Introduction: Bendamustine (BEN) provides effective treatment of hematologic as well as of non-hematologic malignancies. It is characterized by an unique activity profile which differs from common nitrogen mustard drugs. In particular, it causes only partial cross resistance to other alkylating agents, anthracyclines and anti-metabolites, respectively. BEN is used in patients with chemo naïve, relapsed or refractory chronic lymphocytic leukemia (CLL), however, no head-to-head study has been performed so far. Therefore, a multicenter, international phase III study was initiated to compare the activity of BEN against chlorambucil in treatment-naive B-CLL patients with Binet stage B/C.

Patients and Methods: Patients are randomized to either Arm A (BEN 100 mg/m2, d 1+2) or to Arm B (chlorambucil 0,8mg/kg Broca’s weight, d 1+15) to receive a maximum of 6 treatment cycles. Primary objectives are overall remission rate and progression-free survival. The anticipated effects are an overall remission rate of 60% vs. 30% and a median progression free survival of 20 vs.14 months. Secondary objectives are additional efficacy parameters, safety, and quality of life. The study design is adaptive with four interim analyses to adjust the final number of patients, plus one safety analysis. A maximum of 350 patients is planned. Toxicities regarding hemoglobin, platelets and neutrophils are graded according to the NCIWG for CLL, while leukocyte and lymphocyte counts are graded according to CTC as in many other CLL trials.

Results and Summary: To assess safety, twenty patients in each treatment arm with at least one completed treatment cycle have been evaluated. The results have been reviewed by an independent data monitoring committee (IDMC). It was concluded that the dosages selected for both treatment arms are safe and that the study is to be continued. Furthermore, another safety analysis was performed with respect to the rate of major infections in the same patient cohort after having completed study treatment. While the infection rate has been reported to be 29% in patients treated with fludarabine as published by Rai et al., in our study two BEN-patients (10%) experienced major infections whereas none occurred in the chlorambucil arm. One BEN-patient developed fever CTC grade 3 without neutropenia. Another patient experienced pneumonia CTC grade 2 requiring hospitalization and intravenous antibiotic treatment. In the BEN-arm, 87% of the scheduled dose was applied whereas 89% was given in the chlorambucil arm. Patients treated with BEN remained longer on study as compared to the chlorambucil patients. The toxicity rate, both hematologic and non-hematologic, was in favour for chlorambucil. In total, three patients were withdrawn from study due to toxicity: one patient in each treatment arm due to infection and one BEN-patient due to an allergic reaction. Meanwhile, the first planned interim analysis on remission rate was done. 43 patients in each treatment arm were evaluated. The IDMC recommended to continue the study. A second interim analysis will be performed after 160 patients will have completed the first tumor evaluation to adjust the number of patients finally required.

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