Statin use and survival in SLL/CLL treated with ibrutinib: Pooled analysis of four randomized controlled trials

• Statin use significantly improves overall and progression-free survival in CLL/SLL patients treated with ibrutinb

• No significant increase in severe adverse effects was observed with statin use in the study cohort.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients have seen significant treatment advancements with the emergence of Bruton's tyrosine kinase (BTK) inhibitors like ibrutinib. Statin use has been linked to reduced mortality in several cancers, including CLL. However, their concomitant use with targeted therapies such as ibrutinib remains unexplored. This study investigates the association of statin use with survival and adverse event outcomes in CLL/SLL patients initiating contemporary treatment regimens, including ibrutinib. Individual participant data from four randomized trials-RESONATE, RESONATE-2, iLLUMINATE, and HELIOS-were utilized. Associations between baseline statin use and treatment outcomes were examined using Cox proportional hazards models for overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CCS), and logistic regression models for grade ≥3 adverse effects. Analyses were adjusted for age, sex, weight, ECOG performance status, disease diagnosis, bulky disease (≥5 cm), time since initial diagnosis, comorbidity count, and the use of beta-blockers, calcium channel blockers, ACEIs/ARBs, and diuretics. Out of 1,467 patients, 424 (29%) were using statins. Statin use was significantly associated with improved OS (adjusted HR[aHR] 0.55[0.42‑0.72], P<0.001), PFS (aHR 0.73[0.61-0.88],P=0.001), and CCS (aHR 0.39[0.22-0.70],P=0.001). Findings were consistent across ibrutinib vs non-ibrutinib treatment arms (OS P-interaction=0.52, PFS P-interaction=0.31) and CLL vs SLL diagnosis(OS P-interaction=0.77, PFS P-interaction=0.32). No significant association between statin use and grade≥3 adverse effects was observed. Statin use was identified as an independent positive prognostic factor in CLL/SLL patients, irrespective of the treatment employed. Further research is needed to validate these results and explore the underlying impacts of statins in CLL/SLL. RESONATE: NCT01578707, RESONATE2: NCT01722487, iLLUMINATE: NCT02264574, HELIOS: NCT01611090