REVIEW  ACUTE LEUKEMIAS IN 2020: STATE OF THE ART Free access

Minerva Medica 2020 October;111(5):411-26

DOI: 10.23736/S0026-4806.20.07024-X

Copyright © 2020 EDIZIONI MINERVA MEDICA

language: English

Enasidenib and ivosidenib in AML

Maria Paola MARTELLI ¹ ✉, Giovanni MARTINO ¹, Valeria CARDINALI ¹, Brunangelo FALINI ¹, Giovanni MARTINELLI ², Claudio CERCHIONE ³

¹ Section of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy; ² IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy; ³ Unit of Hematology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Forlì-Cesena, Italy

The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.

KEY WORDS: Leukemia, myeloid, acute; Enasidenib; Isocitrate dehydrogenase; Ivosidenib