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Review
. 2021 Apr;16(2):207-217.
doi: 10.1007/s11899-021-00619-3. Epub 2021 Apr 30.

IDH Inhibitors in AML-Promise and Pitfalls

Hannah McMurry  1 , Luke Fletcher  2 , Elie Traer  3
Affiliations
Review

IDH Inhibitors in AML-Promise and Pitfalls

Hannah McMurry et al. Curr Hematol Malig Rep. 2021 Apr.

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. 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.

Keywords: Acute myeloid leukemia (AML); Enasidenib; IDH inhibitors; IDH1; IDH2; Isocitrate dehydrogenase (IDH); Ivosidenib.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
    1. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. Comprehensive paper defining genetic abnormalities in AML.
    1. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. - DOI
    1. Gilliland DG. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol. 2002;39(4 Suppl 3):6–11. - DOI
    1. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–65. - DOI
    1. Fletcher L, Joshi SK, Traer E. Profile of quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD-positive acute myeloid leukemia: evidence to date. Cancer Manag Res. 2020;12(1179-1322 (Print)):151–63. - DOI

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