title: The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients.
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.
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Lasho
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rotunno
authors.affiliation: Wessex Reg Genetics Lab, Salisbury, UK.
authors.forename: J
authors.initials: J
authors.lastname: Score
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mannarelli
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pancrazzi
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Biamonte
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Zoi
authors.affiliation: III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reiter
authors.affiliation: Department of Haematology, Southampton University Hospital, Southampton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Duncombe
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Fanelli
authors.affiliation: Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rumi
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Finke
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gangat
authors.affiliation: Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Knudson
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hanson
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bosi
authors.affiliation: Hemotherapy & Hemostasis, Hospital Clínic, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pereira
authors.affiliation: Centre for Regenerative Medicine 'Stefano Ferrari', University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Manfredini
authors.affiliation: Hematology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Cervantes
authors.affiliation: Center for the Study of Myelofibrosis, IRCCS Policlinico S.Matteo Foundation, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
authors.affiliation: Laboratorio Congiunto MMPC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D037282:Calreticulin / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D037282:Calreticulin; D012097:Repressor Proteins