Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis

Paola Guglielmelli, Annalisa Pacilli, Giada Rotunno, Elisa Rumi, Vittorio Rosti, Federica Delaini, Margherita Maffioli, Tiziana Fanelli, Alessandro Pancrazzi, Daniela Pietra, Silvia Salmoiraghi, Carmela Mannarelli, Annalisa Franci, Chiara Paoli, Alessandro Rambaldi, Francesco Passamonti, Giovanni Barosi, Tiziano Barbui, Mario Cazzola and Alessandro M. Vannucchi on behalf of the AGIMM Group

Key Points

  • Differential diagnosis of pre-PMF and overt PMF by 2016 WHO criteria underscores uniqueness in disease presentation and outcome.

  • Patterns of driver and nondriver myeloid gene mutations contribute to prognosis in both pre-PMF and overt PMF.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


The 2016 revision of the World Health Organization (WHO) classification of myeloproliferative neoplasms defines 2 stages of primary myelofibrosis (PMF): prefibrotic/early (pre-PMF) and overt fibrotic (overt PMF) phase. In this work, we studied the clinical and molecular features of patients belonging to these categories of PMF. The diagnosis of 661 PMF patients with a bone marrow biopsy at presentation was revised according to modern criteria; clinical information and annotation of somatic mutations in both driver and selected nondriver myeloid genes were available for all patients. Compared with pre-PMF, overt PMF was enriched in patients with anemia, thrombocytopenia, leukopenia, higher blast count, symptoms, large splenomegaly, and unfavorable karyotype. The different types of driver mutations were similarly distributed between the 2 categories, whereas selected mutations comprising the high mutation risk (HMR) category (any mutations in ASXL1, SRSF2, IDH1/2, EZH2) were more represented in overt PMF. More patients with overt PMF were in higher International Prognostic Scoring System risk categories at diagnosis, and the frequency increased during follow-up, suggesting greater propensity to disease progression compared with pre-PMF. Median survival was significantly shortened in overt PMF (7.2 vs 17.6 years), with triple negativity for driver mutations and presence of HMR mutations representing independent predictors of unfavorable outcome. The findings of this “real-life” study indicate that adherence to 2016 WHO criteria allows for identification of 2 distinct categories of patients with PMF where increased grades of fibrosis are associated with more pronounced disease manifestations, adverse mutation profile, and worse outcome, overall suggesting they might represent a phenotypic continuum.

  • Submitted January 11, 2017.
  • Accepted March 22, 2017.
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