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Chronic Myeloproliferative Neoplasias

Mutations and prognosis in primary myelofibrosis

Leukemia volume 27, pages 1861–1869 (2013)Cite this article

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Abstract

Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

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Acknowledgements

This work was supported by AIRC ‘Special Program Molecular Clinical Oncology 5 × 1000’ to AGIMM group (project no. 1005; a detailed description of the AGIMM project is available at http://www.progettoagimm.it). AMV and RM were also supported by AIRC (IG9034 and 12055, respectively). AMV, RM, MC were supported by a FIRB project, no. RBAP11CZLK.

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Authors and Affiliations

  1. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    A M Vannucchi, P Guglielmelli, F Biamonte, C Mannarelli, G Rotunno, M C Susini, A Spolverini, A Pancrazzi & L Pieri

  2. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    T L Lasho, A Pardanani, C Finke, N Gangat & A Tefferi

  3. Hemotherapy and Hemostasis, Hospital Clínic, Barcelona, Spain

    A Pereira

  4. Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK

    J Score, A Jones & N C P Cross

  5. Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    R P Ketterling, R A Knudson & R R Laborde

  6. Centre for Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy

    R Manfredini & R Zini

  7. Center for Genome Research University of Modena and Reggio Emilia, Modena, Italy

    E Tagliafico

  8. Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece

    K Zoi

  9. Universitätsmedizin Mannheim, Mannheim, Germany

    A Reiter

  10. Department of Haematology, Southampton University Hospital, Southampton, UK

    A Duncombe

  11. Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy

    D Pietra, E Rumi & M Cazzola

  12. Hospital Clínic, Barcelona, Spain

    F Cervantes

  13. Center for Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    G Barosi

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  1. A M Vannucchi
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Correspondence to A M Vannucchi or A Tefferi.

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Preliminary presentation of results has been done at the Annual Meeting of the American Society of Hematology, Atlanta 2012.

Supplementary Information accompanies this paper on the Leukemia website

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Vannucchi, A., Lasho, T., Guglielmelli, P. et al. Mutations and prognosis in primary myelofibrosis. Leukemia 27, 1861–1869 (2013). https://doi.org/10.1038/leu.2013.119

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