Ibrutinib Associated Bleeding

Ibrutinib (Imbruvica) is an orally administered irreversible inhibitor of Bruton tyrosine kinase (BTK), which plays an important role in the B cell receptor signaling pathway. Ibrutininb has received FDA approval for treatment of naive and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), relapsed mantle cell lymphoma(MCL), and Waldenstrom macroglobulinemia.

BTK also plays a role in platelet signaling through GP1b and GPVI, which mediate platelet aggregation and adhesion through von Willebrand factor and collagen, respectively. A recently published systematic review of observational studies and randomized controlled trials determined the incidence rate of bleeding and risk of bleeding in patients treated with ibrutinib.

This study provided moderate-quality evidence that ibrutinib increases overall bleeding compared with alternative treatments.  The pooled annual incidence of any bleeding in ibrutinib treated patients was 20.8 per 100 patient years (95% confidence interval [CI], 19.1-22.1) and the pooled incidence of major bleeding was 2.76 95% CI, 2.07-3.53) per 100 patient-years. The relative risk of major bleeding in ibrutinib recipients as compared with recipients of an alternative therapy was 1.66. For comparison, major bleeding complications in patients receiving anticoagulant therapy for atrial fibrillation occur at rates of 2.1 to 3.6 per 100 patient years.

With the expected rise in ibrutinib use for the treatment of B-cell lymphoproliferative diseases, bleeding events will likely become an increasingly significant clinical concern, especially among elderly patients requiring concurrent antithrombotic therapy. Patients should be cautioned against using non-steroidal anti-inflammatory drugs, fish oil, vitamin E and aspirin containing products. Ibrutinib should probably not be prescribed for patients with stents requiring dual antiplatelet therapy.

The product monograph recommends discontinuation of ibrutinib for 7 days prior to an invasive procedure. In bleeding occurs, ibrutinib should be withheld until it resolves. Some practitioners recommend transfusion of one or two units of apheresis platelets to achieve immediate hemostasis.

Caron F. et al. Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood Advances. 2017;1:772-778.

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