Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

SIMPLE SUMMARY: Venetoclax has proven to be a promising therapy for newly diagnosed, relapsed and refractory AML patients ineligible for induction chemotherapy. Current ongoing clinical trials are evaluating its effectivity as frontline therapy for all acute myeloid leukemia (AML) patients. However, response rates vary wildly, depending on patient characteristics and mutational profiles. This review elaborates on the efficacy and safety of venetoclax compared to conventional chemotherapy for treatment of AML patients, comparing the response rates, overall survival and adverse events. Moreover, it gives an overview of genetic and epigenetic AML cell characteristics that give enhanced or decreased response to venetoclax and offers insights into the pathogenesis of venetoclax sensitivity and resistance. Additionally, it suggests possible treatment combinations predicted to be successful based on identified mechanisms influencing venetoclax sensitivity of AML cells. ABSTRACT: Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.