Clinical Experience with Bendamustine: A New Treatment for Patients with Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, primarily affecting patients aged > 60 years. Because of the lack of curative therapies and the increasing prevalence of comorbid conditions in this older population, it is imperative that effective and tolerable agents be developed for patients with CLL. Although the exact mechanism of action has not been fully elucidated, bendamustine is an alkylator that appears to be structurally and mechanistically distinct from agents historically used in CLL treatment. Bendamustine induces extensive and durable double-stranded DNA breaks that result in initiation of the p53-dependent stress response and apoptosis. In addition, although most DNA alkylators target an alkyltransferase DNA-repair mechanism, bendamustine activates a base-excision DNA-repair pathway; this might partially explain bendamustine's activity in relapsed/refractory disease. Preclinical studies indicate that bendamustine and rituximab synergistically inhibit tumor growth and induce apoptosis in non-Hodgkin lymphoma and CLL disease models. Despite bendamustine's availability in Europe for 4 decades, the available clinical data shed little light on its role in the treatment of CLL. Adverse effects include myelosuppression and gastrointestinal complaints. In a recent phase III trial of previously untreated patients with CLL, bendamustine produced superior response rates and progression-free survival compared with chlorambucil, leading to its approval by the US Food and Drug Administration.