venetoclax + decitabine + azacitidine

Venetoclax combined with decitabine or azacitidine is a therapeutic regimen for elderly patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Venetoclax is a potent, selective, oral inhibitor of BCL-2, a protein that maintains myeloblast survival by sequestering pro-apoptotic BAX. When BCL-2 is antagonized by venetoclax, BAX is released, resulting in mitochondrial outer membrane permeabilization and cell death. The hypomethylating agents (decitabine or azacitidine) work synergistically with venetoclax, with azacitidine potentially reducing levels of MCL-1, an anti-apoptotic protein critical in AML pathogenesis. This combination disrupts energy metabolism in leukemia stem cells by inhibiting electron transport chain complex II, suppressing oxidative phosphorylation, and targeting leukemia stem cells.