The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia

Therapeutic Advances in Hematology
Iman Abou Dalle, Courtney D DiNardo

Abstract

Recurrent mutations affecting cellular metabolism and epigenetic regulation are implicated in the pathogenesis of acute myeloid leukemia (AML). Isocitrate dehydrogenase 2 (IDH2) gene mutations are described in 12% of patients with AML and 5% of patients with myelodysplastic syndromes. IDH2 enzyme is involved in the Krebs cycle, catalyzing α-ketoglutarate from isocitrate. Mutant IDH2 enzymes acquire a neomorphic enzymatic activity with the ability to produce 2-hydroxyglutarate from α-ketoglutarate, inhibiting multiple α-ketoglutarate-dependent dioxygenase reactions; leading to aberrant DNA hypermethylation and differentiation block in myeloid precursors and ultimately promoting leukemogenesis. Enasidenib (formerly AG-221) is an oral small molecule selective targeted inhibitor of the mutant IDH2 enzyme, approved in August 2017 by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory (R/R) IDH2-mutated AML. Preclinical studies showed the effectiveness of enasidenib in inhibiting the production of 2-hydroxyglutarate with high potency, and alleviating the mutant IDH2-induced differentiation block. In the original AG221-001 phase I/II trial, patients with R/R AML were treated with en...Continue Reading

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Citations

Jan 15, 2020·Current Treatment Options in Oncology·Shaheedul A SamiShaker A Mousa
Jun 27, 2019·Cancers·Carmelo GurnariEmiliano Fabiani
Dec 20, 2019·Dose-response : a Publication of International Hormesis Society·Xiao HuangZhijun Yang
Jun 2, 2020·Biomarker Research·Jifeng YuYongping Song
Feb 6, 2019·Therapeutic Advances in Hematology·Jan Philipp BewersdorfAmer M Zeidan
Apr 2, 2020·Experimental Hematology & Oncology·Jifeng YuZhongxing Jiang
Apr 16, 2020·International Journal of Analytical Chemistry·Shuang-Long LiXiang-Jun Qiu
Jun 5, 2021·Blood Cancer Journal·Ghayas C Issa, Courtney D DiNardo
Jun 11, 2021·Frontiers in Oncology·Stefano RattiRoberta Fiume

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Methods Mentioned

BETA
MDS
fluorescence-activated cell sorting
xenograft

Clinical Trials Mentioned

NCT01915498
NCT02677922
NCT02577406
NCT02632708
NCT03013998
NCT03383575

Software Mentioned

IDHENTIFY

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