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Cytogenetics and molecular genetics

The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution

Abstract

Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with “Very low” or “Low” Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.

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References

  1. 1.

    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

  2. 2.

    Bhatia S. Therapy-related myelodysplasia and acute myeloid leukemia. Sem Oncol. 2013;40:666–75.

  3. 3.

    Ok CY, Hasserjian RP, Fox PS, Stingo F, Zuo Z, Young KH, et al. Application of the international prognostic scoring system-revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia. Leukemia. 2014;28:185–9.

  4. 4.

    Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C, et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia. 2013;27:1275–82.

  5. 5.

    Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–47.

  6. 6.

    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;122:3616–27.

  7. 7.

    Makishima H, Yoshizato T, Yoshida K, Sekeres MA, Radivoyevitch T, Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2016;49:204–12.

  8. 8.

    Ok CY, Patel KP, Garcia-Manero G, Routbort MJ, Fu B, Tang G, et al. Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases. Leuk Res. 2015;39:348–54.

  9. 9.

    Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552–55.

  10. 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;120:2454–65.

  11. 11.

    Luana F, Livio P, Alfonso P, Anna C, Gianluca G, Massimo B, et al. Characteristics and outcome of therapy-related myeloid neoplasms: report from the Italian network on secondary leukemias. Am J Hematol. 2015;90:E80–E85.

  12. 12.

    Bacher U, Haferlach C, Alpermann T, Schnittger S, Kern W, Haferlach T. Patients with therapy-related myelodysplastic syndromes and acute myeloid leukemia share genetic features but can be separated by blast counts and cytogenetic risk profiles into prognostically relevant subgroups. Leuk Lymphoma. 2013;54:639–42.

  13. 13.

    Hiwase DK, Singhal D, Strupp C, Chhetri R, Kutyna MM, Wee LA, et al. Dynamic assessment of RBC-transfusion dependency improves the prognostic value of the revised-IPSS in MDS patients. Am J Hematol. 2017;92:508–14.

  14. 14.

    Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T. Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia. 2003;18:120–25.

  15. 15.

    Zeidan AM, Al Ali N, Barnard J, Padron E, Lancet JE, Sekeres MA, et al. Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium. Leukemia. 2017;31:1391.

  16. 16.

    Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood. 2003;102:43–52.

  17. 17.

    Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

  18. 18.

    Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686–98.

  19. 19.

    Voso MT, Fabiani E, Fianchi L, Falconi G, Criscuolo M, Santangelo R, et al. Mutations of epigenetic regulators and of the spliceosome machinery in therapy-related myeloid neoplasms and in acute leukemias evolved from chronic myeloproliferative diseases. Leukemia. 2013;27:982–5.

  20. 20.

    Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2008;22:240–8.

  21. 21.

    Shih AH, Chung SS, Dolezal EK, Zhang SJ, Abdel-Wahab OI, Park CY, et al. Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Haematologica. 2013;98:908–12.

  22. 22.

    Fabiani E, Falconi G, Fianchi L, Criscuolo M, Leone G, Voso MT. SETBP1 mutations in 106 patients with therapy-related myeloid neoplasms. Haematologica. 2014;99:e152–e53.

  23. 23.

    Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76.

  24. 24.

    Strahm B, Wlodarski MW, Pastor VB, Przychodzien B, Catala A, Dworzak M, et al. Impact of somatic mutations on the outcome of children and adolescents with therapy-related myelodysplastic syndrome. Blood. 2016;128:3162.

  25. 25.

    Sallman DA, Komrokji R, Vaupel C, Cluzeau T, Geyer SM, McGraw KL, et al. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes. Leukemia. 2015;30:666–73.

  26. 26.

    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

  27. 27.

    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

  28. 28.

    Alfonso Pierola A, Marchesini M, Takahashi K, Gañán-Gómez I, Fiorini E, Ogoti Y, et al. The role of Chip-related DNA damage response dysfunction in therapy-related myeloid neoplasms. Blood. 2016;128:958.

  29. 29.

    Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jädersten M, Jansson M, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126:233–41.

  30. 30.

    Kamp WM, Wang P-y, Hwang PM. TP53 mutation, mitochondria and cancer. Curr Opin Genet Dev. 2016;38:16–22.

  31. 31.

    Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95.

  32. 32.

    Crosby WH. Acute granulocytic leukemia, a complication of therapy in Hodgkin’s disease? Clin Res. 1969;17:463.

  33. 33.

    Steinberg MH, Geary CG, Crosby WH. Acute granulocytic leukemia complicating hodgkin’s disease. Arch Intern Med. 1970;125:496–98.

  34. 34.

    Kayser S, Dohner K, Krauter J, Kohne CH, Horst HA, Held G, et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood. 2011;117:2137–45.

  35. 35.

    Kern W, Haferlach T, Schnittger S, Hiddemann W, Schoch C. Prognosis in therapy-related acute myeloid leukemia and impact of karyotype. J Clin Oncol. 2004;22:2510–11.

  36. 36.

    Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone RM, et al. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant. 2007;13:655–64.

  37. 37.

    Singh ZN, Huo D, Anastasi J, Smith SM, Karrison T, Le Beau MM, et al. Therapy-related myelodysplastic syndrome morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 2007;127:197–205.

  38. 38.

    Traina F, Visconte V, Elson P, Tabarroki A, Jankowska AM, Hasrouni E, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28:78–87.

  39. 39.

    Yoshizato T, Nannya Y, Atsuta Y, Shiozawa Y, Iijima-Yamashita Y, Yoshida K, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129:2347–58.

  40. 40.

    Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47.

  41. 41.

    Della Porta MG, Alessandrino EP, Bacigalupo A, van Lint MT, Malcovati L, Pascutto C, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood. 2014;123:2333–42.

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Acknowledgements

This work was supported by the Royal Adelaide Hospital Research Committee, Contributing Hematologists Committee, and Royal Adelaide Hospital.

Author contributions

DS: planned and performed mutational analysis, analyzed data, and wrote the manuscript. LYAW: processed samples, analyzed data, and edited the manuscript. MMK and RC: analyzed data and edited the manuscript. JG, AWS, JF, and PP-SW: analyzed bioinformatics data and provided critical comments. MB, WTP, and SH: processed samples and analyzed data. SE: provided statistical advice. SM and PA: analyzed data and provided critical comments. SB and ALB: provided critical comments and edited the manuscript. NS and RG: provided clinical information and critical comments. TK, LBT, PGB, IDL, RJD: provided critical comments. JPM: provided critical comments and edited the manuscript. HSS: developed the project, analyzed data, and edited the manuscript. CNH: developed the project, analyzed data, and edited the manuscript. DKH: developed the project, analyzed data, and edited the manuscript.

Author information

Conflict of interest

SB received research funding and honoraria and served on advisory committees from Novartis and Bristol-Myers Squibb, and consultancy fees and honoraria from Qiagen and Cepheid. HSS received honoraria from Celgene. The other authors declare that they have no conflict of interest.

Correspondence to Devendra K. Hiwase.

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