Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG).

Introduction: Bendamustine has shown considerable activity in monotherapy for solid and lymphoid malignancies including CLL and has been used for more than 30 years in anti-cancer treatment. In vitro and ex vivo studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary B-CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory NHL or mantle cell lymphoma. The present phase II trial represents the first study assessing efficacy and toxicity of bendamustine in combination with rituximab in pts with relapsed/refractory B-CLL.

Patients and Methods: Between March 2006 and June 2007 81 pts with relapsed/refractory B-CLL and a median number of 2 pretreatments were enrolled into this trial. Bendamustine was given at a dose of 70 mg/m² on day 1 and 2, combined with 375mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH), analysis of the IgV_H mutational status and expression of ZAP70/CD38. Assessment of minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry.

Results: So far data of 31 pts (median age 66 years) with a total of 126 treatment cycles are available for analysis. There was notable toxicity with 48 reported CTC grade 3/4 adverse events, particularly myelosuppression and infections: grade 3/4 anemia occurred in 6.3.%, leukopenia/neutropenia in 10.8% and thrombocytopenia in 11.9% of all courses. 6 episodes of CTC grade 3/4 infections were documented: 1 sinusitis maxillaris, 1 FUO and 1 abscess, all of them being reversible after antibiotics. However, 3 pts died due to severe infections including 2 fatal pneumonias and 1 urosepsis. One pt died due to myocardial infarction. Regarding efficacy, 23 pts were evaluable for response: The overall response rate (ORR) was 65.2% with a CR rate of 13.0% (3 pts) and a PR rate of 52.2% (12 pts). No molecular remission was observed by 4-colour cytometry. Stable disease (SD) was achieved in 26.1% (6 pts) whereas 2 pts had progressive CLL (PD, 8.7%). Responses were observed in the majority of pts with genomic aberrations 11q deletion (ORR: 4/5) and trisomy 12 (ORR: 2/3), while none of the pts with 17p deletion (ORR: 0/4) was responsive (P=0.006).

Conclusion: Bendamustine plus rituximab is an effective regimen in refractory/relapsed B-CLL. Major treatment toxicities were myelosuppression and infections. Updated data with respect to toxicity and efficacy based on the entire study population will be available for the Meeting.