SOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies

The discovery of Venetoclax (VEN) has transformed the therapeutic landscape of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). However, the response is heterogeneous with 10% to 50% of newly diagnosed AML patients not responding to hypomethylating agent (HMA) and VEN. Furthermore, up to 40% of responding patients relapse shortly. This review discusses the mechanism of action of Venetoclax and the major mechanisms of inherent and acquired resistance to VEN. VEN is highly specific to BCL-2 binding, as such other antiapoptotic proteins in BCL-2 family induce resistance. These antiapoptotic proteins can also be upregulated via a number of compensatory cell signaling pathways including PI3K/AKT/mTOR, the MAPK/ERK pathway, and mutant FLT3-ITD. Mutations can occur in BCL-2 and BAX proteins, or they can be silenced by TP53 mutations and other epigenetic changes. Changes to mitochondrial structure and metabolism can induce resistance. Key metabolic regulators include OXPHOS and alternative amino acid metabolism. Finally microenvironmental factors can influence VEN responses. This paper evaluates subsets of AML by differentiation, histology, cytogenetics and molecular markers and their different responses to VEN; with spliceosome mutations, ASXL1, NPM1 and IDH1/2 being favorable while others such as FLT3, TP53 and BCL-2 mutations being less responsive. Currently intensive multiagent chemotherapy and Venetoclax combinations such as 7+3+VEN are favored in fit younger AML patients. However, with resistant patients’ subsets targeted combination therapies are becoming an increasingly attractive option. We explore the incorporation of non-BCL-2 inhibitors, next-generation BCL-2 and multi-protein agents, other inhibitors most prominently FLT-3 inhibitors in addition to Venetoclax, and other novel approaches for resolving Venetoclax resistance.