5.10 Combination of Bendamustine and Ofatumumab (Bendofa) in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia: A Preliminary Report

Abstract

We designed a multicentric, single-arm, dose escalation study to determine the maximum tolerated dose (MTD) of the Ben Cam combination and evaluate its efficacy and safety in patients with refractory and relapsed CLL. Methods: Previously treated patients with CLL requiring therapy were enrolled. Therapy consisted of stepwise dose escalation exploring MTD. Starting dosages were Ben 50 mg/m d 1 and 2 and Cam 20 mg sc d 1-3. If MTD was not reached in the first cohort, the second cohort received an increased dose of Cam 30 mg with a subsequent further increase of Ben 70 mg/m if MTD was not reached. Treatment was repeated every 28 days up to 4 cycles. On the basis of phase 1 results (12 patients), the MTDs were Ben 70 mg/m d 1 and 2 and Cam 30 mg sc d 1–3. Results: Between July 2008 and October 2010, we enrolled 29 patients with active disease. Median age was 69 years (range 54–82 years). Median number of prior regimens was 2 (range 1–6); 76% were previously exposed to fludarabine-based regimens and 55% to monoclonal antibodies (rituximab 34%, alemtuzumab 14%, and both 7%). The population was characterized by high-risk biological and clinical disease profiles: 45% of patients were in Binet stage C, bulky lymph nodes ( 5 cm) were present in 28%, and 24% had refractory disease. According to a hierarchical model, del17p was present in 31% of patients and del11q in 17%. Fifty-five percent were IgVH unmutated, 59% were ZAP70-positive, and 45% were CD38-positive. The 29 patients received 104 courses overall (median 4 [range 2–4]). All patients were evaluable for response. The overall response rate was 69%, including 28% complete remissions and 41% partial remissions. Disease progression during treatment was observed in 14% of cases. Grade III–IV hematological toxicity was manageable and consisted of neutropenia in 36% of courses, anemia in 7%, and thrombocytopenia in 9%. Fever of unknown origin developed in 19% of cycles, and 6 major infections (2 cases of sepsis, 3 of pneumonia, 1 of enteritis) were observed. Reactivation of cytomegalovirus occurred in 10 patients; no cytomegalovirus disease was recorded. Extrahematological toxicity was mild. Conclusion: Results from interim analysis of this new, 4-weekly-dosing Ben Cam regimen suggest that combination therapy with bendamustine and alemtuzumab is feasible, safe, and effective in patients with relapsed and refractory CLL. Major treatment toxicities were acceptable myelosuppression and manageable infections. No toxic deaths were recorded during treatment.