patients had ≥ grade 2 neurotoxicity and at the 1.3mg/m2 dose of B, 33% of patients required a dose reduction or discontinuation of B. Other significant toxicities were neutropenic fever/infection in 8% of cycles and grade 3 or 4 thrombocytopenia in 34% of cycles. Conclusions: B does not appear to add to the efficacy of DA-EPOCH-R in MCL. This may be related to scheduling – B may put cells into cycle arrest and reduce the efficacy of DA-EPOCH-R. In an early analysis, maintenance B following induction therapy does not appear to improve PFS compared to observation alone, suggesting that maintenance B may not be a useful strategy in MCL. However, accrual continues. Ongoing translational studies on biopsied tissue taken before and after B (during Part A) will attempt to elucidate the mechanism of action of B in MCL.