title: Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.
abstract: We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Pascutto
authors.affiliation: Laboratorio Congiunto Malattie Mieloproliferative Croniche, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Hematology and Hematopathology Departments, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Martínez-Trillos
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Ilaria
authors.initials: I
authors.lastname: Casetti
authors.affiliation: Hematology and Hematopathology Departments, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Laboratorio Congiunto Malattie Mieloproliferative Croniche, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Lisa
authors.initials: L
authors.lastname: Pieri
authors.affiliation: Hematology and Hematopathology Departments, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and.
authors.forename: Marta
authors.initials: M
authors.lastname: Pratcorona
authors.affiliation: Laboratorio Congiunto Malattie Mieloproliferative Croniche, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Giada
authors.initials: G
authors.lastname: Rotunno
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Emanuela
authors.initials: E
authors.lastname: Sant'Antonio
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Marta
authors.initials: M
authors.lastname: Bellini
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavalloni
authors.affiliation: Laboratorio Congiunto Malattie Mieloproliferative Croniche, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Carmela
authors.initials: C
authors.lastname: Mannarelli
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Milanesi
authors.affiliation: Anatomic Pathology Section and.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Boveri
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferretti
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and.
authors.forename: Cesare
authors.initials: C
authors.lastname: Astori
authors.affiliation: Center for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Hematology and Hematopathology Departments, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.affiliation: Center for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Laboratorio Congiunto Malattie Mieloproliferative Croniche, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000150:complications; D037282:Calreticulin / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000235:genetics; D007964:Leukocytosis / Q000150:complications; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis / Q000150:complications / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D013921:Thrombocytopenia / Q000150:complications; D055815:Young Adult
chemical_list: D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2