Phase I-II study of bendamustine in patients with acute leukemia and high risk myelodysplastic syndrome

Background: Alkylating agents have shown activity in leukemia. Bendamustine, an active alkylating agent in lymphoma and chronic lymphocytic leukemia, was given in a fractionated twice daily schedule for 4 days to patients with acute leukemia and myelodysplastic syndrome (MDS) to define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD). Patients and Methods: Adults with refractory acute leukemia or high-risk MDS were treated with bendamustine at a starting dose of 50 mg/m² IV over 1-2 hours twice daily for 4 days. Dose escalations were by 25 mg/m² in the 1st 3 levels. The study used the 3 + 3 design. Results: A total of 25 patients were treated. Their median age was 57 years; the median salvage number was 3. Grade 2 creatinine elevations were observed in 1 of 6 patients at the 50 mg/m ² dose, in 2 of 13 patients at the 75 mg/m² dose, and in 3 of 6 patients at the 100 mg/m² dose. This was considered significant, even though DLT was not reached. One patient achieved marrow complete remission. Significant reductions of marrow blasts (50% or more) were observed in 6 of 25 patients (24%). Conclusion: Bendamustine fractionated dose level of 100 mg/m² IV twice daily for 4 days (800 mg/m² per course) was associated with Grade 2 renal toxicity. The proposed phase II schedule is 75 mg/m² IV twice daily for 4 days. Future studies should evaluate this schedule in less heavily treated patients.