Direct Oral Anticoagulants for Myeloproliferative Neoplasms (MPN-DOACs): Results from an International Study on 442 Patients
Authors: Barbui Tiziano , De Stefano Valerio , Carobbio Alessandra , Iurlo Alessandra , Alvarez-Larran Alberto , Vannucchi Alessandro M. , Palandri Francesca , Harrison Claire , Sibai Hassan , Griesshammer Martin , Bonifacio Massimiliano , Elli Elena M , Trotti Chiara , Koschmieder Steffen , Carli Giuseppe , Benevolo Giulia , Ianotto Jean-Christophe , Goel Swati , Falanga Anna , Betti Silvia , Cattaneo Daniele , Arellano-Rodrigo Eduardo , Mannelli Lara , Vianelli Nicola , Doyle Andrew , Gupta Vikas , Wille Kai , Tremblay Douglas , Mascarenhas John 
Published: February 2021

Background
Direct oral anticoagulants (DOACs) have emerged as a treatment of choice in patients with chronic atrial fibrillation (AF) or for secondary prevention of venous-thromboembolism (VTE). In myeloproliferative neoplasms (MPN) very small series have been reported and robust data reporting the safety/efficacy profile of these drugs is not available. We conducted an international, multi-country, retrospective study involving 19 hematologic centers from Europe, US and Canada, with the aim to describe in a large cohort of MPN patients the incidence of thrombosis and bleeding complications associated with DOAC use in real word clinical practice.
Methods
Centers reported in an electronic CRF data on 442 patients (M/F: 221/221; median age: 65 years) with a WHO diagnosis of polycythemia vera (PV, n=178), essential thrombocythemia (ET, n=172) and primary myelofibrosis (PMF, n=92) who had received DOACs (Rivaroxaban n=187; Apixaban n=157; Dabigatran n=50; Edoxaban n=48) for either primary and secondary antithrombotic prophylaxis in atrial fibrillation (AF, n=203) or secondary prophylaxis of venous thromboembolism (VTE, n=239). Eighty-two patients (18.6%) shifted to DOAC after a previous exposure to a vitamin K antagonist (VKA) mainly due to patient preference (8.4%), bleeding/thrombosis (5.2%) or INR instability (4.1%). In 60 patients, DOAC was discontinued after a median duration of 1.1 years; reasons included completion of a pre-determined duration (2.9%), patient decision (0.9%), major bleeding (2.5%) or thrombosis (2.9%), minor bleeding (0.9%), thrombocytopenia (2.0%), surgery (0.9%), or other (0.5%).
Results
Median time from MPN diagnosis to DOAC initiation was 4.4 years (range: 0-34.7 years). Concomitant therapies included antiplatelet agents (31%) and cytoreductive drugs in 90% (hydroxyurea in 87%of cases). After a median follow-up of 1.83 years, 32 major thrombotic events (rate: 3.3% pts/yr) and 26 major bleeding events (rate: 2.6% pts/yr) were reported.
1. AF. Ten thrombotic events (rate: 2.1% pts/yr) occurred in patients receiving DOACs: 4 TIA, 3 MI and 3 DVT of the lower extremities (LE); the rate was remarkably different in primary prevention (1.5% pts/yr) vs. secondary prophylaxis (i.e. after a previous thrombosis, mainly arterial: 4.6% pts/yr). This rate was almost double that reported in secondary prophylaxis in non-MPN population in randomized clinical trials (RCTs) (2.1-3.2% pts/yr). Previous arterial thrombosis was the only significant risk factor for recurrences in this subset (HR: 3.89, p=0.035).
2. VTE. Twenty-two recurrences while receiving DOACs were reported (5 arterial, 10 DVT of the LE +/- PE, 3 splanchnic vein and 4 others venous; rate: 4.5% pts/yr) and irrespective of initial site of thrombosis and type of DOACs. This rate was similar to MPN patients receiving VKAs (5.3% pts/yrs - De Stefano V et al, Leukemia 2016) but higher than in non-MPN population in RCTs (1.4-1.9% pts/yr). In univariate analysis, significant factors for recurrences were: previous arterial thrombosis (HR: 3.55, p=0.023), hypertension (HR: 2.88, p=0.021) and diabetes (HR: 3.33, p=0.018).
3. Among 26 major bleeding events, 12 were gastrointestinal, 7 intramuscular, 1 CNS and 6 in other sites. The overall rate was 2.6% patients/year, which is comparable to that reported in MPN patients under VKA (2.4% pt/yrs, De Stefano V et al, ibidem) and in non-MPN population of RCTs (1.60-3.11% pt/yrs). The frequency of major bleeding was similar in AF (3% pt/yrs) and VTE (2.3% pt/yrs) setting. In univariate analysis, significant risk factors were PMF diagnosis (HR: 2.95, p=0.007) and the use of Dabigatran in comparison to the other DOACs (HR: 2.91, p=0.016) whereas no increase was due to antiplatelet drugs.
Conclusions
This is the largest observational study describing vascular events in MPN patients receiving DOACs for prevention of thrombosis in AF or secondary prevention of VTE. Overall, the rate of re-thrombosis is similar to that reported with warfarin in MPN and double the rate of non-MPN population. The highest rate was found in patients with a previous history of arterial thrombosis and with cardiovascular risk factors. In regard to bleeding, we highlight the significant bleeding tendency in PMF and treatment with Dabigatran. In conclusion, the risk/benefit profile of DOACs in MPN is similar to that of Warfarin.

Disclosures
Barbui: AOP-Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. De Stefano:Novartis: Other: Personal fee, Research Funding; Amgen: Other: Personal fee; Bayer: Other: Non-financial support; Celgene: Other: Non-financial support, personal fee; Janssen Cilag: Other: Non-financial support. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri:Novartis: Consultancy, Honoraria. Harrison:Celgene: Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau. Griesshammer:Novartis: Honoraria, Speakers Bureau; AOP Orphan: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; CTI: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Koschmieder:Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Geron Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte/Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; CTI Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Promedior: Other. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Gupta:Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.