Skip to main content


Log in

Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia

  • Acute Myeloid Leukemias (H Erba, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript


Purpose of Review

Over the past decade, the pathogenic role of mutations in isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with AML, has been defined, allowing for the development of specific therapeutic strategies for IDH-mutant AML. In this review, the landscape and progress of targeted therapeutics aimed at IDH mutations in AML and related myeloid malignancies will be described.

Recent Findings

Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies. Preliminary results for several of these investigations have shown evidence of safety, tolerability, and encouraging evidence of efficacy.


Targeting IDH mutations in AML is a biologically informed and rational strategy to promote clinical responses, primarily through differentiation and maturation of the malignant clone. The use of IDH targeted therapy is expected to soon become part of a genomically defined and individualized AML treatment strategy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Yang H, Ye D, Guan K-L, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res: Off J Am Assoc Cancer Res. 2012;18(20):5562–71.

    Article  CAS  Google Scholar 

  2. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. JNCI J Natl Cancer Inst. 2010;102(13):932–41.

    Article  CAS  PubMed  Google Scholar 

  3. Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016;21(117):373–80.

    PubMed  Google Scholar 

  4. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010;29(49):6409–17.

    Article  CAS  PubMed  Google Scholar 

  6. Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 2010;16(9):387–97.

    Article  CAS  PubMed  Google Scholar 

  7. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S-H, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Figueroa ME, Wahab OA, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL, et al. Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production. Oncogene. 2012;31(19):2491–8.

    Article  CAS  PubMed  Google Scholar 

  11. Rakheja D, Medeiros LJ, Bevan S, Chen W. The emerging role of D-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms. Front Oncol. 2013;3:169.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Fathi AT, Sadrzadeh H, Borger DR, Ballen KK, Amrein PC, Attar EC, et al. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood. 2012;120(23):4649–52.

    Article  CAS  PubMed  Google Scholar 

  13. DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013;121(24):4917–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 17(3):225–34.

  15. Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6.

    Article  CAS  PubMed  Google Scholar 

  16. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Marcucci G, Maharry K, Wu Y-Z, Radmacher MD, Mrózek K, Margeson D, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer And Leukemia Group B Study. J Clin Oncol. 2010;28(14):2348–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Krönke J, Bullinger L, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3636–43.

    Article  CAS  PubMed  Google Scholar 

  19. DiNardo CD, Ravandi F, Agresta S, Konopleva M, Takahashi K, Kadia T, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chou WC, Lei WC, Ko BS, Hou HA, Chen CY, Tang JL, et al. The prognostic impact and stability of isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia. 2011;25(2):246–53.

    Article  CAS  PubMed  Google Scholar 

  21. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272–81.

    Article  CAS  PubMed  Google Scholar 

  22. Stein EM. IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol. 2015;28(2–3):112–5.

    Article  PubMed  Google Scholar 

  23. Platt MY, Fathi AT, Borger DR, Brunner AM, Hasserjian RP, Balaj L, et al. Detection of dual IDH1 and IDH2 mutations by targeted next-generation sequencing in acute myeloid leukemia and myelodysplastic syndromes. J Molr Diagnostics : JMD. 2015;17(6):661–8.

    Article  CAS  Google Scholar 

  24. •• 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. Important characterization of mutational landscape and prognostic implication of molecular abnormalities in AML.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Green CL, Evans CM, Zhao L, Hills RK, Burnett AK, Linch DC, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118(2):409–12.

    Article  CAS  PubMed  Google Scholar 

  26. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;340(6132):622–6.

    Article  CAS  PubMed  Google Scholar 

  27. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science (New York, NY). 2013;340(6132):626–30.

    Article  CAS  PubMed Central  Google Scholar 

  28. Losman J-A, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, et al. R-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339(6127):1621–5.

    Article  CAS  PubMed  Google Scholar 

  29. • Fathi A, DiNardo C, Kline I, Kenvin L, Gupta I, Attar E, Stein E, de Botton S. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2). J Clin Oncol. 2017;35 (suppl; abstr 7015). Description of clinical differentiation syndrome associated with IDH inhibition.

  30. • Birendra KC, CD DN. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clinical Lymphoma Myeloma and Leukemia. 2016;16(8):460–5. Multi-case description of clinical differentiation syndrome associated with IDH inhibition.

