Untangling the Role
of IDH in Oncology

Mutations in IDH drive cancer progression
via epigenetic dysregulation – high-level
changes in methylation altering chromatin
structure, blocking cellular differentiation,
and ultimately driving oncogenesis.1

Mutations in IDH drive cancer progression via epigenetic dysregulation – high-level changes in methylation altering chromatin structure, blocking cellular differentiation, and ultimately driving oncogenesis.1

What is IDH?

Thumbnail, click for more info: Isocitrate dehydrogenase 1 and 2

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes critical for the conversion of isocitrate to α-ketoglutarate (α-KG), a key functional metabolite.1 Mutations in IDH genes result in increased concentrations of the related oncometabolite 2-hydroxyglutarate (2-HG), which blocks the action of α-KG, interfering with the epigenetic regulation of numerous cellular processes and promoting an immunosuppressive tumor microenvironment.1,2

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes critical for the conversion of isocitrate to α-ketoglutarate (α-KG), a key functional metabolite.1 Mutations in IDH genes result in increased concentrations of the related oncometabolite 2-hydroxyglutarate (2-HG), which blocks the action of α-KG, interfering with the epigenetic regulation of numerous cellular processes and promoting an immunosuppressive tumor microenvironment.1,2

LearnMore about the role of IDH

The MDS-AML Spectrum

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are thought to be part of a spectrum of disease with increasing blast counts when moving from MDS to AML.4 This blast count cutoff is traditionally defined at 20%, however guidelines and prognostic scoring systems are rapidly changing to reflect the overlap of the two related disease states and take into account mutational status which may influence risk stratification.5–7

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are thought to be part of a spectrum of disease with increasing blast counts when moving from MDS to AML.4 This blast count cutoff is traditionally defined at 20%, however guidelines and prognostic scoring systems are rapidly changing to reflect the overlap of the two related disease states and take into account mutational status which may influence risk stratification.5–7

LearnMore about the MDS-AML spectrum

The Impact of mIDH in
Oncology

The Impact of mIDH in Oncology

Thumbnail, click for more info. Kaplan-Meier curves for overall and event-free survival

Although the full prognostic significance of IDH mutations is still being established, existing data indicates that patients with IDH1 mutations are more often in adverse risk categories and may have worse overall outcomes than those with IDH wild-type in MDS and AML.8-10

Although the full prognostic significance of IDH mutations is still being established, existing data indicates that patients with IDH1 mutations are more often in adverse risk categories and may have worse overall outcomes than those with IDH wild-type in MDS and AML.8-10

LearnMore about the prognostic impact of mIDH in oncology

Visualizing the Effect of
IDH Mutations in MDS

Visualizing the Effect of IDH Mutations in MDS

Using the IPSS-M Risk Calculator

The most recent version of the International Prognostic Scoring System, the IPSS-M, incorporates molecular gene mutations (such as IDH1 and IDH2) to improve risk stratification and therapeutic decision-making in MDS.11,12

The most recent version of the International Prognostic Scoring System, the IPSS-M, incorporates molecular gene mutations (such as IDH1 and IDH2) to improve risk stratification and therapeutic decision-making in MDS.11,12

Note that IPSS-M results are less confident with missing mutation data.12

LearnMore about the IPSS-M calculator

The Importance of Expedited
Mutational Testing

Molecular profiling is recommended as part of the initial evaluation for AML and MDS, and should be repeated at relapse.16,17

Due to the negative prognostic impact of certain mutations, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia recommend expedited testing at diagnosis, and repeated testing at relapse and progression.16

A large, real-world data analysis has demonstrated that a short delay for mutational testing has no negative bearing on outcomes in AML.18

Molecular profiling is recommended as part of the initial evaluation for AML and MDS, and should be repeated at relapse.16,17

Due to the negative prognostic impact of certain mutations, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia recommend expedited testing at diagnosis, and repeated testing at relapse and progression.16

A large, real-world data analysis has demonstrated that a short delay for mutational testing has no negative bearing on outcomes in AML.18

LearnMore about Mutational Testing

IDH Testing Center Coverage in the
United States*

Recent advances in mutational testing techniques, and availability at commercial reference laboratories, have improved turnaround times in some cases to as few as 3-5 days.16,19-23

Multiple types of assays exist from simple panel tests to full NGS sequencing. Bone marrow aspirate or peripheral blood plasma can be used for mutational testing.16,19 Different methods can be combined to obtain fast answers while waiting for comprehensive results. Consult your local pathologist to discuss ways to optimize sample collection and preservation.16

*Map illustrates general availability of IDH1 panel test across the United States. Servier makes no guarantees to availability of a specific test or testing site in your area. Please contact one of these testing sites directly for additional information.

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References:

1. Pirozzi CJ, Yan H. Nat Rev Clin Oncol. 2021;18(10):645-661. doi:10.1038/s41571-021-00521-0 2. Phillips, Carmen. National Cancer Institute Website. https://www.cancer.gov/news-events/cancer-currents-blog/2022/idh1-cancer-metabolite-blocks-immune-cells. Accessed May 12, 2023. 3. RCSB Protein Data Bank website. https://www.rcsb.org/structure/3MAP. Accessed May 18, 2023. 4. Ambinder AJ, DeZern AE. Front Oncol. 2022;12:1033534. doi:10.3389/fonc.2022.1033534 5. Zeidan AM, Pollyea DA, Garcia JS, et al. Blood. 2019;134(Supplement_1):565-565. doi:10.1182/blood-2019-124994  6. Arber DA, Orazi A, Hasserjian RP, et al. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850 7. Khoury JD, Solary E, Abla O, et al. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1 8. Thol F, Weissinger EM, Krauter J, et al. Haematologica. 2010;95(10):1668-1674. doi:10.3324/haematol.2010.025494 9. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Leukemia. 2017;31(2):272-281. doi:10.1038/leu.2016.275 10. Jin J, Hu C, Yu M, et al. PLoS ONE. 2014;9(6):e100206. doi:10.1371/journal.pone.0100206 11. Bernard E, Tuechler H, Greenberg PL, et al. NEJM Evidence. 2022;1(7). doi:10.1056/EVIDoa2200008 12. IPSS-M Risk Calculator website. https://mds-risk-model.com/. Accessed March 25, 2023. 13. Aguirre LE, Al Ali N, Sallman DA, et al. Leukemia. Published online May 5, 2023. doi:10.1038/s41375-023-01910-3 14. Cazzola M. Hematology. 2022;2022(1):375-381. doi:10.1182/hematology.2022000349 15. Abbas S, Lugthart S, Kavelaars FG, et al. Blood. 2010;116(12):2122-2126. doi:10.1182/blood-2009-11-250878 16. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed February 29, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 17. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myelodysplastic Syndromes V.1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed February 14, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 18. Röllig C, Kramer M, Schliemann C, et al. Blood. 2020;136(7):823-830. doi:10.1182/blood.2019004583 19. Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P. BLCTT. 2019;Volume 9:19-32. doi:10.2147/BLCTT.S177913 20. Duncavage EJ, et al. Blood. 2022;140(21):2228-2247. doi: 10.1182/blood.2022015853 21. Pollyea DA, George TI, Abedi M, et al. eJHaem. 2020;1(1):58-68. doi:10.1002/jha2.16 22. Nelson EJ, et al. Mol Diagn Ther. 2023;27:371-381. doi: 10.1007/s40291-022-00638-7 23. Guijarro F, et al. Curr. Oncol. 2023;30:5201-5213. doi: 10.3390/curroncol30060395

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