Bendamustine for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B-cell non-hodgkin lymphoma

Background: Bendamustine is a mechlorethamine derivative with a purine-like benzimidazole ring, which may enhance its clinical efficacy. Bendamustine was approved by the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) in March 2008 and for the treatment of rituximab-refractory, indolent B-cell non-Hodgkin lymphoma (NHL) in October 2008. Objective: This article reviews the pharmacologic and pharmacodynamic properties of bendamustine, together with data on efficacy and toxicity from trials investigating the use of bendamustine for the treatment of various hematologic malignancies, including CLL, NHL, and multiple myeloma (MM). Methods: MEDLINE and International Pharmaceutical Abstracts (1970–April 15, 2009) were searched using the terms bendamustine, bendamustin, Treanda, Ribomustin, SDX-105, IMET-3393, and Cytostasan. References from relevant articles were also reviewed for additional sources and material. The databases of the American Society of Hematology (2004–2008) and the American Society of Clinical Oncology (1995–2008) were searched for relevant abstracts. Results: Bendamustine is a mechlorethamine derivative with structural similarity to chlorambucil and other drugs from the nitrogen mustard class, as well as a benzimidazole ring, which may act as an antagonist to purines and amino acids. It has good oral bioavailability but has been studied almost exclusively in the intravenous formulation. It undergoes extensive first-pass metabolism by cytochrome P450 1A2 to active metabolites γ-hydroxy bendamustine and N-desmethyl-bendamustine, but clinical activity appears to be associated primarily with the parent compound. The t½ of bendamustine is ~40 minutes. While bendamustine has 2 moieties with possible antitumor effect, it is unclear to what extent the benzimidazole ring enhances the efficacy of the drug. Numerous studies including in vitro assays have reported, however, that bendamustine has little cross-resistance with other alkylating agents and remains active even in extensively pretreated patients. FDA approval for use in CLL was based on findings from a randomized, open-label, Phase III study comparing bendamustine with chlorambucil as single-agent therapy in treatmentnaive patients with CLL (Binet stage B or C). Bendamustine was administered intravenously at a dose of 100 mg/m2 on days 1 and 2, while chlorambucil was administered orally at 0.8 mg/kg daily, both over 4-week cycles for up to 6 cycles. At interim analysis (the data used for FDA approval), bendamustine was associated with a greater overall response (68% vs 39%; P < 0.001), median progression-free survival (21.7 vs 9.3 months; P < 0.001) and median duration of remission (18.9 vs 6.1 months; P < 0.001) compared with chlorambucil. FDA approval for rituximabrefractory, indolent B-cell NHL followed a Phase III, open-label, single-arm study evaluating bendamustine monotherapy in patients who did not respond to rituximab or had progressive disease within 6 months of rituximab therapy. Bendamustine 120 mg/m2 was administered intravenously on days 1 and 2 of a 21-day cycle for up to 8 cycles. At interim analysis, the overall response rate was 84%, including 29% complete response. The median progression-free survival was 9.7 months. The efficacy of bendamustine has also been reported in the treatment of MM in clinical studies, and bendamustine has been approved in Europe for treating MM, NHL, CLL, breast cancer, and Hodgkin lymphoma. Dose-limiting toxicity is primarily hematologic. Treatment-associated infections have been reported in some studies; however, nonhematologic adverse events have rarely been dose limiting. The most common nonhematologic adverse events include fatigue, nausea, xerostomia, and pyrexia. Conclusions: Bendamustine is a mechlorethamine derivative with a purine-like benzimidazole ring, which may enhance its clinical efficacy. It has been approved in the United States for the treatment of CLL and rituximab-refractory, indolent B-cell NHL. It has been approved in Europe for use in other malignancies, and clinical studies have reported activity in MM.