Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia

Abstract

The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the heterogeneous molecular basis of the disease. Since genetic sequencing has become a standard practice, several driver mutations have been identified. Accordingly, novel targeted therapeutic agents have been developed and are now approved for the treatment of subsets of patients that carry mutations in FLT3, IDH1, and IDH2 [1, 2]. The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.

Fig. 1. Mutated IDH1/2 converts α-ketoglutarate to R-2-hydroxyglutarate, which competitively inhibits α-ketoglutarate dependent enzymes required for DNA and histone demethylation, DNA repair pathways, and HIF-1α hydroxylation and proteasomal degradation.

This leads to altered gene expression, chromosomal instability, and persistent pseudohypoxia which drive leukemic transformation. Figure Key: IDH isocitrate dehydrogenase, HIF-1α hypoxia-inducible factor 1α, HPH hypoxia-inducible factor prolyl hydroxylases, JHDM JmjC-domain-containing histone lysine demethylase, TET2 ten-eleven translocation 2, alkB Alkylation B.