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IDH Inhibitors in AML—Promise and Pitfalls

  • Acute Myeloid Leukemias (U Borate, Section Editor)
  • Published:
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Abstract

Purpose of Review

Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML.

Recent Findings

IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens.

Summary

IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.

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Acknowledgements

The authors would like to acknowledge our patients treated with IDH inhibitors. We also thank Willow Traer for her rendering of the mitochondria and nucleus in Fig. 1.

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Authors and Affiliations

  1. Department of Internal Medicine, Oregon Health & Science University, Portland, OR, 97239, USA

    Hannah McMurry

  2. Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA

    Luke Fletcher & Elie Traer

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  1. Hannah McMurry
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  2. Luke Fletcher
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All authors contributed equally to this work.

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Correspondence to Elie Traer.

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Conflict of Interest

E. Traer potential competing interests: advisory board/consulting: Abbvie, Agios, Astellas, Daiichi-Sankyo. Clinical trial funding: Janssen, Incyte, LLS BeatAML. Stock options: notable Labs. H. McMurry and L. Fletcher declare that they have no competing interests.

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McMurry, H., Fletcher, L. & Traer, E. IDH Inhibitors in AML—Promise and Pitfalls. Curr Hematol Malig Rep 16, 207–217 (2021). https://doi.org/10.1007/s11899-021-00619-3

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