Effective AML Therapy via Apoptosis Promotion

A key reason why AML (stem) cells fail to die upon exposure to cytotoxic chemotherapy may lie in overexpression of anti-apoptotic molecules such as BCL-2 and MCL-1.  BCL-2,  for example,  binds to other BH3 proteins such as BAD and BIM , which left unfettered, would impair the integrity of the mitochondrial membrane and lead to apoptosis during times of cellular stress. Venetoclax, an orally available small molecule which binds to BCL-2, thus aids in promoting apoptosis. The response to single agent venetoclax in advanced AML was only 19%. However, when venetoclax at the tolerable dose of 400 mg  daily was given to previously untreated older adults who were deemed not be candidates for standard induction  in combination with low dose cytarabine or either of the DNA hypomethylating agents decitabine or azacitdine, the overall response rate was approximately 70%, double what would have been expected with the chemotherapeutic agent alone. Tumor lysis, noted in CLL pts treated with venetoclax was rarely seen with the ramp-up dosing employed in the trials; myelosuppression was more pronounced with the combination. These venetoclax combinations were granted accelerated FDA approval for use in this setting; full approval rests on the positive overall survival outcome of a phase III trial of azacitidine +/- venetoclax.  Clinical research involving the use of venetoclax in a variety of clinical settings in myeloid malignancies as well as strategies to overcome venetoclax resistance for example by down regulating MCL1 are underway.