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Blood. 2014 Aug 14;124(7):1062-9. doi: 10.1182/blood-2014-05-578435. Epub 2014 Jul 1.

Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.

Author information

1
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;
2
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and.
3
Laboratorio Congiunto Malattie Mieloproliferative Croniche, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
4
Hematology and Hematopathology Departments, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and.
5
Department of Molecular Medicine, University of Pavia, Pavia, Italy;
6
Anatomic Pathology Section and.
7
Center for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

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.

PMID:
24986690
PMCID:
PMC4133481
DOI:
10.1182/blood-2014-05-578435
[Indexed for MEDLINE]
Free PMC Article

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