Bendamustine: An old drug for a potential new indication!

Bendamustine was first synthesized in the early 1960s by Ozegowski and Krebs in the German Democratic Republic.[1] Among cancer therapeutics, this dual functional alkylator was no less than a popular double agent in the Eastern Bloc before the fall of the Iron Curtain. After its introduction in Europe in the 1990s and in the United States of America in 2001, several preclinical and clinical studies have shown its activity across malignancies including plasma cell disorders, Hodgkin and non-Hodgkin lymphoma, lung cancer, breast cancer, soft-tissue sarcomas, and germ cell tumors.[2–9] Bendamustine has a unique structure with three parts: a bis chloroethyl group acting as nitrogen mustard and conferring alkylating properties; a benzimidazole ring acting as a purine analog which has antimetabolite properties; and a third butyric acid chain which makes it water-soluble. Like other alkylators, it acts by forming interstrand and intrastrand crosslinks but they are more extensive and more durable with bendamustine. It also activates the base excision DNA repair pathway while other alkylators induce an alkyl transferase mechanism of DNA repair which probably makes bendamustine less susceptible to drug resistance based on alkyl guanyl transferase expression.[1,10] Squamous cell carcinoma of the head-and-neck (HNSCC) is a common cancer.[11,12] The feasibility of using bendamustine in combination with radiotherapy or other systemic agents has been suggested by a few prospective and retrospective studies.[13–15] Bendamustine increases Ser and Bax protein levels which are the key components known to trigger p53-mediated apoptosis that plays an important role in the pathogenesis of HNSCC. Moreover, bendamustine has shown only partial cross-resistance with other alkylators like cisplatin.[9] In their retrospective analysis, Patil et al. reported the results of 25 patients with recurrent/refractory HNSCC.[15,16] The enrolled population had already received cisplatin, taxane, and oral metronomic therapy; thus, this was a heavily pretreated cohort with resistant/refractory disease; 52% of the patients had an Eastern Cooperative Oncology Group performance status score of 2 or 3, not unlike what is usually encountered in daily clinical scenarios. Approximately two-thirds of patients were able to receive only one cycle. The strength of the study was in the partial response seen in 53.3% of patients and grade 3/4 adverse events in only 14% of the patients. The median overall survival of 3.2 months is similar to that reported with best supportive care, and less than the 10 months of overall survival reported with standard regimens.[17] Thus, more robust evidence regarding the optimum dose, schedule, and its impact on quality of life is required before bendamustine can be recommended in relapsed refractory HNSCC. Whether bendamustine can be combined with low-dose immunotherapy (immune checkpoint inhibitors), similar to hematological malignancies is likely to be an area of research in future studies.[17] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.