Bendamustine Induces Higher Remission Rates, Prolongs Progression Free Survival as Well as Time to Next Treatment, and Improves Overall Survival for Patients In Complete Remission without Compromising Quality of Life When Compared to Chlorambucil In First Line Treatment of Chronic Lymphocytic Leukemia

Bendamustine (BEN), either alone or in combination with Rituximab, is increasingly used in the treatment of chronic lymphocytic leukemia (CLL) and various types of low grade Non Hodgkin's Lymphoma (NHL). The approval to treat CLL with BEN is based on a prospectively randomized trial (Knauf et al., J Clin Oncol. 2009; 27: 4378–4384) comparing single drug BEN with chlorambucil (CLB). Here, we report on follow-up data of this pivotal trial with specific reference to survival times, time to next treatment, and efficacy of second line regimens. Since CLL is a disease of the elderly and potentially co-morbid patients, we also analyzed quality of life (QoL) parameters in relation to the treatment with both BEN and CLB.

The efficacy and safety of BEN and CLB have been compared in a randomized, open-label, multicenter, phase III trial in patients with previously untreated advanced (Binet stage B/C) CLL. Patients were randomized to receive either BEN (100 mg/m² on days 1 + 2) or CLB (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The primary endpoints were overall response rate (ORR), which was defined as complete (CR) or partial response (PR), and progression-free survival (PFS). Secondary endpoints included overall survival (OS), and QoL. The latter was analyzed by using both the EORTC questionnaires QLQ C30 and QLQ-CLL25. We also looked at time to next treatment and efficacy of second line regimens. The response to treatment was evaluated by a blinded Independent Response Assessment Committee.

A total of 319 patients were randomized (162 BEN and 157 CLB), all of whom were included in the efficacy analysis, while 308 patients were evaluable for QoL analysis (158 BEN and 150 CLB). Median age was 64 years (range 35 to 78). The mean number of treatment cycles was 5 in both study arms, regardless of an age above or below 65 years. The median observation time was 54 months. ORR was significantly higher with BEN than with CLB (68% versus 31%, P<0.0001). A CR was achieved in 31% of pts with BEN and in 2% of pts with CLB (P<0.0001). In the intent to treat (ITT) population, the median PFS was 21.2 months with BEN and 8.8 months with CLB (P<0.0001). Sixty-three patients in the BEN treated group and 35 in the CLB treated group had not received any second line therapy (P<0.001) at the time of this analysis. The median time to next treatment in the ITT population was 31.5 months with BEN and 10.1 months with CLB (P<0.0001). ORR after second line therapy of any type was 35.4% in the BEN first line arm and 45.9% in the CLB first line arm (P=0.131). So far, there is no difference in OS (P = 0.24; hazard ratio = 1.3 in favour of BEN) in the ITT population. However, patients achieving a CR (almost exclusively after BEN) experienced a longer OS than pts not in CR (median not reached versus 76.2 months; P=0.002). Also, pts with any response (CR + PR) either after BEN or CLB had a longer OS than the non-responders (median not reached versus 68.3 months; P< 0.0001). Base line scores regarding QoL parameters showed no difference between the groups. After completion of study treatment (mean 5 cycles administered), no differences became evident with respect to physical, social, emotional, and cognitive functioning. The self assessment of the global health status also revealed no difference.

This study has shown that BEN offers significantly greater response rates, PFS, and a much longer time to next treatment than CLB. OS is prolonged significantly in all responders and especially in those patients who achieve CR after BEN. In comparison to CLB, the additional efficacy of BEN was achieved without compromising QoL. BEN should be considered as a backbone drug in first-line chemotherapy of patients with advanced CLL.

Knauf: Mundipharma: Consultancy, Honoraria. Klein: Mundipharma: Honoraria. Merkle: Mundipharma: Honoraria.