The risk of bleeding in patients receiving ibrutinib combined with novel direct oral anticoagulants

Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, is an established therapeutic agent in a variety of Bcell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction, and concurrent treatment with ibrutinib and warfarin has been shown to significantly increase the risk of bleeding. The current study was designed to investigate the safety of direct oral anticoagulants (DOACs) in patients receiving ibrutinib, taking into consideration their expanding employment together with the lack of data regarding their safety. Between January 2010 and October 2018, we conducted a retrospective cohort study in five participating centres to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage, blood count and chemistry tests, bleeding site and grade. The study included 30 patients (Table I, patient characteristics) with a median age of 71 6 years (range 50 9–88 2). Most patients were treated for chronic lymphocytic leukaemia (CLL) (n = 18, 60%) and mantle cell lymphoma (MCL) (n = 8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63 3% and 30%, respectively. Twenty-three patients were treated with apixaban (76 7%), four with rivaroxaban (13 3%) and three (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). Median follow-up after initiation of ibrutinib-DOAC combination was 13 4 months (range 1 8–47 9 months). Bleeding was reported in 22 patients (73 3%), mostly mucocutaneous (n = 12, 40%) and gastrointestinal tract (n = 7, 23 3%), followed by central nervous system (CNS) bleeding (n = 4, 13 3%). Mucocutaneous bleedings were all grade 1–2, and gastrointestinal tract and CNS bleeding events were grade 1– 4. Major bleeding events, defined as grade 3 or 4, occurred in five patients (16 6%) and did not result in the death of any of the patients. Major bleeding sites involved the gastrointestinal tract (n = 1), CNS (n = 2), intraocular (n = 1) and postoperative hip fracture repair (n = 1). Serious bleeding sequelae occurred in two patients, as well as urgent craniotomy due to grade 4 CNS bleeding and right eye blindness due to grade 4 intraocular bleeding. None of the patients died of bleeding. The median time for bleeding following ibrutinib-DOAC initiation was 5 6 months. Over a follow-up period of 21 months of combined treatment, the incidence of bleeding events (of all grades) increased to 75% and was similar between all DOAC subtypes (73 9% with apixaban, 75% with rivaroxaban and 66 7% with dabigatran). No statistically significant predictors for increased risk of bleeding in patients receiving ibrutinib combined with DOACs were detected. Ibrutinib was stopped in eight patients (26 7%) due to grade 1–4 bleeding events and was re-initiated in six patients, resulting in recurrent grade 3 and 4 bleeding events in two patients. Despite the insufficient data regarding the safety of DOACs in combination with ibrutinib, the employment of this combination in patients with CLL and NHL is rapidly expanding. Most of the patients included in our study experienced bleeding events. However, the majority were grade 1– 2 mucocutaneous bleeding only, and their incidence and severity were not higher than previously reported with ‘old’ anticoagulation agents (Boriani et al., 2018) (Table II). Major bleeding events occurred in five patients (16 6%); one of them was a life-threatening bleeding event and the other eventuated in right eye blindness. In previous CLL trials among ibrutinib-treated patients who received any type of anticoagulant (including four cases only treated with DOACs), major bleeding events were reported in 9% in the PCYC-1102 study and 2% in the PCYC-1112 study (Resonate) (Brown, 2018) during a median follow-up 22 and 10 months, respectively. In these studies, the most frequent anticoagulant treatment being used was LMWH (low molecular weight heparin), which was usually given in a prophylactic dose and for a limited duration of less than 3 months, whereas few patients only received DOACs (Brown et al., 2019). Similar to our results, most of these bleeding events occurred early, during the first 3–6 months of therapy. Patients with MCL had a significantly higher risk for major hemorrhage than patients with CLL, a finding which is probably dose-related (560 mg per day vs. 420 mg per day in patients with CLL) (Byrd et al., 2014). According to our study, risk of bleeding in patients treated with DOACs is higher than reported in previous trials studying bleeding in patients treated with ibrutinib and anticoagulants. However, DOACs are much easier to handle compared with warfarin and LMWH, being administered orally and not requiring any surveillance blood tests to monitor their activity. There is no consensus regarding the preferable DOAC in patients concomitantly treated with ibrutinib. Some studies correspondence