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Molecular testing in myeloid malignancies

Understand why genetic testing is important for MDS

Driver mutations regulate distinct molecular pathways in the evolution of MDS, which can inform disease classification and prognostic stratification.1 The pathogeneses of MDS involve recurrent genomic alterations, including somatic gene mutations and/or chromosomal abnormalities, that can define biologically distinct clinical subtypes.2,3

The IPSS-M is an important prognostic tool that factors in information about somatic gene mutations along with hematologic and cytogenetic parameters to improve risk stratification in patients with MDS.2,4

Assess patient risk in MDS

The isocitrate dehydrogenase-1 (IDH1) gene encodes for the cytoplasmic protein IDH1, an enzyme that participates in the citric acid cycle by catalyzing the conversion of isocitrate to alpha-ketoglutarate (α-KG).5

The mutated IDH1 (mIDH1) gene is associated with unfavorable outcomes in MDS. The mIDH1 enzymes catalyze the reduction of α-KG to the oncometabolite of 2-hydroxyglutarate, which is associated with5:

DNA and histone hypermethylation6
Altered gene expression6
Blocked differentiation of hematopoietic progenitor cells5,6

IDH1 mutations play a role in MDS

Incidence

Up to 4% of patients with MDS harbor IDH1 mutations, and the mutation rate may double in patients who progress to AML7

Prognosis

mIDH1 MDS may be associated with poorer survival7

Molecular mutations found in MDS8

Image showing the molecular mutations found in MDS Image showing the molecular mutations found in MDS
As the molecular landscape of MDS continues to expand, there is hope that novel therapeutic modalities will be available in the future to target specific aspects of MDS biology.9

When is the best time to test your patients?

Due to clonal evolution, a patient’s molecular profile may change over time.2,10 Molecular testing at the time of diagnosis, disease progression, and relapse can help guide risk stratification and management of patients with MDS.2,10,11

Diagnosis11
MDS diagnosis icon
First sign of disease progression9
Green caution icon
Relapse9,10
Green relapse icon
Molecular profiles evolve over time.2,10 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommends retesting higher-risk MDS at post-transplant relapse.12

How to test for mutations found in MDS with molecular testing

Polymerase chain reaction (PCR)-based single-gene test for MDS Polymerase chain reaction (PCR)-based single-gene test for MDS

Polymerase chain reaction (PCR)–based single-gene test

Identifies genetic mutations such as IDH1, IDH2, and FLT313-17
Increased sensitivity and higher resolution13
Rapid turnaround time and associated with lower costs13-17
Next generation sequencing (NGS) for MDS Next generation sequencing (NGS) for MDS

Next generation sequencing (NGS)

Parallel sequencing of multiple genes in a single test13
Improved sensitivity with reduced sequencing error and background noise13
Slower turnaround time compared with single-gene tests such as PCR13

Understand why genetic testing is important for AML

Genetic testing results reflect the heterogeneity of AML. Mutations change over the course of a disease, and a molecular profile may be different at diagnosis than at relapse.18

Molecular profiling of AML through targeted sequencing panels has become a cornerstone in risk-stratifying AML patients and directing clinicians toward the best treatments for their patients.19

The NCCN Guidelines® recommends expediting analyses for AML patients with immediately actionable mutations or chromosomal abnormalities such as IDH1, IDH2, CBF, FLT3 [ITD and TKD], and NPM1.20

IDH1 mutations play a role in AML

Incidence

Up to 14% of patients with AML harbor IDH1 mutations.21

Higher frequency of IDH1 mutations in elderly AML patients (~17%)22
Prognosis

mIDH1 is a driver mutation in AML and may be associated with a poor prognosis23‑25

IDH1 mutations are associated with an increased risk of relapse for patients in remission26

Molecular mutations found in AML6,27

Mulecular mutations found in aml Mulecular mutations found in aml

Purple stars represent mutations and yellow circles indicate methyl groups. The main epigenetic changes involve mutations in IDH1, IDH2, TET2, and DNMT3a, which modify DNA methylation patterns.

When is the best time to test your patients?

Molecular testing at the time of diagnosis, remission, and relapse can provide a wide range of data to help guide the customized clinical therapy of AML patients.28

Diagnosis Diagnosis Icon
Remission Remission Icon
Relapse Relapse Icon
The NCCN Guidelines recommends performing a targeted NGS panel including IDH1, IDH2, FLT3 mutations in AML patients to help with selection of therapy. Furthermore, the National Comprehensive Cancer Network® (NCCN®) recommends repeating testing at each relapse or progression.20

How to test for mutations found in AML with molecular testing

Amplicon graphic Amplicon graphic

Polymerase chain reaction (PCR)–based single-gene test

Identifies genetic mutations such as IDH1, IDH2, and FLT313-17
Increased sensitivity and higher resolution13
Rapid turnaround time and associated with lower costs13-17
Reads graphic Reads graphic

Next generation sequencing (NGS)

Parallel sequencing of multiple genes in a single test13
Improved sensitivity with reduced sequencing error and background noise13
Slower turnaround time compared with single-gene tests such as PCR13
Understanding AML borchure

Learn more about the role of molecular testing in AML and how you can help your patients

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Rapid PCR tests by platforms such as NeoGenomics can provide test results in under 4 days. It is recommended to repeat molecular testing at the first sign of disease progression as new mutations may be revealed.9,10,17,29
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AML, acute myeloid leukemia; IPSS-M, International Prognostic Scoring System-Molecular; MDS, myelodysplastic syndromes.

