Real-world overall survival outcomes of BTK inhibitors vs. venetoclax-based therapy as second-line treatment for chronic lymphocytic leukemia.

7052 Background: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with highly variable clinical behavior. The treatment landscape has shifted from chemoimmunotherapy to targeted agents, specifically Bruton’s tyrosine kinase inhibitors (BTKi) and venetoclax (BCL-2 inhibitor). While both are established first-line options, the optimal treatment sequence to maximize long-term survival remains undefined. This real-world analysis evaluates overall survival (OS) when utilizing BTKi or venetoclax-based therapy as second-line (2L) treatment. Methods: This retrospective, propensity-matched cohort study utilized de-identified electronic medical record data from the TriNetX network (through Jan. 2026), covering 189 million patients. Adult patients with CLL (ICD-10: C91.1) were identified based on treatment sequencing of 1L BTKis followed by 2L Venetoclax or vice-versa. The index event was the initiation of 2L therapy with either a BTKi or venetoclax. Patients receiving traditional chemotherapy were excluded from analysis. To minimize confounding, 1:1 Propensity Score Matching (PSM) was performed using a greedy nearest-neighbor algorithm based on demographics (age, sex, race/ethnicity) and comorbidities (hypertension, ischemic heart disease, diabetes, CKD, COPD, obesity). Standardized mean differences (<0.1) confirmed covariate balance. The primary endpoint was OS through 10 years. Results: A total of 5,841 patients met inclusion criteria (BTKi n=2,589; venetoclax n=2,892). After PSM, 1,959 patients were included per cohort. Ten-year OS was significantly higher in patients receiving BTKi as 2L therapy compared to venetoclax (71.5% vs. 68.0%; HR 0.651, 95% CI 0.55-0.77; p <0.0001). Median follow-up duration was longer for the BTKi group (1,287 days) than the venetoclax group (639 days). Conclusions: In this real-world analysis, treatment sequence with Venetoclax (1L) and BTKis (2L) was associated with a significant long-term survival advantage compared to venetoclax. The observed reduction in mortality risk (HR 0.651) suggests that treatment sequencing of immunotherapy with Venetoclax followed by a BTKi may offer superior clinical outcomes for treatment of CLL. While these results support preferential sequencing of BTKis after venetoclax, additional prospective studies are needed for further evaluation and confirmation.