Optimizing Next-Generation AML Therapy: Activity of Mutant IDH2 Inhibitor AG-221 in Preclinical Models

Abstract

<b/> AG-221 or enasidenib is a first-in-class selective inhibitor of mutated isocitrate dehydrogenase 2 (IDH2) with early demonstrated clinical efficacy in acute myeloid leukemia as a single agent, yet with persistence of mutant IDH2 clones. Two articles in this issue of Cancer Discovery provide further insight into the biological activity of AG-221 in promoting differentiation of IDH2-mutant cells and reversing aberrant DNA methylation over time, and demonstrating preclinical activity in combination with a targeted FLT3 kinase inhibitor to eliminate IDH2-mutant clones. Cancer Discov; 7(5); 459-61. ©2017 AACR.See related article by Yen et al., p. 478See related article by Shih et al., p. 494.

Figure 1. Schematic of AG-221 Effects on IDH2-Mutant AML

In vivo and in vitro treatment of IDH2 R140Q mutated leukemic blasts with the IDH2-mutant specific inhibitor AG-221 promotes differentiation in a significant proportion of cells. These changes include increased granulation and phagocytic activity and upregulation of mature myeloid markers with concomitant downregulation of global DNA hypermethylation and histone methylation. Consistent with early results from clinical trials, differentiated cells are IDH2 mutation positive and persist in the bone marrow after blast reduction in pre-clinical models and in some patients. In vivo studies in murine models of IDH2-mutated leukemia suggest AG-221 in combination with anti-proliferative strategies including cytarabine or FLT3 kinase inhibitors may be beneficial in achieving further eradication of IDH2-mutant positive cells.