Bendamustine Versus Chlorambucil in Treatment-Naive Patients with B-Cell Chronic Lymphocytic Leukemia (B-CLL): Results of an International Phase III Study.

Introduction: Bendamustine (BEN) is a purine analog / alkylator hybrid agent with a particular mechanisms of action that provides effective treatment for a number of hematologic and non-hematologic malignancies. It is used primarily for chemo-naïve, relapsed or refractory B-CLL as well as for other types of non-Hodgkin’s lymphomas. The aim of this randomized phase III, open-label, multicenter study was to compare the efficacy and safety of BEN versus chlorambucil (CLB) in treatment-naïve patients (pts) with B-CLL Binet stage B/C.

Patients and Methods: Pts with untreated B-CLL were randomized to receive BEN (100 mg/m² on days 1+2) or CLB (0.8 mg/kg on days 1+15) for up to 6 treatment cycles. Primary endpoints were overall remission rate (ORR), defined as complete response (CR), nodular partial response (nPR) and partial response (PR), confirmed after 8 weeks, and progression-free survival (PFS). Secondary endpoints were duration of remission, overall survival (OS), safety, and quality of life (QoL). Follow-up was for ≥12 months after completion of treatment of the last patient, or until progression for pts with CR, nPR or PR and stable disease, or until death or lost to follow-up. A 5-stage, adaptive-group, sequential procedure was used with planned interim analyses to adjust the number of pts. Safety and efficacy were assessed by an Independent Data Monitoring Committee.

Results: 305 pts were randomized to receive BEN (n=156) or CLB (n=149). As 7 pts did not receive study medication, 298 pts were included in the safety analysis. At the time of this analysis, 264 pts (139 BEN; 125 CLB) were available for the efficacy analysis. For both treatment groups: median age was 64 years; 70% had Binet stage B and 30% Binet stage C disease; median number of cycles/patient was 6; median follow-up was 18.5 months. ORR was significantly higher with BEN than with CLB (68% vs 39%; p<0.0001), with a CR of 30% vs 2%, respectively. Among the subgroups with Binet stage B and C disease, ORR was 70% and 61%, respectively, with BEN, vs 47% and 22%, respectively, with CLB. Median PFS (Kaplan-Meier estimate) was 21.7 months with BEN and 9.3 months with CLB (p<0.0001), and median duration of remission was 18.9 months with BEN and 6.1 months with CLB (p<0.0001). No difference in OS was seen between groups. Toxicity of BEN was manageable and did not impair QoL when compared with CLB. Infection rates (common toxicity criteria grades III+IV) were low in both groups (5.8% BEN; 3.5% CLB).

Conclusions: BEN was significantly more effective than CLB in achieving remissions in treatment-naïve pts with B-CLL Binet stage B/C; median PFS and duration of remission were also significantly longer. Furthermore, safety data indicate that BEN toxicities are manageable and the drug is well tolerated. On the basis of these results, BEN should be considered as first-line chemotherapy for patients with B-CLL Binet stage B or C.