Abstract
PurposeThe influence of JAK2 V617F mutation on blast transformation (BT) and overall survival (OS) in primary myelofibrosis (PMF) is controversial. In a large cohort of patients we applied competing risks analysis for studying the influence of JAK2V617F mutation on BT in PMF.Patients and MethodsIn 462 PMF–fibrotic type patients (bone marrow [BM] fibrosis grade >0) we computed the incidence of BT and death in the framework of Cox regression analysis and of Fine and Gray competing risks analysis for BT.ResultsAt the Cox regression analysis, having either a wild-type (wt) or a homozygous JAK2V617F genotype were factors for BT (HR, 1.98 and 2.04, respectively, with respect to the heterozygous genotype), but not for OS. At the competing risks regression analysis, the risk for BT in wt and homozygous V617F patients increased with respect to Cox analysis, giving a sHR of 2.17 and 2.12, respectively. Correcting the results for the variables that could have influence on BT, JAK2V617F wt and homozygous genotypes remained independently associated with BT. In a validation cohort of 133 independent cases with PMF-prefibrotic type (BM fibrosis grade = 0), the BT predictive model including JAK2V617F genotype and older age retained high discriminant capacity (C statistics, 0.70; 95% CI, 0.47 to 0.92).ConclusionThe accumulation of mutated alleles in the JAK2V617F clone or the selective acquisition of a proliferative advantage in the wt clone are two relevant routes to BT in PMF. The influence of these results on treatment decisions with anti-JAK2 agents should be tested.
Highlights
The somatically acquired Janus Kinase 2 (JAK2) mutation (V617F) is borne by approximately 60% of patients with primary myelofibrosis (PMF) [1,2,3]
Campbell and coworkers reported that JAK2V617F mutated patients had poorer overall survival (OS) than non mutated patients [4], and Tefferi and coworkers claimed that low allele burden of JAK2V617F was the major determinant for blast transformation (BT) and OS [10]
Study Cohorts The study cohorts were composed by patients seen from 1990 to 2011 in our centre who received a diagnosis of PMF according to the WHO criteria [14], and in which we performed JAK2V617F mutation assay on peripheral blood granulocytes at diagnosis or during the follow-up
Summary
The somatically acquired Janus Kinase 2 (JAK2) mutation (V617F) is borne by approximately 60% of patients with primary myelofibrosis (PMF) [1,2,3]. The mutation increases JAK2 kinase activity, with the potential to affect phenotype and clinical outcome of mutated subjects. Campbell and coworkers reported that JAK2V617F mutated patients had poorer OS than non mutated patients [4], and Tefferi and coworkers claimed that low allele burden of JAK2V617F was the major determinant for BT and OS [10]. We documented that the presence of a JAK2V617F hematopoietic clone was significantly associated with BT, but not death for any cause [2], while Guglielmelli and coworkers pointed out that low allele burden at diagnosis represented an independent factor associated with shortened OS but not BT [11,12]
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