Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 2 mutation

ABSTRACT

Introduction

Isocitrate dehydrogenase 2 (IDH2) is a key metabolic enzyme that converts isocitrate to α-ketoglutarate (αKG). Somatic point mutations in IDH2 confer a gain-of-function in blast cells resulting in overproduction of D-2-hydroxyglutarate (D-2HG). High intracellular concentrations of D-2HG inhibit α-ketoglutarate-dependent dioxygenases including histone, DNA and RNA demethylases, leading to histone, DNA and RNA hypermethylation, and cell differentiation blockade. In vitro and in vivo preclinical studies have demonstrated that inhibition of IDH2-mutant enzymes with enasidenib decrease intracellular D-2HG levels, reverse epigenetic dysregulation, and release the differentiation block. The US Food and Drug Administration (FDA) approved enasidenib, a mutant-IDH2 enzyme inhibitor for patients with relapsed or refractory (R/R) IDH2-mutated AML.

Areas covered

We review the biology and prognostic significance of IDH2 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of enasidenib. We highlight areas of ongoing preclinical and clinical research.

Expert opinion

Enasidenib was FDA approved due to high response rates, durability of the responses that translated into an impressive OS in that heavily pretreated population. Promising ongoing clinical trials are evaluating combination therapies with enasidenib frontline.

KEYWORDS:

• Tumor metabolism
• epigenetic
• oncogene
• idh2
• acute myeloid leukemia
• 2-HG
• targeted therapies
• enasidenib

Declaration of interest

Stephane de Botton declares consulting for and research funding from AGIOS; consulting for and a member of the speakers bureau of CELGENE; consulting for PIERRE FABRE; consulting for SERVIER; consulting for PFIZER; consulting for NOVARTIS; consulting for JANSSEN; consulting and researching funding from FORMA; consulting for SYROS; consulting for BAYER; consulting for ABBVIE; consulting for DAIICHI; consulting for ASTELLAS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.