The Risk of Bleeding in Patients Receiving Ibrutinib Combined with Novel Direct Oral Anticoagulants

Abstract

Introduction: Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, is an established therapeutic agent in a variety of B-cell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction and concurrent treatment with ibrutinib and warfarin was 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, considering their expanding employment together with the lack of data regarding their safety in patients receiving ibrutinib. Methods: We conducted a retrospective cohort study to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders (CLL, MCL, DLBCL, MZL or WM) that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy, between January 2010 and October 2018 in 5 participating centers. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage (including the adjustment for renal function), blood count and chemistry tests, bleeding site and grade. Results: The study included 30 patients, median age at starting concurrent administration of ibrutinib and DOACs was 71.58 years (range 50.9-88.2). Most patients were treated for CLL (n=18, 60%) and MCL (n=8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63.3% and 30% of patients respectively. None of the patients received an additional antiplatelet agent. Twenty-three patients were treated with apixaban (76.7%), 4 with rivaroxaban (13.3%) and 3 (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). The median follow-up after initiation of the 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 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 5 patients (16.6%) and did not result in death of any of the patients. 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% (Figure 1). Incidence of bleeding events (including all grades) was quite 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 8 patients (26.7%) due to grade 1 to 4 bleeding events and was re-initiated in 6 patients, resulting in recurrent grade 3 and 4 bleeding events in 2 patients. Conclusions: Concurrent administration of DOACs and ibrutinib appears to be feasible. However, risk of bleeding is not neglectable, and treatment resumption in patients that experienced a significant bleeding event should be considered with caution. Disclosures Arnason: Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Herishanu:Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria.

Rate of major bleeding with ibrutinib versus bendamustine‐rituximab in chronic lymphocytic leukemia: A population‐based cohort study

“…The crude incidence rate of major bleeding among ibrutinibtreated individuals in our study (3.1 per 100 person-years [p-y], 95% CI: 2.0-4.7) is comparable to that found in a meta-analysis of ibrutinib clinical trials, 1 which reported a pooled major bleeding incidence rate of 2.8 per 100 p-y. Though prior real-world observational studies did not report incidence rates, their crude incidence proportions (8%-18%) 3,4 were notably higher than that of our study (0.87%). Potential reasons for this difference are described in Supplemental Discussion 3.1.…”

“…1 Indeed, higher incidences of major bleeding (8%-18%) have been reported in real-world populations compared to clinical trials. 3,4 Few studies have examined this topic, however, and those that have did not directly compare the rate of major bleeding between ibrutinibtreated individuals and individuals treated with therapeutic alternatives. Furthermore, many of these studies were limited to a single institution.…”

Real-world management of targeted therapies in chronic lymphocytic leukemia

“…[81][82][83][84] One real-world analysis suggests DOACs may be safely used with ibrutinib, albeit with a modestly increased overall bleeding risk compared to patients treated on clinical trials. 85,86 Bleeding events occurred in 10% to 16% of patients, the majority of which were grade 1 to 2 with no fatal bleeding events reported.…”

Management of cardiovascular complications of bruton tyrosine kinase inhibitors

“…47 In multivariate analysis, the use of antiplatelet or anticoagulant (AP/AC) was associated with an increased risk of MH in the total ibrutinib pool (HR, 1Á7; 95% CI, 1Á0-2Á7; P = 0Á041) but not in the total randomised pool. 48 The risk of MH with the concomitant use of anticoagulants and/or antiplatelets (AP/AC) and ibrutinib from retrospective cohort studies was much higher (16-18%), 21,49,50 underscoring the need for thejudicious use of these agents in the more vulnerable group. 51 Each individual DOAC manifests a different risk-benefit profile, but we recommend the use of a label-adherent dose of DOAC due to its superior safety and efficacy relative to warfarin.…”

“…61,62 The use of dual antiplatelets and OAC in combination should be used for a minimal duration in high thrombotic risk AF patients with a recent coronary stent; in high bleeding risk patients, dual therapy with OAC plus a P2Y12 inhibitor (clopidogrel) may be used judiciously. 62,50 Patients with a stable vascular disease can be managed with an OAC alone in long-term treatment (more than 12 months). The management of these niche patients should be discussed in a multidisciplinary team meeting (MDT) involving the treating haematologist, cardiologist and the haemostasis and thrombosis specialist.…”