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Simple Summary  Venetoclax is a BH3-mimetics that specifically inhibits the antiapoptotic protein BCL-2. The drug has considerably expanded the treatment options of acute myeloid leukemia (AML) patients unfit for intensive treatment regimens. In recent phase III trials, combination of venetoclax with the hypomethylating agents azacitidine or with low dose cytarabine, was associated with a 48–65% response rate and a 7.2–14.7 months overall survival. Recent studies also suggest that the drug is highly efficient in combination with high-dose chemotherapy and targeted therapeutics, including IDH and FLT3 inhibitors. In this review, we summarize the molecular basis of BCL-2 inhibition in AML, the effect of venetoclax in preclinical models and clinical studies and discuss the main molecular pathways and therapeutic options for overcoming venetoclax resistance. Identifying new therapeutic strategies increasing BH3 mimetics activity and/or sensitizing toward apoptotic cell death will represent a major challenge for treating AML patients in the near future.    Abstract  Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery.

Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance