Prognostic Value of Next-Generation Sequencing Data in Patients with Myelodysplastic Syndrome

NYu Tsvetkov1, EV Morozova1, IM Barkhatov1, IS Moiseev1, MV Barabanshchikova1, AV Tishkov2, DS Bug2, NV Petukhova2, EA Izmailova1, SN Bondarenko1, BV Afanasyev1

1 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 Research Center for Bioinformatics, Academic Institute of Biomedicine, IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Nikolai Yur’evich Tsvetkov, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(911)233-48-77, +7(812)338-62-27; e-mail:

For citation: Tsvetkov NYu, Morozova EV, Barkhatov IM, et al. Prognostic Value of Next-Generation Sequencing Data in Patients with Myelodysplastic Syndrome. Clinical oncohematology. 2020;13(2):170–5 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-170-175


Aim. To assess the prognostic value of the mutation of DNA methylation genes, SF3B1, and TP53 in patients with myelodysplastic syndrome (MDS).

Materials & Methods. Out of 35 MDS patients included into the trial 2 had multilineage dysplasia, 13 with excess blasts-I, 19 with excess blasts-II, and 1 had 5q-syndrome (criteria WHO 2016). In 30 patients primary MDS was identified, in 5 patients it was detected after prior chemo- or radiotherapy. 25 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to IPSS-R there were 1 low-risk, 5 intermediate risk, 17 high-risk, and 12 very high-risk patients. Hypomethylating agents were administered to 28 patients. Median age of patients was 49 years (range 18–80 years). Next-generation sequencing was applied for identifying somatic mutations in DNA methylation genes (TET2, IDH1/2, ASXL1, and DNMT3A) as well as in SF3B1, TP53, IDH, and RUNX1. Time to progression (TTP) was defined as the time from the initial diagnosis to the date of acute leukemia diagnosis. Allo-HSCT- or antitumor therapy-associated death was considered as competing risk.

Results. Methylation gene analysis showed no mutation in 37 % of patients, in 40 % mutation was detected only in one of the genes, in 23 % mutation was identified in ≥ 2 genes. SF3B1 mutations were reported in 23 % and TP53 in 11 % of patients. Median follow-up was 25 months (range 5–116 months). Univariate analysis showed no considerable differences in overall survival depending on mutation status. Median TTP in the group with allo-HSCT was not achieved, in the group without allo-HSCT it was 6 months (= 0.0001). In patients with no SF3B1 mutation median TTP was 35 months, in patients with this mutation it was not achieved (= 0.043). With ≥ 2 mutations in methylation genes median TTP was 12 months, in other cases it was not achieved (= 0.024). In cases of TP53 mutation median TTP was 6 months, in cases without this mutation it was 43 months (= 0.023). Multivariate analysis confirmed unfavorable prognostic value of TP53 mutation or ≥ 2 mutations in methylation genes in terms of TTP regardless of the drug treatment or allo-HSCT performed (hazard ratio 7.1; 95% confidence interval 2.6–19.6; = 0.0001).

Conclusion. The analysis of molecular markers yields additional data concerning the MDS prognosis. Further research is required to determine the prognostic value of molecular markers in clinical practice which will enable to individualize approaches to MDS treatment.

Keywords: myelodysplastic syndrome, molecular markers, mutations, next-generation sequencing, prognosis.

Received: December 27, 2019

Accepted: March 25, 2020

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  1. Ma X. Epidemiology of Myelodysplastic Syndromes. Am J Med. 2012;125(7):S2–S5. doi: 10.1016/j.amjmed.2012.04.014.

  2. Greenberg P, Cox C, LeBeau MM, et al. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes. 1997;89(6):2079–88. doi: 10.1182/blood.v89.6.2079.

  3. Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood. 2008;112(3):895–902. doi: 10.1182/blood-2008-03-143735.

  4. Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood. 2012;120(12):2454–65. doi: 10.1182/blood-2012-03-420489.

  5. Montalban-Bravo G, Garcia-Manero G. Myelodysplastic syndromes: 2018 update on diagnosis, risk-stratification and management. Am J Hematol. 2018;93(1):129–47. doi: 10.1002/ajh.24930.

  6. Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol. 2014;32(25):2691–8. doi: 10.1200/jco.2013.52.3381.

  7. Bains A, Luthra R, Medeiros LJ, et al. FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia. Am J Clin Pathol. 2011;135(1):62–9. doi: 10.1309/ajcpei9xu8pybcio.

  8. Della Porta MG, Galli A, Bacigalupo A, et al. Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol. 2016;34(30):3627–37. doi: 10.1200/jco.2016.67.3616.

  9. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.

  10. Bejar R. CHIP, ICUS, CCUS and other four-letter words. 2017;31(9):1869–71. doi: 10.1038/leu.2017.181.

  11. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. doi: 10.1056/nejmoa1409405.

  12. Young AL, Tong RS, Birmann BM, et al. Clonal hematopoiesis and risk of acute myeloid leukemia. 2019;104(12):2410–7. doi: 10.3324/haematol.2018.215269.

  13. Figueroa ME, Skrabanek L, Li Y, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. 2009;114(16):3448–58. doi: 10.1182/blood-2009-01-200519.

  14. Reilly B, Tanaka TN, Diep D, et al. DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes. Blood Adv. 2019;3(19):2845–58. doi: 10.1182/bloodadvances.2019000192.

  15. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429–40. doi: 10.1200/jco.2002.04.117.

  16. Kantarjian H, Issa J-PJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. 2006;106(8):1794–803. doi: 10.1002/cncr.21792.

  17. Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. 2017;123(10):1703–13. doi: 10.1002/cncr.30585.

  18. Duong VH, Lin K, Reljic T, et al. Poor outcome of patients with myelodysplastic syndrome after azacitidine treatment failure. Clin Lymphoma Myel Leuk. 2013;13(6):711–5. doi: 10.1016/j.clml.2013.07.007.

  19. Prebet T, Cluzeau T, Park S, et al. Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy. 2017;8(23):81926–35. doi: 10.18632/oncotarget.15200.

  20. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol. 2018;36(17):1769–70. doi: 10.1200/jco.2018.78.9867.

  21. Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. 2019;33(7):1747–58. doi: 10.1038/s41375-018-0351-2.

  22. Montalban-Bravo G, Takahashi K, Patel K, et al. Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. 2018;9(11):9714–27. doi: 10.18632/oncotarget.23882.

  23. van Gelder M, de Wreede LC, Schetelig J, et al. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia. 2013;27(4):879–88. doi: 10.1038/leu.2012.297.

  24. de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. 2017;129(13):1753–62. doi: 10.1182/blood-2016-06-724500.

  25. Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. 2011;25(7):1147–52. doi: 10.1038/leu.2011.71.

  26. Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375(21):2023–36. doi: 10.1056/nejmoa1605949.