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

The 2016 revision of the World Health Organization (WHO) classification of myeloproliferative neoplasms defines 2 stages of primary myelofibrosis (PMF) that is, 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 non-driver myeloid genes were available for all patients. Compared to pre-PMF, overt-PMF was enriched in patients with anemia, thrombocytopenia, leucopenia, higher blast count, symptoms, large splenomegaly and unfavorable karyotype. The different types of driver mutations were similarly distributed between the 2 categories, while selected mutations comprising the high mutation risk category (HMR; any mutations in ASXL1, SRSF2, IDH1/2, EZH2) were more represented in overt-PMF. More patients with overt-PMF were in higher IPSS 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 versus 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 to identify two 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.