    Article  CAS  Google Scholar 

  31. • Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017; Preclinical results of AG-221 in ex vivo and xenograft models

  32. Shih AH, Shank KR, Meydan C, Intlekofer AM, Ward P, Thompson CB, et al. AG-221, a small molecule mutant IDH2 inhibitor, remodels the epigenetic state of IDH2-mutant cells and induces alterations in self-renewal/differentiation in IDH2-mutant AML model in vivo. Blood. 2014;124(21):437.

    Google Scholar 

  33. •• Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017. Published current clinical results for enasidenib in relapsed/refractory IDH-mutant AML.

  34. •• IDHIFA(R) [package insert]. Celgene Corporation. Summit NA. [Available from: Package insert for first FDA approved IDH targeted agent.

  35. Abbott RealTime IDH 2 [package insert]. Abbott Laboratories. Des Plaines, IL; August 2017.

  36. Tallman MS, Knight RD, Glasmacher AG, Dohner H, Group obotISI. Phase III randomized, open-label study comparing the efficacy and safety of AG-221 vs conventional care regimens (CCR) in older patients with advanced acute myeloid leukemia (AML) with isocitrate dehydrogenase (IDH)-2 mutations in relapse or refractory to multiple prior treatments: the IDHENTIFY trial. Journal of Clinical Oncology. 2016;34(15_suppl):TPS7074-TPS.

  37. • Hansen E, Quivoron C, Straley K, Lemieux RM, Popovici-Muller J, Sadrzadeh H, et al. AG-120, an oral, selective, first-in-class, potent inhibitor of mutant IDH1, reduces intracellular 2HG and induces cellular differentiation in TF-1 R132H cells and primary human IDH1 mutant AML patient samples treated ex vivo. Blood. 2014;124(21):3734. Preclinical evaluation of AG-120

    Google Scholar 

  38. • DiNardo CD, de Botton S, Stein EM, Roboz GJ, Swords RT, Pollyea DA, et al. Determination of IDH1 mutational burden and clearance via next-generation sequencing in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class inhibitor of mutant IDH1. Blood. 2016;128(22):1070. Early clinical results for AG-120 in IDH-mutant hematologic malignancies

    Google Scholar 

  39. Han CH, Batchelor TT. Isocitrate dehydrogenase mutation as a therapeutic target in gliomas. Chinese Clinical Oncology. 2017;6(3).

  40. DiNardo CD, Schimmer AD, Yee KWL, Hochhaus A, Kraemer A, Carvajal RD, et al. A phase I study of IDH305 in patients with advanced malignancies including relapsed/refractory AML and MDS that harbor IDH1R132 mutations. Blood. 2016;128(22):1073.

    Google Scholar 

  41. Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R, Stichel D, et al. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia 2017.

  42. Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Parker SJ, Metallo CM. Metabolic consequences of oncogenic IDH mutations. Pharmacol Ther. 2015;152:54–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015;126(11):1346–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, et al. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget. 2016;7(48):79722–35.

    PubMed  PubMed Central  Google Scholar 

  49. Konopleva M, Flinn I, Wang E, DiNardo CD, Bennett M, Molineaux C, Le M, Maris M, Frankfurt O. Phase 1 study: safety and tolerability of increasing doses of CB-839, an orally-administered small molecule inhibitor of glutaminase, in acute leukemia. EHA Annual Meeting 2015;Abstract 99749.

  50. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478(7370):524–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen C, Liu Y, Lu C, Cross JR, Morris JP, Shroff AS, et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev. 2013;27(18):1974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol. 2014;42(4):247–51.

    Article  CAS  PubMed  Google Scholar 

Download references


Supported in part by the MD Anderson Cancer Center Support Grant CA016672 and NIH T32 Training Grant CA009666

Author information

Authors and Affiliations



Brittany Ragon and Courtney DiNardo participated in the discussion, wrote, and have reviewed and approved the current version of the manuscript.

Courtney DiNardo is responsible for the overall content as guarantor.

Corresponding author

Correspondence to Courtney D. DiNardo.

Ethics declarations

Conflict of Interest

Brittany Knick Ragon declares that he has no conflicts of interest.

Courtney D. DiNardo has served on advisory boards for Agios, Celgene, and Novartis.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Acute Myeloid Leukemias

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ragon, B.K., DiNardo, C.D. Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia. Curr Hematol Malig Rep 12, 537–546 (2017).

Download citation

  • Published:

  • Issue Date:

  • DOI: