Background and objectives: Although bendamustine has been used for more than 30 years in the treatment of lymphoma, little is known about the optimal dosing schedule in relapsed or refractory B-cell chronic lymphocytic leukemia (CLL). Various dose and treatment schedules have been used empirically, and several phase II studies have shown impressive efficacy. To determine the maximal tolerated dose, dose-limiting toxicity and the optimal therapeutic dose of bendamustine for further phase III clinical trials the GCLLSG designed a phase I/II study for pre-treated CLL patients.
Design and methods: Sixteen patients (median age 67 years) with relapsed or refractory CLL were enrolled. All patients had been pre-treated with a median of three different regimens. Bendamustine was given at a starting dose of 100 mg/m2 on day 1 and 2, repeated every 3-4 weeks.
Results: Major toxicities were leukocytopenia (CTC grade 3+4) in 8/16 and infections (CTC grade 3+4) in 7/16 patients. Six patients had dose-limiting toxicity which led to dose de-escalation from 100 to 70 mg/m2 in three patients. The maximum tolerated dose was 70 mg/m2. According to NCI-WG criteria, 9/16 patients (56%) responded to therapy, seven to doses <or=80 mg/m2. Two patients achieved complete remission. Five patients had a partial response and two patients stable disease. The median duration of response was 42.7 months. After a follow-up period of 53.2 months, five patients (31%) were still in remission. The median overall survival time for all patients was 45.6 months.
Interpretation and conclusions: The study confirms the excellent efficacy of bendamustine in heavily pre-treated and treatment-refractory patients, even at reduced doses of 140 mg/m2 per course. In pre-treated CLL patients, impaired bone marrow function is likely to enhance the myelotoxic side effects of bendamustine. Based on these results, the recommended optimal therapeutic dose of bendamustine in refractory CLL is 70 mg/m2 on days 1 and 2 every 4 weeks.