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Chronic Myeloproliferative Neoplasias

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

Leukemia volume 28, pages 1804–1810 (2014)Cite this article

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Abstract

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five ‘prognostically detrimental’ mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the ‘number’ of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6–5.7) vs 7.0 years (HR 1.9, 95% CI 1.4–2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6–3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2–3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5–10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the ‘number’ of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.

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Acknowledgements

This study was supported by a special grant from Associazione Italiana per la Ricerca sul Cancro-‘AIRC 5 per Mille’- to AGIMM, ‘AIRC-Gruppo Italiano Malattie Mieloproliferative’ (#1005); for a description of the AGIMM project, see at http://www.progettoagimm.it/). The study was partially supported by Ministero della Università e Ricerca (MIUR; FIRB project #RBAP11CZLK and PRIN 2010NYKNS7 to AMV). It was also supported by the Bando ricerca finalizzata e giovani ricercatori, Ministero della Salute GR-2011-02352109 to PG. JS and NCPC were supported by Leukemia and Lymphoma Research. Studies at the Mayo Clinic were supported by the Mayo Clinic Brian and Phyllis Harvey and Janet Yulman Charitable Foundation for Myelofibrosis Tissue Bank and Clinical Database of Molecular and Biological Abnormalities.

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Author notes

  1. P Guglielmelli, A M Vannucchi and A Tefferi: These authors contributed equally to this work and share correspondence.

Authors and Affiliations

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

    P Guglielmelli, G Rotunno, C Mannarelli, A Pancrazzi, F Biamonte, T Fanelli, A Bosi & A M Vannucchi

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

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

  3. Wessex Reg Genetics Lab, Salisbury, UK

    J Score

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

    K Zoi

  5. III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany

    A Reiter

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

    A Duncombe

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

    D Pietra & E Rumi

  8. Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    R P Ketterling & R A Knudson

  9. Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    C A Hanson

  10. Hemotherapy & Hemostasis, Hospital Clínic, Barcelona, Spain

    A Pereira

  11. Centre for Regenerative Medicine ‘Stefano Ferrari’, University of Modena and Reggio Emilia, Modena, Italy

    R Manfredini

  12. Hematology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain

    F Cervantes

  13. Center for the Study of Myelofibrosis, IRCCS Policlinico S.Matteo Foundation, Pavia, Italy

    G Barosi

  14. Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy

    M Cazzola

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

    N C P Cross

Authors
  1. P Guglielmelli
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  2. T L Lasho
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  3. G Rotunno
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  4. J Score
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  5. C Mannarelli
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  6. A Pancrazzi
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  7. F Biamonte
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  8. A Pardanani
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  9. K Zoi
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  10. A Reiter
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  11. A Duncombe
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  12. T Fanelli
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  13. D Pietra
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  14. E Rumi
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  15. C Finke
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  16. N Gangat
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  17. R P Ketterling
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  18. R A Knudson
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  19. C A Hanson
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  20. A Bosi
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  21. A Pereira
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  22. R Manfredini
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  23. F Cervantes
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  24. G Barosi
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  25. M Cazzola
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  26. N C P Cross
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  27. A M Vannucchi
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  28. A Tefferi
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Corresponding authors

Correspondence to A M Vannucchi or A Tefferi.

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Guglielmelli, P., Lasho, T., Rotunno, G. et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 28, 1804–1810 (2014). https://doi.org/10.1038/leu.2014.76

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  • DOI: https://doi.org/10.1038/leu.2014.76

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