Efficacy and Safety Profile of Ivosidenib in the Management of Patients with Acute Myeloid Leukemia (AML): An Update on the Emerging Evidence.

Abstract

The isocitrate dehydrogenase enzyme, catalyzing isocitrate conversion to α-ketoglutarate (αKG) in both the cell cytoplasm and mitochondria, contributes to the production of dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as a reductive potential in various cellular processes. IDH1 gene mutations are revealed in up to 20% of the patients with acute myeloid leukemia (AML). A mutant IDH enzyme, existing in the cell cytoplasm and possessing neomorphic activity, converts αKG into oncometabolite R-2-hydroxyglutarate (R-2-HG) that accumulates in high amounts in the cell and inhibits αKG-dependent enzymes, including epigenetic regulators. The resultant alteration in gene expression and blockade of differentiation ultimately lead to leukemia development. Myeloid differentiation capacity can be restored by obstruction of the mutant enzyme, inducing substantial reduction in R-2-HG levels. Ivosidenib, a potent selective inhibitor of mutant IDH1, is a differentiating agent shown to be clinically effective in newly diagnosed AML (ND-AML) and relapsed/refractory (R/R) AML harboring this mutation. The drug is approved by the Food and Drug Administration (FDA) as a single-agent treatment for R/R AML. Significance of mutated IDH1 targeting and a potential role of ivosidenib in AML management, when used either as a single agent or as part of combination therapies, will be reviewed herein.