Bendamustine: mechanism of action and clinical data

Bendamustine is a chemotherapeutic agent that displays a unique pattern of cytotoxicity compared with conventional alkylating agents. Bendamustine was originally synthesized in the former East German Democratic Republic in the 1960s. It was designed to have both alkylating and antimetabolite properties. The alkylating agent properties are similar to those seen with cyclophosphamide, chlorambucil, and melphalan, and the benzimidazole ring is similar to cladribine. Molecular analyses have revealed that bendamustine differs from other alkylating agents in its mechanism of action. Differences have been observed in regard to its effects on DNA repair and cell cycle progression. Moreover, bendamustine can induce cell death through both apoptotic and nonapoptotic pathways, thereby retaining activity even in cells without a functional apoptotic pathway. Bendamustine has demonstrated significant efficacy in patients with indolent lymphomas and chronic lymphocytic leukemia (CLL), including in patients with disease refractory to conventional alkylating agents and rituximab. The toxicity profile of bendamustine is also superior to that of conventional alkylating agents. Combination therapy with bendamustine and rituximab has demonstrated superior efficacy to a standard rituximab-containing chemotherapy regimen in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, and it is currently being compared against the standard first-line regimen in CLL: fludarabine, cyclophosphamide, and rituximab. Ongoing and planned studies are evaluating new strategies in which bendamustine is being combined with existing agents and with novel therapies to optimize use in different clinical settings.