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Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.

The discovery of oncogenic mutations in isocitrate dehydrogenase (IDH) enzymes has highlighted the delicate interplay of metabolism, cellular signaling, and transcriptional regulation that was off-focus for some time in the genomic era. Although IDH inhibitors are being evaluated for clinical efficacy, an in-depth understanding of disease pathogenesis linked to IDH mutations is required to develop rational combination treatments and to be evaluated in the clinic. To gain such an understanding, several questions need to be addressed: Why do IDH mutations occur selectively in subsets of a disease entity although they are found to be present in a very heterogeneous set of unrelated tumors? Why are 2-hydroxyglutarate-producing tumors specifically selected for the R-enantiomer and not for the S-enantiomer? Are the changes in 2-hydroxyglutarate-induced DNA methylation primary or secondary alterations in tumorigenesis? What are the roles of hypoxia-inducible factor (HIF) and its prolyl 4-hydroxylases in IDH-mutant tumors? Here, we address these questions and discuss the consequences for basic and clinical research related to IDH-mutant tumors., (Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)