Akif AYAZ, Yaşa Gül MUTLU, Fatma SECA, Berrin BALIK AYDIN, Ömür Gökmen SEVİNDİK

Mutation profile of the patients diagnosed with myeloid neoplasia tested with next generation sequencing and clinical implications

Aim: To analyze the distribution of gene mutations in myeloid neoplasias, based on next generating sequencing technology (NGS) and evaluate their clinical implications and impact on the risk stratification. Materials and Methods: 67 bone marrow samples which belong to 48 different patients who were diagnosed with myeloid neoplasia and tested with 30 gene myeloid panel by NGS in our center were evaluated retrospectively. Distribution of genomic alterations and clinical implications were compared in different groups. Results: Samples were separated into different groups according to the diagnostic categories. Most common diagnosis was acute myeloid leukemia (AML) with the rate of 58.3%. FLT3 mutation was the most common mutation in AML and whole population. After the incorporation of the NGS results into the prognostic classification in newly diagnosed AML group, 47.1% of the patients were up-staged or down-staged according to the European Leukemia Network (ELN) risk stratification system. Conclusion: Analyzing the mutation profiles with NGS in myeloid neoplasias has an important and remarkable effect on diagnosis and management of this group of diseases.

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1. Shumilov E, Flach J, Kohlmann A, Banz Y, Bonadies N, Fiedler M, et al. Current status and trends in the diagnostics of AML and MDS. Blood Rev. 2018;32(6):508-19.
2. Aguilera-Diaz A, Vazquez I, Ariceta B, Manu A, Blasco-Iturri Z, Palomino-Echeverria S, et al. Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design. PLoS One. 2020;15(1):e0227986.
3. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405.
4. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-47.
5. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776-84.
6. Devillier R, Mansat-De Mas V, Gelsi-Boyer V, Demur C, Murati A, Corre J, et al. Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes. Oncotarget. 2015;6(10):8388-96.
7. Zuo Z, Li S, Xu J, You MJ, Khoury JD, Yin CC. PhiladelphiaNegative Myeloproliferative Neoplasms: Laboratory Workup in the Era of Next-Generation Sequencing. Curr Hematol Malig Rep. 2019;14(5):376-85.
8. Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol. 2018;36(4):310-8.
9. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616-27; quiz 99.
10. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-65.
11. Nazha A, Narkhede M, Radivoyevitch T, Seastone DJ, Patel BJ, Gerds AT, et al. Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Leukemia. 2016;30(11):2214-20.
12. Kamps R, Brandao RD, Bosch BJ, Paulussen AD, Xanthoulea S, Blok MJ, et al. Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification. Int J Mol Sci. 2017;18(2).
13. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19(1):4-23.
14. Zhao CX, Wang JM, Li JM, Zou SH, Chen FY, Liang AB, et al. [Using next generation sequencing technology to analyze gene mutations in patients with acute myeloid leukemia and the impact on prognosis]. Zhonghua Yi Xue Za Zhi. 2019;99(40):3145- 51.
15. Sasaki K, Kanagal-Shamanna R, Montalban-Bravo G, Assi R, Jabbour E, Ravandi F, et al. Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. Cancer. 2020;126(4):765-74.
16. Leisch M, Jansko B, Zaborsky N, Greil R, Pleyer L. Next Generation Sequencing in AML-On the Way to Becoming a New Standard for Treatment Initiation and/or Modulation? Cancers (Basel). 2019;11(2).
17. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-64.
18. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386-98.
19. Bacher U, Shumilov E, Flach J, Porret N, Joncourt R, Wiedemann G, et al. Challenges in the introduction of next-generation sequencing (NGS) for diagnostics of myeloid malignancies into clinical routine use. Blood Cancer J. 2018;8(11):113.
20. McNamara CJ, Panzarella T, Kennedy JA, Arruda A, Claudio JO, Daher-Reyes G, et al. The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. Blood Adv. 2018;2(20):2658-71.
21. Zhang SJ, Rampal R, Manshouri T, Patel J, Mensah N, Kayserian A, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood. 2012;119(19):4480-5.
22. Elliott MA, Pardanani A, Hanson CA, Lasho TL, Finke CM, Belachew AA, et al. ASXL1 mutations are frequent and prognostically detrimental in CSF3R-mutated chronic neutrophilic leukemia. Am J Hematol. 2015;90(7):653-6.