Bendamustine and rituximab act synergistically in vitro and are effective in the treatment of relapsed or refractory indolent and mantle cell lymphomas

Abstract

6565 Bendamustine combines a purine-like benzimidazol and bifunctionally alkylating nitrogen mustard group. The drug is active in a variety of lymphoproliferative disorders without crossresistance to cyclophosphamide. We investigated simultaneous combination of rituximab with bendamustine and found synergistic effects of apoptosis in vitro on lymphoma cell lines (DOHH-2, WSU-NHL) as well as on ex vivo cells of pat. with CLL. Apoptosis was determined by Annexin V and JC-1. The synergistic effects of rituximab in combination with bendamustine were evenly strong when rituximab was applied at a dose, at which half of the CD20 molecules per cell were saturated. Based on our in vitro results we initiated a phase-II study to examine efficacy and toxicity of bendamustine combined with rituximab (BR) as therapy of 1st, 2nd or 3rd relapse. Treatment schedule: 6 x Rituximab 375 mg/qm day 1 combined with 4 x Bendamustine 90 mg/qm day 2+3, every 4 weeks. Included entities: 17 immunocytomas, 16 mantle cell (MCL), 24 follicular, 6 marginal zone lymphomas. 63 pat. entered the study. Results: 57 pat. responded to therapy yielding to an ORR of 90% with a CR-rate of 60%. In MCL an ORR of 75% was achieved with an CR-rate of 50%. All pat. with immunocytome achieved a remission with a CR-rate of 53%. The median duration of remission was 25 months. BR induced considerable low hematological toxicity with only 16% granulocytopenias grade 3 and 4. We conclude that BR seems to be very effective in the treatment of relapsed indolent and mantle cell lymphomas reaching an overall response rate of 90% and a CR rate of 60%. Based upon the encouraging results obtained with BR in this study we initiated two Phase III trials that compare BR to established chemo-immunotherapy regimens. One trial compares BR versus R-CHOP in pat. with previously indolent lymphomas to demonstrate a non-inferiority of BR in comparison to R-CHOP with respect to efficacy but to show a more favorable toxicity profile. The second trial compares BR to fludarabine/rituximab in pat. with relapsed indolent lymphomas. These studies should provide considerable guidance for the appropriate role of bendamustine in the treatment of indolent lymphomas. No significant financial relationships to disclose.