Bendamustine has an interesting history that spans more than 50 years. Bendamustine was first synthesized in the early 1960s in the former East Germany. It was first used to treat multiple myeloma and was subsequently extended to patients with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. Unfortunately, not much information is available from these original patients treated with bendamustine. It might have been possible to answer some of the questions regarding the long-term effects of bendamustine if these original patients had been followed up and their data recorded. Since bendamustine was first studied in prospective clinical trials in the 1990s, a large amount of information of single-agent and more recently combination therapy has become available.
This article points out the compound structure of bendamustine and its dual mechanisms of action with both alkylating agent activity and purine analog-like activity. Therefore, bendamustine causes cellular death by several mechanisms, including activation of DNA damage stress responses, apoptosis, and inhibition of mitotic checkpoints. When combined with monoclonal antibodies and/or other chemotherapeutic agents, multiple mechanisms of cell death can be combined, thereby increasing malignant cell death. With chemotherapy-resistant malignant cells, this method of attack from multiple mechanisms may be more beneficial.
An interesting aspect of bendamustine is its approval at a number of different doses and for different clinical indications in various areas of the world. With the growing clinical information in a variety of malignancies, extension of the indications for bendamustine seem likely in the United States. Clinically, bendamustine has demonstrated a wide therapeutic usefulness; however, dose reductions in heavily pretreated patients are frequently needed.
The metabolism of bendamustine is primarily through hydrolysis to metabolites. The majority of the elimination is through feces; however, a small amount is excreted in the urine. Bendamustine should be used with caution in patients with renal and hepatic impairment.
This series of articles will discuss data concerning the clinical use of bendamustine in its current indications of CLL and indolent NHL, as well as some of the areas of ongoing investigation in different indications and with a variety of combination therapies.