Real-World Risk of Major Bleeding Events in BTKi-Treated Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL)
Authors: Moslehi Javid J. , Wahlstrom Svea K. , Teschemaker Anna , Mackey Rachel H. , DeVincenzo Diana , Carabuena Leslie A. , Thompson Samantha L. , Gordon Brittaney-Belle Elizabeth , Rosenthal Ning A. 
Published: December 2024

Introduction: Bruton tyrosine kinase inhibitors (BTKi) are effective targeted therapies that have altered the treatment landscape of CLL/SLL. Although major bleeding is rare, bleeding events are associated with BTKi therapy (tx). Our group recently reported a real-world analysis of US patients diagnosed with CLL/SLL, where the risk of bleeding events increased (HR [95% CI] 2.33 [1.83-2.98]) in patients (pts) receiving BTKi and concurrent prescription anticoagulants (Moslehi et al. ASCO 2024. Abstract #7052). In this study we are interested in the risk of major bleeding in CLL/SLL pts taking BTKi, who are often elderly with comorbidities requiring anticoagulant (AC) or antiplatelets (AP). Therefore, we aimed to evaluate the real-world prevalence of major bleeding among BTKi treated CLL/SLL pts and to define associated risk factors.
Methods: A retrospective observational cohort study was conducted using the claims-linked Premier PINC AI Healthcare Database. Pts aged ≥18 years diagnosed with CLL/SLL between July 1, 2016 and March 31, 2022 with no BTKi exposure 3 months prior to index date (first prescription fill date for BTKi) were included. Pts were followed during their BTKi exposure period from index date to earliest of BTKi discontinuation, death, or end of the study period (March 31, 2023). Prescription claim data was used to capture BTKi and AC/AP use over time. Major bleeding events defined as any hospitalizations with clinically validated diagnosis codes for bleeding. Multivariable-adjusted risk for major bleeding events was assessed with Cox proportional-hazards regression.
Results: A total of 2091 patients with CLL/SLL initiating BTKi from July 2016 to March 2022 were included in the analysis. The mean (SD) age was 65.7 (11.3) years, 61.8% were male, and 77.7% were White, with the mean (SD) Charlson comorbidity index of 3.5 (2.2). At baseline, 44.5% had hypertension, 20.8% had diabetes, 19.3% thrombocytopenia, 13.3% had chronic kidney disease, 12.1% had prior bleeding events, and 7.5% had atrial fibrillation. BTKi included ibrutinib (86.3%), acalabrutinib (13.1%), and zanubrutinib (&lt;1%). Overall, 4.3% of pts switched BTKi during follow-up; 615 (29.4%) had prescription AC/AP at any time during the study period, of whom 411 (66.8%) started after BTKi initiation.
Major bleeding events occurred in 136 (6.5%) pts during a mean BTKi exposure of 14.2 months, with an incidence of 5.2 per 100 person-years (PYs) overall, and 10.6 and 3.3 per 100 PYs in pts with and without any prescription AC/AP use, respectively. The proportion of pts with fatal bleeding was &lt;0.3%. The median (IQR) time to first major bleeding event during BTKi exposure in overall, and in pts with and without any prescription AC/AP were 124 (45-385) days, 145 (45-524) days, and 110 (45-279) days, respectively. In the adjusted model, the risk of first bleeding event in pts with BTKi was higher for time-varying AC use (HR [95% CI] 5.59 [3.67-8.53]), and history (during 90 days prior to BTKi start) of bleeding (3.45 [2.26-5.25]) or peptic ulcers (3.09 [1.03-9.23]) (all P≤0.05). Time-varying prescription AP use, age, sex, race/ethnicity, and history of hypertension, diabetes, chronic kidney disease, thrombocytopenia and ischemic heart disease were not significantly associated with risk of major bleeding.
Conclusions: In this large real-world study of major bleeding risk in pts receiving BTKi with or without AC/AP, major bleeding events occurred in 5.2 per 100 patients per year, with &gt;5-fold higher risk in AC users, and &gt;3-fold higher risk in patients with history of bleeding, or peptic ulcers. The risk of fatal bleeding was low (&lt;0.3%).