The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has
illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted
therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms
of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular
metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2-
hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes.
As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating
in an arrest of normal myeloid differentiation. These discoveries have motivated the development
of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes
while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity
in animal models and early clinical trials, and are now entering Phase 3 study. This review will
focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of
IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism
of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience
IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in
combination with other AML therapies, both to evaluate potential synergistic combinations as well
as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.
Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant
