Top

Current Hematologic Malignancy Reports

Published in:

01-12-2017 | Acute Myeloid Leukemias (H Erba, Section Editor)

Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia

Authors: Brittany Knick Ragon, Courtney D. DiNardo

Published in: Current Hematologic Malignancy Reports | Issue 6/2017

Abstract

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.

Summary

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.

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.CrossRef

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.CrossRefPubMed

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

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.CrossRefPubMedPubMedCentral

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

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

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

22.

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

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.CrossRef

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. CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedCentral

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.CrossRefPubMed

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. CrossRef

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.

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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf. 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

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

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.

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

44.

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

45.

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

46.

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

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.CrossRefPubMedPubMedCentral

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.PubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

Title: Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia
Authors: Brittany Knick Ragon
Courtney D. DiNardo
Publication date: 01-12-2017
Publisher: Springer US
Published in: Current Hematologic Malignancy Reports / Issue 6/2017
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI: https://doi.org/10.1007/s11899-017-0418-6

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia

Abstract

Purpose of Review

Recent Findings

Summary

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 6/2017

Novel Pathways and Potential Therapeutic Strategies for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): CD123 and Beyond

Predicting Chemotherapy Resistance in AML

Novel Therapies for Myelofibrosis

Using Social Media at National Meetings in Hematology—Optimal Use, Tips, Strategies, and Limitations

Rare Cancers and Social Media: Analysis of Twitter Metrics in the First 2 Years of a Rare-Disease Community for Myeloproliferative Neoplasms on Social Media—#MPNSM

Methods of Detection of Measurable Residual Disease in AML

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page