The somatically acquired Janus Kinase 2 (JAK2) mutation (V617F) is borne by approximately 60% of patients with primary myelofibrosis (PMF). The mutation increases JAK2 kinase activity, with the potential to affect phenotype and clinical outcome of mutated subjects. Accordingly, PMF V617F mutants result associated with higher white-blood cell counts, higher propensity to develop large splenomegaly, and are less likely to require transfusion during follow-up. At variance, different results have been obtained as far as the influence of JAK2 V617F mutation on the major disease outcomes, such as blast transformation (BT) and overall survival (OS). In this work we considered our cohort of patients with PMF-fibrotic type consecutively registered from 1990 and prospectively followed, who reached a median follow-up of more than 4 years and we used statistical analysis to account for competing risks. With this cohort of patients we strove to provide a more informative population and appropriate analysis for studying the influence of JAK2 V617F mutation on BT and OS in PMF.
In 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.
At the Cox regression analysis, having either a wild-type (wt) or a homozygous JAK2 V617F 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, JAK2 V617F 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 JAK2 V617F genotype, older age, and lower hemoglobin retained high discriminant capacity (C statistics, 0.70; 95% CI, 0.47 to 0.92). A total of 147 patients were genotyped with a quantitative assay for JAK2 V617F mutation in granulocyte DNA collected within 6 months from diagnosis, provided that no treatment had been delivered in the meantime. A total of 97 patients were JAK2 V617F mutated, giving an overall frequency of 65.9%. Comparing the four groups, the time to BT, death for any cause, and death for BT among the 4 quartiles were not significantly different (P=0.5). However, there was a shorter time to BT in the upper quartile compared with lower quartiles (P= 0.04).
The accumulation of mutated alleles in the JAK2 V617F 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.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.