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Chronic myleproliferative neoplasms

Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis

Leukemia volume 30, pages 136–143 (2016)Cite this article

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Abstract

Most patients with KIT D816V+ advanced systemic mastocytosis (SM) are characterized by somatic mutations in additional genes. We sought to clarify the prognostic impact of such mutations. Genotype and clinical characteristics of 70 multi-mutated KIT D816V+ advanced SM patients were included in univariate and multivariate analyses. The most frequently identified mutated genes were TET2 (n=33 of 70 patients), SRSF2 (n=30), ASXL1 (n=20), RUNX1 (n=16) and JAK2 (n=11). In univariate analysis, overall survival (OS) was adversely influenced by mutations in SRSF2 (P<0.0001), ASXL1 (P=0.002) and RUNX1 (P=0.03), but was not influenced by mutations in TET2 or JAK2. In multivariate analysis, SRSF2 and ASXL1 remained the most predictive adverse indicators concerning OS. Furthermore, we found that inferior OS and adverse clinical characteristics were significantly influenced by the number of mutated genes in the SRSF2/ASXL1/RUNX1 (S/A/R) panel (P<0.0001). In conclusion, the presence and number of mutated genes within the S/A/R panel are adversely associated with advanced disease and poor survival in KIT D816V+ SM. On the basis of these findings, inclusion of molecular markers should be considered in upcoming prognostic scoring systems for patients with SM.

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References

  1. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007; 37: 435–453.

    Article  CAS  Google Scholar 

  2. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001; 25: 603–625.

    Article  CAS  Google Scholar 

  3. Pardanani A . Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 2013; 88: 612–624.

    Article  CAS  Google Scholar 

  4. Theoharides TC, Valent P, Akin C . Mast cells, mastocytosis, and related disorders. N Engl J Med 2015; 373: 163–172.

    Article  CAS  Google Scholar 

  5. Pardanani A . Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol 2015; 90: 250–262.

    Article  CAS  Google Scholar 

  6. Erben P, Schwaab J, Metzgeroth G, Horny HP, Jawhar M, Sotlar K et al. The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol 2014; 93: 81–88.

    Article  CAS  Google Scholar 

  7. Kristensen T, Vestergaard H, Moller MB . Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn 2011; 13: 180–188.

    Article  CAS  Google Scholar 

  8. Sotlar K, Colak S, Bache A, Berezowska S, Krokowski M, Bultmann B et al. Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). J Pathol 2010; 220: 586–595.

    Article  CAS  Google Scholar 

  9. Schwaab J, Schnittger S, Sotlar K, Walz C, Fabarius A, Pfirrmann M et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013; 122: 2460–2466.

    Article  CAS  Google Scholar 

  10. Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol 2010; 28: 3858–3865.

    Article  CAS  Google Scholar 

  11. 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: 241–247.

    Article  CAS  Google Scholar 

  12. Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 2012; 120: 3080–3088.

    Article  CAS  Google Scholar 

  13. Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 2014; 123: 2220–2228.

    Article  CAS  Google Scholar 

  14. Jawhar M, Schwaab J, Schnittger S, Sotlar K, Horny HP, Metzgeroth G et al. Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event. Leukemia 2015; 29: 1115–1122.

    Article  CAS  Google Scholar 

  15. Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 2014; 28: 1804–1810.

    Article  CAS  Google Scholar 

  16. 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: 3616–3627.

    Article  CAS  Google Scholar 

  17. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013; 31: 2428–2436.

    Article  CAS  Google Scholar 

  18. Patnaik MM, Wassie EA, Padron E, Onida F, Itzykson R, Lasho TL et al. Chronic myelomonocytic leukemia in younger patients: molecular and cytogenetic predictors of survival and treatment outcome. Blood Cancer J 2015; 5: e280.

    Article  CAS  Google Scholar 

  19. Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, Mannarelli C et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia 2014; 28: 1494–1500.

    Article  CAS  Google Scholar 

  20. Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Rock J, Paschka P et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 2011; 29: 1364–1372.

