Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose of obatoclax mesylate in combination with fludarabine phosphate-rituximab (FR) in patients with relapsed chronic lymphocytic leukemia. SECONDARY OBJECTIVES: I. To evaluate toxicity of obatoclax mesylate in combination with FR in this patient population. II. To determine objective response rate and progression-free survival of obatoclax mesylate in combination with FR. III. To correlate levels of anti-apoptotic Bcl-2 family members with drug response. IV. To determine whether apoptosis is induced via the mitochondrial pathway in response to obatoclax mesylate and further enhanced by FR. OUTLINE: This is a dose-escalation study of obatoclax mesylate. Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing. After completion of study therapy, patients are followed every 6 months.