Testing for IDH Mutation in Patients With AML or Hematologic Malignancies | ExploreIDH.com

Isocitrate dehydrogenase (IDH) mutations associated with acute myeloid leukemia (AML) and hematologic malignancies can be detected by molecular profiling

Why you should test for IDH mutations in AML

IDH1 or IDH2 mutations are present in approximately 20% of patients with AML.1,2

AML and other hematologic malignancies are heterogeneous diseases associated with multiple chromosomal aberrations and gene mutations.3,4 Our understanding of the vast molecular heterogeneity of AML is rapidly evolving due to advances in genomic technologies.5-7

Mutations in IDH1 and IDH2 have been found in a number of hematologic malignancies including8-11:

  • AML
  • Angioimmunoblastic T-cell lymphoma
  • Myelodysplastic syndromes/myeloproliferative neoplasms

While the prognostic impact of IDH mutations is not yet clear in patients with AML, patients with an IDH mutation may be eligible for approved targeted therapies and participation in clinical trials.12

When to test for IDH mutations

Due to ever-changing biology of the disease, including clonal evolution, a patient's molecular profile may be different at diagnosis and at relapse.13 In AML and other hematologic malignancies, molecular profiling is most commonly performed on bone marrow samples, but peripheral blood may also be used.14

How to test for IDH mutations

Tests for IDH mutations may be available as part of a gene panel or as gene-specific tests. Several methods are used to test samples from patients with hematologic malignancies for genetic mutations, including polymerase chain reaction (PCR)-based methods and other techniques such as Sanger sequencing, pyrosequencing, and next-generation sequencing (NGS).16-22

Clinical guidelines recommend molecular profiling of patients with relapsed/refractory AML

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) notes that evaluation of several molecular markers may be important for risk assessment and prognostication, and may also guide treatment decisions.12

  • Molecular profiling is suggested upon initial evaluation and at time of relapse as it may assist with selection of appropriate clinical trials
  • If a test is not available at your institution, consult the pathology team (prior to performing the marrow evaluation) about preserving material from the original diagnostic sample for future testing at an outside reference lab.

The College of American Pathologists (CAP) and the American Society of Hematology (ASH) strongly recommend testing for FLT3-ITD and recommend IDH1, IDH2, TET2, WT1, DNMT3A, and/or TP53 mutations.15

Technological platforms for the identification of genetic mutations in AML


  • A genome-wide screen for translocation and other numeric or structural defects
  • Semiquantitative with limited sensitivity
  • Cytogenetic examination requires high-quality marrow samples, and definitive results may be difficult to obtain

fluorescence in situ hybridization

  • Confirms karyotypic defects
  • Identifies deletions or duplications not evident by karyotype
  • Detects cryptic translocations
  • Uncovers cytogenetic information in specimens that have failed to proliferate in tissue culture
  • Cytogenetic examination requires high-quality marrow samples, and definitive results may be difficult to obtain

polymerase chain reaction

  • Identifies common mutations, such as IDH1 and 2
  • Limited utility in detecting mutations in genes with a wide array of potential mutations

Sanger sequencing20,21

  • Allows for genetic mutation characterization
  • Limited throughput, large sample requirements, and slow turnaround time

next-generation sequencing

  • Parallel sequencing of multiple genes in a single panel
  • Improved sensitivity and lower cost per base pair
  • Takes time to interpret data and slow turnaround time

Clinical trials are available for AML patients who test positive for an IDH mutation.


How to test for IDH mutations in AML patients

Partner with your pathologist to optimize sample collection and molecular-profiling strategy12

  • Determine clinically relevant genes to test for in patients with AML12,16,19,22
  • Clearly articulate turnaround time requirements22
  • Understand the strengths and limitations of various molecular-profiling technologies16,22
  • Discuss the ideal testing approach—single-gene vs multigene panel
  • Determine best practices for specimen collection and storage12,16

Talk with your pathologist about how to test your AML patients for IDH mutations.

IDH mutations in AML

  1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.
  2. McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9):3672-3677.
  3. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006;368(9550):1894-1907.
  4. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
  5. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
  6. Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008;359(7):722-734.
  7. Wouters BJ, Löwenberg B, Delwel R. A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects. Blood. 2009;113(2):291-298.
  8. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730-741.
  9. Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochem Biophys Acta. 2014;1846(2):326-341.
  10. Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28(1):78-87.
  11. Cazzola M. IDH1 and IDH2 mutations in myeloid neoplasms--novel paradigms and clinical implications. Haematologica. 2010;95(10):1623-1627.
  12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed [May 20, 2019]. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  13. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506-510.
  14. Sever C, Abbott CL, de Baca ME, et al. Bone marrow synoptic reporting for hematologic neoplasms: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2016;140(9):932-949.
  15. Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology [published online February 22, 2017]. Arch Pathol Lab Med. doi:10.5858/arpa.2016-0504-CP
  16. Gulley ML, Shea TC, Fedoriw Y. Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. J Mol Diagn. 2010;12(1):3-16. http://jmd.amjpathol.org/article/S1525-1578%2810%2960023-2/fulltext. Accessed April 19, 2017.
  17. Yeung DT, Parker WT, Branford S. Molecular methods in diagnosis and monitoring of haematological malignancies. Pathology. 2011;43(6):566-579.
  18. Duncavage EJ, Abel HJ, Szankasi P, Kelley TW, Pfeifer JD. Targeted next generation sequencing of clinically significant gene mutations and translocations in leukemia. Mod Pathol. 2012;25(6):795-804. http://www.nature.com/modpathol/journal/v25/n6/full/modpathol201229a.html. Accessed May 5, 2017.
  19. Ziai JM, Siddon AJ. Pathology consultation on gene mutations in acute myeloid leukemia. Am J Clin Pathol. 2015;144(4):539-554.
  20. Luthra R, Patel KP, Reddy NG, et al. Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. Haematologica. 2014;99(3):465-473.
  21. Black JS, Salto-Tellez M, Mills KI, Catherwood MA. The impact of next generation sequencing technologies on haematological research—a review. Pathogenesis. 2015;2(1-2):9-16. http://www.sciencedirect.com/science/article/pii/S221466361500005X. Accessed April 17, 2017.
  22. Yang F, MD, Press RD, MD, PhD. Next-generation sequencing multi-gene mutation panels in myeloid malignancies. The Hematologist: ASH News & Reports. 2016;13(3):1-8. http://www.hematology.org/Thehematologist/Mini-Review/5496.aspx. Published April 14, 2016. Accessed April 17, 2017.

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