Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?

Combined hypomethylating agent (HMA) plus venetoclax (Ven) therapy enables most older patients with acute myeloid leukemia (AML) to achieve clinical remission. Key objectives are now aimed at developing new triplet combinations to circumvent mechanisms of resistance and extend remission longevity and, by extension, survival. Genomically agnostic approaches combine hypomethylating agents and venetoclax (HMA-Ven) with novel agents directed at oncogenic pathways critical for leukemic cell survival, proliferation, metabolism, or differentiation. Challenges faced in the development of new HMA-Ven triplets include competition from targeted inhibitors, biological heterogeneity of AML, potential for additive toxicity, reduced efficacy from modifications to the HMA-Ven backbone, and the higher bar for success in older AML beyond the current standard of care.