References: 1. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221. doi:10.1056/NEJMoa1516192 2. Caponetti GC, Bagg A. Mutations in myelodysplastic syndromes: core abnormalities and CHIPping away at the edges. Int J Lab Hematol. 2020;42(6):671-684. doi:10.1111/ijlh.13284 3. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850 4. Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1(7). doi:10.1056/EVIDoa2200008 5. Nakajima H. Molecular pathogenesis and treatment of myelodysplastic syndromes. Intern Med. 2021;60(1):15-23. doi:10.2169/internalmedicine.4214-19 6. Raineri S, Mellor J. IDH1: linking metabolism and epigenetics. Front Genet. 2018;9:493. doi:10.3389/fgene.2018.00493 7. Thol F, Weissinger EM, Krauter J, et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica. 2010;95(10):1668-1674. doi:10.3324/haematol.2010.025494 8. Tobiasson M, Kittang AO. Treatment of myelodysplastic syndrome in the era of next-generation sequencing. J Intern Med. 2019;286(1):41-62. doi:10.1111/joim.12893 9. Bewersdorf JP, Xie Z, Bejar R, et al. Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS). Blood Rev. 2023;60:101072. doi:10.1016/j.blre.2023.101072 10. Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia. 2021;35(8):2182-2198. doi:10.1038/s41375-021-01265-7 11. Nazha A, Sekeres MA, Gore SD, Zeidan AM. Molecular testing in myelodysplastic syndromes for the practicing oncologist: Will the progress fulfill the promise? Oncologist. 2015;20(9):1069-1076. doi:10.1634/theoncologist.2015-0067 12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myelodysplastic Syndromes V.1.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed August 10, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. 13. Qin D. Molecular testing for acute myeloid leukemia. Cancer Biol Med. 2021;19(1):4-13. doi:10.20892/j.issn.2095-3941.2020.0734 14. IDH1 Abbott RealTime PCR. Versiti Diagnostic Laboratories. Accessed August 10, 2023. https://media.versiti.org/versiti/versiti/media/downloadables/diagnostic-labs/test-descriptions/idh1_abbott_realtime_pcr.pdf 15. IDH2 Abbott RealTime PCR. Versiti Diagnostic Laboratories. Accessed August 10, 2023. https://media.versiti.org/versiti/versiti/media/downloadables/diagnostic-labs/test-descriptions/idh2_abbott_realtime_pcr.pdf 16. LeukoStrat CDx FLT3 mutation assay. Versiti Diagnostic Laboratories. 2019. Accessed August 10, 2023. https://media.versiti.org/versiti/versiti/media/downloadables/diagnostic-labs/test-descriptions/leukostrat_flt3_desc.pdf 17. Rapid AML therapeutic panel. NeoGenomics Laboratories. Accessed August 10, 2023. https://neogenomics.com/test-menu/rapid-aml-therapeutic-panel 18. Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934-946. doi:10.1200/JCO.2016.71.2208 19. Cai SF, Levine RL. Genetic and epigenetic determinants of AML pathogenesis. Semin Hematol. 2019;56(2):84-89. doi:10.1053/j.seminhematol.2018.08.001 20. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.4.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed August 10, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. 21. Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P. IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood Lymphat Cancer. 2019;9:19-32. doi:10.2147/BLCTT.S177913 22. Steinhäuser S, Silva P, Lenk L, et al. Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML). Leukemia. 2023;37;134-142. doi:10.1038/s41375-022-01751-6 23. Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/1 enzymes and therapy responses. Oncogene. 2018;37(15):1949-1960. doi:10.1038/s41388-017-0077-z [Erratum in Oncogene. 2018;37(43):5810] 24. Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systemic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511-4522. doi:10.1158/1078-0432.CCR-16-2628 25. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. doi:10.1182/blood.2019002140 26. Ok CY, Loghavi S, Sui D, et al. Persistent IDH1/2 mutations in remission can predict relapse in patients with acute myeloid leukemia. Haematologica. 2019;104(2):305-311. doi:10.3324/haematol.2018.191148 27. Lagunas-Rangel FA, Chávez-Valencia V, Gómez-Guijosa MÁ, Cortes-Penagos C. Acute myeloid leukemia—genetic alterations and their clinical prognosis. Int J Hematol Oncol Stem Cell Res. 2017;11(4):328-339. 28. Stuckey R, Bilbao-Sieyro C, Gómez-Casares MT. A summary of the molecular testing recommended in acute myeloid leukemia. Ann Mol Genet Med. 2020;4(1):12-17. doi:10.17352/amgm.000007 29. Data on file. Servier Pharmaceuticals LLC.