Myelofibrosis Therapies and Risk of Major Bleeding, Thrombotic Events and Mortality, a Matched Nationwide Population-Based Study

Introduction

Myelofibrosis (MF) is one of the Philadelphia-negative myeloproliferative neoplasms (MPN) and is characterized by various degrees of bone marrow fibrosis, clonal proliferation of myeloid cells and extramedullary hematopoiesis. Thromboembolic events and bleeding are known complications in MF, but previous studies reporting on frequency of thrombosis and bleeding has often been based on small cohorts, populations of mixed MPN diagnoses and seldom included controls. In this nationwide population-based study, we assessed the frequency of major bleeding, thrombotic events and all cause-mortality in patients diagnosed with MF compared to matched controls using multiple Swedish Health Care Registers. We also investigated if the different therapies used in MF have an impact of the frequency of thromboembolic events, major bleeding, all-cause stroke and all-cause mortality.

Methods

All adult patients diagnosed with MF in 2008 to 2021 in the Swedish MPN register were included, and for each case, five controls matched by gender, geographical region and age were randomly selected from the Swedish Population register. Stroke-related outcomes were retrieved from the Stroke Register and all other outcomes were collected from the Swedish National Patient Register and Cause of Death Register.

Results

In total, 1079 patients with myelofibrosis and 5395 controls were included, and 939 of the patients were classified as primary myelofibrosis (PMF), 29 as prefibrotic myelofibrosis, and 108 as secondary myelofibrosis (post-PV MF, n=42, post-ET MF, n=65, previous MPN-U, n=1). The median age at MF diagnosis was 72 years and 43.1% were female. The majority of the patients, 64.4%, had IPSS score intermediate-1 or intermediate-2. An arterial or venous event preceding the MF diagnosis was documented in 24.8% and 8.0% of the patients, respectively and 8.5% of the patients had a major bleeding before MF diagnosis.

During follow-up, major bleeding was seen at a rate of 2.27 and arterial or venous thrombotic events 3.11 per 100 years in patients with MF. Compared to controls, the rates of bleedings, thrombotic events and mortality were increased, HR 3.8 (95% CI 3.0-4.9, p<0.001), HR 1.9 (1.5-2.5, p<0.001), and HR 3.9 (3.5-4.4, p<0.001) respectively. Patients treated with JAK-inhibitors had higher rates of major bleeding (5.33), arterial events (4.67) and venous events (1.56) than patients with no ongoing symptoms-directed therapy (rates 2.14, 1.94 and 0.79) or hydroxyurea (rates 2.05, 2.34 and 1.27). Anti-platelet agents were administered to 757 of the MF patients during an accumulated treatment time of 2210 years, in which 37 events of major bleeding occurred (rate 1.67, HR 2.6, 1.7-3.9, p<0.001) compared to rate 0.65 among corresponding controls. In MF patients treated with direct oral anticoagulants (DOAC) major bleeding was seen at a rate of 3.67 (controls 0.90), HR 4.0 (1.8-9.1. p<0.001), and 2.67 in patients treated with warfarin (controls 0.89), HR 3.0 (1.2-7.3, p=0.016). Among patients with no antithrombotic treatment, the rate of major bleeding was 3.18 compared to 0.63 in the controls, HR 5.1 (3.6-7.2, p<0.001). In multivariable analysis hypertension, diabetes and prior ischemic stroke were identified as independent risk factors for arterial event and a preceding VTE as a predictor of recurrent VTE and major bleeding.

Conclusion

We conclude that the rates of major bleeding, arterial and venous events are exceedingly higher in PMF and SMF than described in PV and ET, and significantly higher in MF than in corresponding controls. The diverging frequency of arterial and venous events, major bleeding and all-cause mortality in the different treatment groups clearly shows how the clinical picture in myelofibrosis can vary greatly and highlights the importance of making therapeutic considerations regarding symptoms-directed therapy and antithrombotic treatment based on each patient's individual features and risk factors.