Apoptosis targeted therapies in acute myeloid leukemia: an update

Introduction: Management of acute myeloid leukemia (AML) continues to be a therapeutic challenge despite significant recent advancements. Dysregulation of several components of apoptotic pathways has been identified as potential driver in AML. Areas covered: Overexpression of anti-apoptotic proteins, B-cell lymphoma 2 (BCL2), BCL-XL, and myeloid cell leukemia-1 (MCL1), has been associated with worse outcome in AML. Dysfunction of p53 pathway (often through mouse double minute 2 homolog (MDM2)) and high expression of inhibitor of apoptosis proteins (IAP) constitute other disruptions of apoptotic machinery. Significant antileukemic activity of BCL2 inhibitors (particularly venetoclax) in preclinical models has translated into improved objective response and overall survival in combination with hypomethylating agents in AML. Addition of MCL1, BCL-XL, or MDM2 inhibitors could potentially overcome resistance to BCL2 inhibition. Authors conducted a thorough review of available literature on therapeutic options targeting apoptosis in AML, using PubMed, MEDLINE, meeting abstracts, and ClinicalTrials.gov. Expert opinion: While venetoclax remains the core component of targeting apoptosis, ongoing clinical trials should help find ideal combination regimens in different AML subgroups. Future research should focus on overcoming resistance to BCL2 inhibition, optimal management of adverse events, and development of biomarkers to identify patients most likely to benefit from apoptosis-targeted therapies.