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, an alkylating agent with additional properties of a purine analogue, has shown considerable activity in monotherapy for solid and lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory and previously untreated Non-Hodgkin’s lymphoma. This phase II trial represents the first study evaluating the efficacy and toxicity of bendamustine in combination with rituximab in patients (pts) with relapsed or refractory CLL. Patients and Methods: 81 pts with a median number of 2 (1–3) pretreatments were enrolled between March 2006 and June 2007. Patients received 70 mg/m² bendamustine 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 for up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH) and analysis of the immunoglobulin heavy chain (IgV H ) mutational status prior to the first treatment course. Assessment for minimal residual disease (MRD) was performed by four-colour flow cytometry of peripheral blood and bone marrow. Primary endpoint of the trial was the overall response rate (ORR). Secondary endpoints included toxicity, duration of response, event-free survival, MRD response rate and overall response rate in biological defined risk groups. Results: 81 pts (mean age 66.7 years) received a total of 328 treatment cycles. A mean number of 4.5 courses was administered. In total 123 CTC grade 3/4/5 adverse events were reported, most frequently on myelosuppression and infections: grade 3/4 anemia occurred in 6.1%, grade 3/4 leukopenia/neutropenia and thrombocytopenia in 11.9% and 9.1% of all given courses, respectively. 16 episodes (4.9%) of CTC grade ≥3 infections were documented, most of them could be successfully managed. However, treatment related mortality occurred in 3.7% of pts: three pts died due to severe infections associated with treatment related neutropenia including 1 fatal pneumonia, one sepsis after diagnosis of Richter’s syndrome and 1 urosepsis. In 62 pts data for response assessment were available: 19 pts were not evaluable for response due to withdrawal or missing of consent, violation of enrolment criteria or early discontinuation of therapy. The overall response was 77.4% with complete remissions (CR) in 14.5% (9 pts) and a partial response (PR) in 62.9% of pts (39 pts). An MRD level below 10E-4 was measured after completion of therapy in 2 of 30 evaluable pts in peripheral blood, while none of the pts achieved MRD negativity in bone marrow. Stable disease (SD) was achieved in 17.7% (11 pts) whereas 3 pts (4.8%) had progressive CLL (PD). Differences in response were observed among genetic subgroups: 12 of 13 pts with 11q- achieved a remission with 11 PR and 1 CR (ORR: 92.3%). Accordingly, 8 of 8 patients with +12 responded (7 PR, 1 CR). In the high-risk group with 17p-, four of nine pts showed a partial remission (ORR: 44,4%). 29 of 39 pts (ORR: 74.4%) with unmutated IgV H status were responsive to BR. Conclusion: Bendamustine plus rituximab is an effective treatment regimen for pts with relapsed and/or refractory CLL and has notable activity in high-risk CLL disease. Major but tolerable treatment toxicities were myelosuppression and infections. Ongoing trial follow-up analysis will define response duration and long-term safety. In a forthcoming trial the German CLL Study group will investigate the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) for first-line treatment of CLL.