    Article  Google Scholar 

  21. Horny HP, Akin, Metcalfe DD, Swerdlow SH, Campo E, Harris NL et al. World Health Organization (WHO) Classification of Tumours. Mastocytosis (Mast cell disease). Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, France, 2008; vol. 2: 54–63.

    Google Scholar 

  22. Tefferi A, Thiele J, Vardiman JW . The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 2009; 115: 3842–3847.

    Article  CAS  Google Scholar 

  23. Hanssens K, Brenet F, Agopian J, Georgin-Lavialle S, Damaj G, Cabaret L et al. SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes. Haematologica 2014; 99: 830–835.

    Article  Google Scholar 

  24. Damaj G, Joris M, Chandesris O, Hanssens K, Soucie E, Canioni D et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS One 2014; 9: e85362.

    Article  Google Scholar 

  25. Traina F, Visconte V, Jankowska AM, Makishima H, O'Keefe CL, Elson P et al. Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis. PLoS One 2012; 7: e43090.

    Article  CAS  Google Scholar 

  26. Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009; 23: 900–904.

    Article  CAS  Google Scholar 

  27. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869.

    Article  CAS  Google Scholar 

  28. Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood 2012; 120: 4168–4171.

    Article  CAS  Google Scholar 

  29. Thol F, Kade S, Schlarmann C, Loffeld P, Morgan M, Krauter J et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012; 119: 3578–3584.

    Article  CAS  Google Scholar 

  30. Schnittger S, Dicker F, Kern W, Wendland N, Sundermann J, Alpermann T et al. RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood 2011; 117: 2348–2357.

    Article  CAS  Google Scholar 

  31. Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, Van't Wout JW, Verhoef G, Gerrits WB et al. Cladribine therapy for systemic mastocytosis. Blood 2003; 102: 4270–4276.

    Article  CAS  Google Scholar 

  32. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O et al. Midostaurin (PKC412) demonstrates a high rate of durable responses in patients with advanced systemic mastocytosis: results from the fully accrued global phase 2 CPKC412D2201 trial. Blood 2014; 124: 21.

    Article  Google Scholar 

  33. Ustun C, Reiter A, Scott BL, Nakamura R, Damaj G, Kreil S et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol 2014; 32: 3264–3274.

    Article  Google Scholar 

  34. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica 2015; 100: 479–488.

    Article  CAS  Google Scholar 

  35. Patel KP, Newberry KJ, Luthra R, Jabbour E, Pierce S, Cortes J et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood 2015; 126: 790–797.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (grant no. DJCLS H 11/03 and 13/05) and the Austrian Science Fund (FWF) grant SFB F4704-B20.

Author contributions

MJ, JS, SS, MM, SK, NN, CH, TH, AF, NCPC and AR performed the laboratory work for the study. JS, GM, WKH, PV and AR provided patient material and information. KS and HPH reviewed the bone marrow biopsies. MJ, JS, SS, MP, PV, WKH, NCPC, AF and AR wrote the paper.

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Authors and Affiliations

  1. Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim,, Germany

    M Jawhar, J Schwaab, G Metzgeroth, S Kluger, N Naumann, W-K Hofmann, A Fabarius & A Reiter

  2. MLL Munich Leukemia Laboratory, Munich, Germany

    S Schnittger, M Meggendorfer, C Haferlach & T Haferlach

  3. Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University, Munich,, Germany

    M Pfirrmann

  4. Institute of Pathology, Ludwig-Maximilians University, Munich, Germany

    K Sotlar & H-P Horny

  5. Division of Hematology and Ludwig Boltzmann Cluster Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

    P Valent

  6. Wessex Regional Genetics Laboratory, Salisbury, UK

    N C P Cross

  7. Faculty of Medicine, University of Southampton, Southampton,, UK

    N C P Cross

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  1. M Jawhar
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Correspondence to A Reiter.

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CH and TH have equity ownership of MLL Munich Leukemia Laboratory.

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Jawhar, M., Schwaab, J., Schnittger, S. et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis. Leukemia 30, 136–143 (2016). https://doi.org/10.1038/leu.2015.284

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