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Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy

Authors Nassereddine S, Lap CJ, Tabbara IA

Received 6 October 2018

Accepted for publication 5 December 2018

Published 28 December 2018 Volume 2019:12 Pages 303—308

DOI https://doi.org/10.2147/OTT.S182443

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Leo Jen-Liang Su


Samah Nassereddine,1,2 Coen J Lap,2 Imad A Tabbara1,2

1Department of Internal Medicine, The George Washington University School of Medicine, Washington, DC, USA; 2Division of Hematology/Oncology, The George Washington Cancer Center, Washington, DC, USA

Abstract: Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the oncometabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years.

Keywords: ivosidenib, AML, IDH1, relapsed, refractory

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