INTRODUCTION: Targeted therapies have become the standard first-line treatment for patients with chronic lymphocytic leukemia (CLL/SLL), offering superior survival outcomes compared to traditional chemoimmunotherapy. To date, no prospective clinical studies have directly compared venetoclax-based regimens with second generation covalent Bruton tyrosine kinase inhibitors (cBTKis). This retrospective study aimed to evaluate clinical outcomes in comparable patients with CLL/SLL who received either therapeutic approach.

METHODS: We conducted a retrospective observational cohort analysis and identified patients aged ≥40 years with CLL/SLL using the TriNetX Global Collaborative Network. Patients who had received prior therapies for CLL/SLL with chlorambucil, cyclophosphamide, fludarabine, bendamustine, or ibrutinib were excluded. Two cohorts were defined based on the initial therapeutic regimen. Cohort 1 included patients treated with venetoclax-based regimens (with or without rituximab or obinutuzumab), and cohort 2 included those receiving second-generation BTKis (acalabrutinib or zanubrutinib). Propensity score matching was adjusted for variables including age, sex, race, hypertension, diabetes, chronic kidney disease, lymphadenopathy, elevated white blood count, atrial fibrillation, heart failure, and cardiomyopathy. The incidence of infections, gastrointestinal symptoms, hematologic toxicity, major bleeding events, and tumor lysis syndrome (TLS), as well as overall survival (OS), were assessed within 1 year of treatment and compared between cohorts. Absolute risk increase (ARI), risk ratios (RR), number needed to harm (NNH), and 95% confidence intervals (CI) were calculated. Survival analysis was performed using the log-rank test. A p-value < 0.05 was considered statistically significant.

RESULTS: A total of 5,774 patients were included in the study, with 2,887 patients in each cohort. Venetoclax-based therapy was associated with a significantly higher 1-year incidence of infections compared to second-generation BTK inhibitors, particularly neutropenic fever (ARI: 5.06%; p < 0.0001, NNH: 20; RR: 3.92; 95% CI 2.886-5.324) and sepsis (ARI: 3.26%; p < 0.0001; NNH: 31; RR: 1.67; 95% CI 1.361-2.04). A modest but statistically significant increase in pneumonia incidence was also observed in this group (ARI: 2.70%; p < 0.0005; NNH: 38; RR: 1.32; 95% CI 1.129-1.552). The incidence of thrombocytopenia and neutropenia was significantly higher among patients receiving venetoclax-based therapy (ARI: 5.75%; p < 0.0001; NNH: 18; RR: 1.32; 95% CI 1.19-1.458 and ARI: 17.97%, p < 0.0001, NNH: 6, RR: 4.108, 95% CI 3.497- 4.826, respectively), while rates of anemia did not differ significantly between cohorts (p = 0.1032). Additional adverse events, including gastrointestinal symptoms (p < 0.0001), tumor lysis syndrome (p = 0.022), and major bleeding events (p < 0.0001), were also significantly more frequent in the venetoclax group. Venetoclax-based therapy was associated with inferior 1-year overall survival, with a 3.81% absolute risk increase in mortality compared to second-generation BTKis (RR 1.507; p < 0.0001; 95% CI 1.279%-1.775%). This difference was confirmed by Kaplan-Meier analysis using the log-rank test (p < 0.0001).

CONCLUSIONS: Venetoclax-based regimens were associated with a less favorable safety profile and an inferior 1-year overall survival when compared to second-generation BTKis-based treatments as first line of therapy in patients with CLL/SLL. To inform clinical decision-making and optimize patient outcomes, future studies should include randomized controlled trials with comprehensive clinical data and extended follow-up durations.

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2025
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