Pre-fibrotic myelofibrosis (pre-PMF) and essential thrombocythemia (ET) are characterized by similarly increased rate of thrombotic events, but no study specifically analyzed risk factors for thrombosis in pre-PMF. In a multicenter cohort of 382 pre-PMF patients collected in this study, the rate of arterial and venous thrombosis after diagnosis was 1.0 and 0.95% patients/year. Factors significantly associated with arterial thrombosis were age, leukocytosis, generic cardiovascular risk factors, JAK2V617F and high molecular risk mutations, while only history of previous thrombosis, particularly prior venous thrombosis, was predictive of venous events. The risk of total thromboses was accurately predicted by the the international prognostic score for thrombosis in essential thrombocythemia (IPSET) score, originally developed for ET, and corresponded to 0.67, 2.05, and 2.95% patients/year in the low-, intermediate-, and high-risk categories. IPSET was superior to both the conventional 2-tiered score and the revised IPSET in this cohort of pre-PMF patients. We conclude that IPSET score can be conveniently used for thrombosis risk stratification in patients with pre-PMF and might represent the basis for individualized management aimed at reducing the increased risk of major cardiovascular events. Further refinement of the IPSET score in pre-PMF might be pursued by additional, prospective studies evaluating the inclusion of leukocytosis and/or adverse mutational profile as novel variables.

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In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p.V617F allele burden in patients with PV. Evaluable JAK2 p.V617F-positive patients randomized to ruxolitinib (n = 107) or best available therapy (BAT) who crossed over to ruxolitinib at week 32 (n = 97) had consistent JAK2 p.V617F allele burden reductions throughout the study. At all time points measured (up to weeks 208 [ruxolitinib-randomized] and 176 [ruxolitinib crossover]), mean changes from baseline over time in JAK2 p.V617F allele burden ranged from -12.2 to -40.0% (ruxolitinib-randomized) and -6.3 to -17.8% (ruxolitinib crossover). Complete or partial molecular response was observed in 3 patients (ruxolitinib-randomized, n = 2; ruxolitinib crossover, n = 1) and 54 patients (ruxolitinib-randomized, n = 33; ruxolitinib crossover, n = 20; BAT, n = 1), respectively. Among patients treated with interferon as BAT (n = 13), the mean maximal reduction in allele burden from baseline was 25.6% after crossover to ruxolitinib versus 6.6% before crossover. Collectively, the data from this exploratory analysis suggest that ruxolitinib treatment for up to 4 years provides progressive reductions in JAK2 p.V617F allele burden in patients with PV who are resistant to or intolerant of hydroxyurea. The relationship between allele burden changes and clinical outcomes in patients with PV remains unclear.