Ivosidenib to treat adult patients with relapsed or refractory acute myeloid leukemia

摘要

Isocitrate dehydrogenase 1 and 2 (IDH1 and lDH2) are key metabolic enzymes that convert isocitrate to alpha-ketoglutarate (alpha KG). Somatic point mutations in IDH1/2 that are found in rare distinct subsets of cancers confer a gain of function in cancer cells which results in the accumulation and secretion in vast excess of the oncometabolite D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. High levels of D-2HG inhibit alpha KG-dependent dioxygenases including histone, DNA and RNA demethylases, resulting in histone, DNA and RNA hypermethylation and cell differentiation blockade. In addition, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis, and is also predictive of clinical response. The U.S. Food and Drug Administration (FDA) approved ivosidenib, a mutant-IDH1 enzyme inhibitor, for patients with relapsed or refractory IDH1-mutated acute myeloid leukemia (AML) in 2018, and also as front-line therapy for newly diagnosed elderly patients >= 75 years old or who are ineligible to receive intensive chemotherapy in 2019. Ivosidenib represents a novel drug class for targeted therapy in AML.