One-Year Real-World Outcomes of Venetoclax Versus BTK Inhibitors based regimens in CLL: Insights from a Global, Propensity-Matched EHR Study
Introduction/Background/Significance: The emergence of targeted agents, including BCL2 inhibitor venetoclax and Bruton's tyrosine kinase inhibitors (BTKis), has transformed the management of chronic lymphocytic leukemia (CLL). While both are now standard-of-care for relapsed and frontline disease, real-world comparative data on clinical and safety outcomes remain limited. This study assesses 1-year outcomes between venetoclax- and BTKi-based regimens in CLL/SLL patients.
Materials and Methods/Case Presentation/Objective: A retrospective cohort analysis was conducted using the TriNetX Network. Adult patients (≥18 years) with CLL/SLL were included if they initiated either a venetoclax-based regimen without prior/exposure to BTKi (Cohort 1, n=1,704) or a BTKi-based regimen without venetoclax (Cohort 2, n=1,704). Propensity score matching (1:1) was performed on key demographic and clinical covariates, including prior stem cell transplant status. Outcomes were measured from 1 day to 1 year post-index and compared using Kaplan-Meier analysis, hazard ratios (HR), and log-rank tests.
Results/Description/Main Outcome Measures: At one year, all-cause mortality was significantly lower in the venetoclax group compared to the BTKi group (HR 0.78, 95% CI 0.63–0.98; p=0.029). In contrast, venetoclax-treated patients experienced significantly higher risk of hospitalization (HR 1.46, 95% CI 1.11–1.94; p=0.007), neutropenia (HR 3.47, 95% CI 2.73–4.42; p< 0.001), thrombocytopenia (HR 1.46, 95% CI 1.13–1.90; p=0.004), LDH elevation above 250 U/L (HR 2.75, 95% CI 2.14–3.53; p< 0.001), hypogammaglobulinemia (HR 1.37, 95% CI 1.00–1.89; p=0.051), and IVIG requirement (HR 1.97, 95% CI 1.44–2.70; p< 0.001). The risk of outpatient ambulatory visits was significantly lower with venetoclax (HR 0.39, 95% CI 0.21–0.73; p=0.002), while rates of ER visits did not differ between groups (HR 1.09, 95% CI 0.84–1.43; p=0.52).
No statistically significant differences were observed between the two cohorts for anemia (HR 0.92, 95% CI 0.71–1.20; p=0.55), septic shock (HR 1.06, 95% CI 0.63–1.78; p=0.82), pneumonia (HR 1.10, 95% CI 0.83–1.46; p=0.49), CMV infection (HR 1.78, 95% CI 0.60–5.32; p=0.29), candidemia (HR 1.00, 95% CI 0.06–15.98; p=1.00), aspergillosis (HR 0.32, 95% CI 0.07–1.61; p=0.15), intracerebral hemorrhage (HR 0.68, 95% CI 0.29–1.60; p=0.38), or GI bleeding (HR 0.94, 95% CI 0.59–1.50; p=0.79). Similarly, no significant difference was found in the risk of ESRD/hemodialysis, acute heart failure, stroke,
The rates of myocardial infarction were significantly lower in the venetoclax group (HR 0.51, 95% CI 0.29–0.90; p=0.019), though the absolute event rates were low in both arms.
Conclusions: In this large, real-world cohort analysis, venetoclax-based regimens were associated with lower all-cause mortality and outpatient visit rates but increased risk of hospitalizations, cytopenias, immune suppression, and IVIG requirement compared to BTKi-based therapy. Cardiovascular and infectious complication rates were similar between groups, though the risk of myocardial infarction was lower with venetoclax. These findings offer important context for clinicians selecting CLL therapy in practice and highlight the need for individualized treatment and monitoring strategies.
