Background: Ibrutinib, a Bruton tyrosine kinase inhibitor, has transformed the management of chronic lymphocytic leukemia (CLL), but its use is associated with significant cardiotoxicity. Statins, widely prescribed for cardiovascular risk reduction, also exhibit anti-inflammatory and potential anticancer properties. However, their role in modifying outcomes in CLL patients treated with ibrutinib remains unclear.

Methods: We performed a retrospective analysis using the TriNetX database, including patients aged ≥18 years diagnosed with CLL who were treated with ibrutinib. Patients were divided into two cohorts based on statin exposure: those who received statins within 3 months before and up to 6 months after initiating ibrutinib (statin group), and those who did not receive statins (non-statin group). Propensity score matching was performed to balance baseline characteristics, using variables such as age at index, sex, ethnicity, comorbidities (including ischemic heart disease, cerebrovascular disease, and hyperlipidemia), body weight, and use of cardiovascular medications (beta-blockers, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics). The primary outcomes were 3-year overall survival (OS) and progression-free survival (PFS). Secondary outcomes included relapsed CLL, stable disease, or partial response to ibrutinib, and cardiovascular events. The death related to CLL was not captured in the relapsed CLL. Outcomes were analyzed using Kaplan-Meier survival estimates and measures of association.

Results: Baseline characteristics were well balanced following propensity score matching. A total of 2,230 patients were included in each group, with a mean follow-up duration of 768.4 days in the statin group and 748.1 days in the non-statin group. The mean age at index was 71.3 ± 9.41 years in the statin group and 72.0 ± 10.2 years in the non-statin group. Males comprised 64.7% of the statin group and 63.4% of the non-statin group, while females accounted for 32.5% and 33.9%, respectively. The majority of patients were White (77.5% in the statin group and 79.3% in the non-statin group), followed by African American patients (9.1% vs. 8.7%) and Asian patients (1.4% vs. 1.3%). Statin use was associated with a statistically significant improvement in 3-year OS compared to non-use (p = 0.0001), with a hazard ratio (HR) of 0.75 (95% CI: 0.661–0.852). Similarly, 3-year PFS was significantly higher in the statin group (p = 0.0002), with an HR of 0.793 (95% CI: 0.700–0.898). Stable disease (SD) or partial response (PR) was more frequently observed in the statin group compared to the non-statin group (26.04% vs. 13.48%, p < 0.0146). There were no significant differences between groups in rates of relapsed CLL (5.28% vs. 5.98%, p = 0.3315), heart failure (10.29% vs. 9.87%, p = 0.6599), or atrial fibrillation (12.42% vs. 10.71%, p = 0.0950). However, the statin group showed a higher incidence of ischemic heart disease (15.97% vs. 9.08%, p < 0.0001), hyperlipidemia (29.12% vs. 6.87%, p < 0.0001), and cerebral infarction (2.61% vs. 1.15%, p < 0.0004) during follow-up.

Conclusions: In this large real-world analysis of CLL patients treated with ibrutinib, statin use was associated with significantly improved 3-year OS and PFS, as well as higher rates of SD or PR. Although the statin group had a higher incidence of cardiovascular events, this likely reflects baseline comorbidities prompting statin initiation. Importantly, statin use did not increase the risk of heart failure or atrial fibrillation, supporting a favorable safety profile. Given the database's lack of cause-specific mortality, some disease-related deaths may not be captured under relapse, warranting further investigation. These findings suggest statins may serve as both cardioprotective agents and potential adjuncts to enhance outcomes in CLL patients receiving ibrutinib. Incorporating statins into the supportive care of selected high-risk CLL patients, particularly those with existing cardiovascular disease on ibrutinib, could be a valuable strategy to optimize both oncologic and cardiac outcomes. Further research is needed to confirm these results and clarify the underlying mechanisms.

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2025
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