Introduction: Covalent Bruton tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and are part of the standard of care. However, the management of patients on BTKis is complicated by associated toxicities, particularly bleeding events, which represent a significant challenge in patient care. This challenge is further complicated in CLL patients with comorbidities requiring anticoagulation (AC) or antiplatelet (AP) therapy, as the bleeding diathesis from BTKis interacts with the inherent bleeding risks of AC or AP drugs. However, there is limited data available on the bleeding risk in CLL patients. Our study aims to address this knowledge gap by evaluating the rate and the risk of bleeding in three groups of CLL patients in remission: those treated with BTKis alone, those on BTKis and concurrent AC/AP therapy, and those on BTKis with either AC or AP drugs. This analysis is conducted using real-world data (RWD) to provide insights into the complex interplay between CLL treatment and bleeding risk management in clinical practice.

Methods: A retrospective analysis of RWD from multiple centers was carried out using the TriNetX database on July 27, 2025. The study population was divided into two main cohorts: 1) Cohort 1: CLL patients in remission treated with covalent BTKi (ibrutinib/acalabrutinib/zanubrutinib) concurrently treated with AC (rivaroxaban/apixaban/edoxaban/dabigatran) or AP agents (acetylsalicylic acid/clopidogrel/prasugrel/ticagrelor/ticlopidin), and 2) Cohort 2: CLL patients in remission treated with covalent BTKi (ibrutinib/acalabrutinib/zanubrutinib) not concurrently treated with AC or AP agents. Cohort 1 was further subdivided into two groups: those treated only with AC and those treated only with AP. This analysis utilized ICD-10 codes to identify all bleeding events, including post-procedural hemorrhagic events. Standardized mean differences were used to ascertain the distribution balance among baseline variables. The risk of bleeding was evaluated using risk ratios (RR), 95% confidence intervals (CI), and the Z-test. Propensity score matching was employed to control the effects of specific confounders. Focusing only on CLL patients in remission was to avoid active disease as a confounder of the outcomes of interest.

Results: A total of 2885 patients were enrolled, with 1401 patients in Cohort 1 (BTKi with AC/AP) and 1484 in Cohort 2 (BTKi alone). The patients' mean age at the index event (initiation of BTKi and AC/AP for Cohort 1; initiation of BTKi for Cohort 2) differed significantly between the cohorts: for Cohort 1, it was 73.3±9.5, whilst for Cohort 2, it was 69.1±10.9 (p<0.001). Male sex was more prevalent in Cohort 1 (64.3% vs. 59.4%, p=0.006). Over a 3-year follow-up period, Cohort 1 exhibited a statistically significantly higher bleeding rate than Cohort 2 (35.2% vs. 23.2%, respectively, z=7.103, p<0.001; RR 1.518, 95% CI 1.351-1.706). After propensity score matching for covariates (age at index event and sex), for a follow-up time window of 3 years for both cohorts, the bleeding rate was significantly more frequent in Cohort 1 than in Cohort 2 (34.8% vs. 23.1%, respectively, z=6.292, p<0.001; RR 1.507, 95% CI 1.323-1.716). Within Cohort 1, a comparison between patients treated with AC only and those treated with AP only revealed a slightly lower bleeding rate in the AC group; this difference did not reach statistical significance (30.2% vs. 31.1%, respectively, z=-0.272, p=0.786; RR 0.972, 95% CI 0.794-1.190). A limitation of this study is the inability to distinguish between minor and major hemorrhagic events due to insufficient data.

Conclusions: CLL patients in remission treated with covalent BTKis experience a significant risk of bleeding events. This risk is substantially elevated when covalent BTKis therapy is combined with either anticoagulant or antiplatelet agents. Notably, our findings indicate no discernible difference in bleeding risk between AC or AP agents when used concurrently with covalent BTKis. These results underscore the need for careful consideration when prescribing covalent BTKis in combination with AC or AP agents in CLL patients. Further analysis, possibly evaluating patient-level data, is warranted to identify specific risk factors and develop improved management strategies for this patient population.

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2025
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