Thrombosis in primary myelofibrosis: the influence of cohort composition and disease biology

Recent nationwide data from Sweden evaluated thrombosis, major bleeding, and mortality in patients with myelofibrosis (MF), providing valuable population-based insights into vascular complications in overt primary MF (PMF) and post-essential thrombocythemia and polycythemia MF. 1 However, interpreting these results is complicated by the combined analysis of biologically distinct disease entities.In fact, despite sharing molecular features, PMF and secondary MF differ in terms of their natural history, proliferative pattern, the extent of marrow fibrosis, and cumulative exposure to cytoreductive and antithrombotic therapies.2 Here, we highlight how cohort composition influences vascular risk estimates and present data from a homogeneous cohort of patients with overt PMF, underscoring that cohort composition and disease biology are critical determinants.This Swedish study evaluated 1079 patients with PMF or secondary MF compared with 5395 ageand sex-matched population controls.Overall, 40.7% of the patients had an International Prognostic Scoring System (IPSS) score of intermediate-2 or high risk.Rates of major bleeding, arterial events, and venous events were 2.55%, 2.59%, and 1.06% patient-years, respectively.Patients treated with JAK inhibitors (JAKi), mainly ruxolitinib and fedratinib, had higher event rates, including arterial and venous events (4.67% and 1.56% patient-years) and major bleeding (5.33% patient-years) than with interferon therapy (arterial 0.37% and venous 0.37% patient-years; bleeding 1.11% patient-years) or no therapy (arterial 2.15% and venous 0.79% patient-years; bleeding 2.32% patient-years).Lower hemoglobin (11 × 10 9 /L) at diagnosis were associated with increased arterial event rates, particularly among patients who were treated with JAKi.In multivariable analysis, these authors showed that treatment with JAKi, compared with controls, was associated with an increased risk of arterial or venous events (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.27-3.68;P = .005).Of note, in Sweden, ruxolitinib and fedratinib are reimbursed only in intermediate-2 and high-risk IPSS scores.Moreover, low-molecular-weight heparin treatment was also identified as an independent risk factor for arterial or venous events (HR, 3.16; 95% CI, 1.67-5.96;P < .001) as it was previous arterial and venous events and older age with HRs of 1.98 (95% CI, 1.35-2.92;P < .001),2.30 (95% CI, 1.35-3.93;P = .002),and 1.59 (95% CI, 1.22-2.07;P < .001),respectively.The presence of a JAK2 V617F mutation failed to reach statistical significance as a risk factor for arterial or venous events (HR, 1.38; 95% CI, 0.92-2.07;P = .12).In contrast to the Swedish study, we obtained different results by analyzing thrombotic and bleeding events, focusing exclusively on overt PMF. 3 We studied 584 patients enrolled in the European Registry for Myeloproliferative Neoplasms towards a Better Understanding of Epidemiology, Survival, and Treatment registry, diagnosed between 2013 and 2014, and followed with updated clinical data until December 2020.Patients were stratified according to baseline IPSS and molecular profile, and