Building on Foundations: Venetoclax-Based Combinations in the Treatment of Acute Myeloid Leukemia

Simple Summary Treatment of acute myeloid leukemia continues to progress. Although a number of therapies are efficacious in treating acute myeloid leukemia, some are intolerable to older patients or patients who have more advanced disease. In light of this, newer therapies that are both efficacious and tolerable are being studied as a monotherapy and in combination with other therapies. In this review article, we aim to summarize on going clinical trials of venetoclax in combination with other targeted therapies. When combined with other therapies, venetoclax demonstrates synergy in comparison to venetoclax monotherapy or alternate therapy alone. In addition, venetoclax combinations appear to overcome a number of known resistance mechanisms to venetoclax. Frontline acute myeloid leukemia (AML) treatment is determined by a combination of patient and genetic factors. This includes patient fitness (i.e., comorbidities that increase the risk of treatment-related mortality) and genetic characteristics, including cytogenetic events and gene mutations. In older unfit patients, the standard of care treatment is typically venetoclax (VEN) combined with hypomethylating agents (HMA). Recently, several drugs have been developed targeting specific genomic subgroups of AML patients, enabling individualized therapy. This has resulted in investigations of doublet and triplet combinations incorporating VEN aimed at overcoming known resistance mechanisms and improving outcomes in older patients with AML. These combinations include isocitrate dehydrogenase-1/2 (IDH1/2) inhibitors (i.e., ivosidenib and enasidenib), fms-like tyrosine kinase 3 (FLT3) inhibitors (i.e., gilteritinib), anti-CD47 antibodies (i.e., magrolimab), mouse double minute-2 (MDM2) inhibitors, and p53 reactivators (i.e., eprenetapopt). This review summarizes ongoing trials aimed at overcoming known VEN resistance mechanisms and improving outcomes beyond that observed with HMA + VEN combinations in the treatment of AML.