Alterations in genes involved in cellular metabolism and epigenetic regulation are common in myeloid malignancies. In approximately 20% of acute myeloid leukaemia patients and 5% of patients suffering from myelodysplastic syndromes, recurring mutations in isocitrate dehydrogenase (IDH) are found. Wild-type IDH catalyses the oxidative decarboxylation of isocitrate, thereby contributing to histone demethylation, DNA modification and cellular adaptation to hypoxia. Mutant IDH has neomorphic activity and reduces α-ketoglutarate to 2-hydroxyglutarate. High levels of 2-hydroxyglutarate are associated with hypermethylation, altered gene expression and differentiation block of haematopoietic progenitor cells. There is no prognostic significance of mutant IDH using standard treatment approaches. However, new oral treatments specifically targeting mutant IDH have shown promising results in inducing responses and are well tolerated. Novel combinations with drugs with non-overlapping mechanisms are underway and may address the clonal heterogeneity of myeloid malignancies. For now, only enasidenib and ivosidinib are FDA approved, but the field of mutant IDH inhibitors is rapidly moving.
(BELG J HEMATOL 2019;10(2):80–4)