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Acute myeloid leukemia (AML) is an aggressive disease which has traditionally been treated with intensive chemotherapy. Survival in patients with high-risk cytogenetic and molecular subsets has been poor with this approach due to suboptimal responses seen with intensive chemotherapy and due to many patients with higher risk disease being older and unable to tolerate intensive therapies. In recent years, several targeted therapies have been under investigation for patients with high-risk AML subsets. This review covers four different subsets of high-risk AML including TP53-mutated, KMT2A-rearranged, FLT3-mutated, and secondary AML developing after prior hypomethylating agent exposure. The research discussed in this review focuses on small molecule inhibitors that have been studied in the treatment of these high-risk AML subsets. There are several small molecule inhibitors that have demonstrated promise in these high-risk AML subsets. Longer follow-up and ongoing investigation are needed to continue to optimize therapy for patients with high-risk AML.

Emerging small molecular inhibitors as targeted therapies for high-risk acute myeloid leukemias