title: Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis.
abstract: 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 inASXL1,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.
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Paola
authors.identifier: 0000-0003-1809-284X
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pacilli
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Rotunno
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.affiliation: Center for the Study of Myelofibrosis, Biotechnology Research Area, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Delaini
authors.affiliation: Division of Hematology, Department of Specialistic Medicine, Ospedale Azienda Socio Sanitaria Territoriale (ASST)-Sette Laghi, Varese, Italy.|Department of Experimental and Clinical Medicine, University of Insubria, Varese, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffioli
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.|GenOMec, University of Siena, Siena, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fanelli
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pancrazzi
authors.affiliation: Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Salmoiraghi
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Mannarelli
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Franci
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Paoli
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.|Department of Oncology-Hematology Università degli Studi di Milano, Milan, Italy; and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Division of Hematology, Department of Specialistic Medicine, Ospedale Azienda Socio Sanitaria Territoriale (ASST)-Sette Laghi, Varese, Italy.|Department of Experimental and Clinical Medicine, University of Insubria, Varese, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.affiliation: Center for the Study of Myelofibrosis, Biotechnology Research Area, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.affiliation: FROM Research Foundation, Bergamo, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Barbui
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Centro Ricerca e Innovazione delle Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy.|Department of Experimental and Clinical Medicine, DENOTHE Centre, University of Florence, Florence, Italy.
authors.forename: Alessandro M
authors.identifier: 0000-0001-5755-0730
authors.initials: AM
authors.lastname: Vannucchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis / Q000235:genetics / Q000401:mortality; D012097:Repressor Proteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics; D015996:Survival Rate; D014944:World Health Organization
chemical_list: C473949:ASXL1 protein, human; D012097:Repressor Proteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein