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

Abstract

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.

Bendamustine: Rebirth of an Old Drug

“…In a recent European Intergroup CLL Study, 305 previously untreated CLL patients under 75 years of age and requiring therapy were randomized to bendamustine 100 mg/m 2 intravenously for 2 consecutive days or oral chlorambucil 0.8 mg/kg on days 1 and 15 of each cycle. 34 The median age was 65 years; 70% had Binet stage B and 30% stage C disease. Overall response rates (ORR) in 156 bendamustine-and 149 chlorambucil-treated patients were 68% (30% complete remission [CR]) and 39% (2% CR), respectively (P Ͻ .0001).…”

“…37 The recommended dose of bendamustine for previously untreated patients with CLL is 100 mg/m 2 on days 1 and 2 every 4 weeks. 34…”

Bendamustine: A New Treatment Option for Chronic Lymphocytic Leukemia

“…Researchers from a phase III study evaluated bendamustine in treatment-naïve patients with CLL. 9 Their study showed a positive response for bendamustine versus chlorambucil, with manageable toxicity at a dose of 100 mg/m 2 on days 1 and 2 given every 28 days.…”

“…3 First-line treatment options for CLL include the those listed in Table 1. 1,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] In patients with advanced CLL requiring treatment, the 2009 National Comprehensive Cancer Network (NCCN) guidelines recommend several options, including chemotherapy and chemoimmunotherapy. Unfortunately, none of these regimens are curative; therefore, research is focused on developing treatment options for patients with newly diagnosed disease and for patients receiving firstline therapy whose disease continues to progress.…”

“…1 Because of findings from the international phase III comparison of bendamustine with chlorambucil, bendamustine is indicated for use as a first-line agent in patients with CLL. 1,9 Efficacy data for bendamustine compared with other first-line agents besides chlorambucil are not yet available. Also lacking are data about its efficacy in combination with other agents.…”