Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. 1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. 4 It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.
Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.5 One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.6
Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.7 Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.8
However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.6,9
Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.10 Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.