Despite rapid advances in our understanding of acute myeloid leukemia (AML), the disease remains challenging to treat with 5-year survival for adult patients 20 years or older estimated to be 26% (Cancer 2021). The use of new targeted therapies including BCL2, IDH1/IDH2, and FLT3 inhibitors has revolutionized treatment approaches but also changed the disease trajectory with unique modes of resistance. Recent studies have shown that stem cell maturation state drives expression level and/or dependence on various pathways, critical to determining drug response. Instead of anticipating these changes, we remain behind the curve chasing the next expanded clone. This review will focus on current approaches to treatment in AML, including defining the significance of blast differentiation state on chemotherapeutic response, signaling pathway dependence, metabolism, immune response, and phenotypic changes. We conclude that multimodal treatment approaches are necessary to target both the immature and mature clones, thereby, sustaining drug response.
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