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Simple Summary: The combination of venetoclax and azacititine (VEN–AZA) has recently been approved for the treatment of unfit newly diagnosed (ND) acute myeloid leukemia (AML) patients. Few data are available for the relapsed and/or refractory (R/R) AML group. We retrospectively compared the outcome of 39 R/R to 38 concomitant ND AML patients treated in our institution between 01/20 and 12/21. Response rates were lower in R/R AML (37% versus 56%); adverse cytogenetics was associated with treatment failure only in the R/R group (Relative Risk = 0.10, p = 0.005). ASXL1, IDH and SFSR2 mutations were associated with a trend in a higher response rate in the R/R group. Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months in the ND and R/R groups, respectively). In conclusion, VEN–AZA can be efficient as a salvage treatment for selected R/R AML patients. Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN–AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22–86) and 73 (61–81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN–AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN–AZA is a promising treatment for ND AML and for selected R/R AML patients. [ABSTRACT FROM AUTHOR]

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. 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. [ABSTRACT FROM AUTHOR]