Real-World Outcomes Comparing Venetoclax and BTK Inhibitors Among Patients with Chronic Lymphocytic Leukemia
Key Highlights
• Venetoclax-based therapy was associated with significantly lower all-cause mortality than BTKi-based therapy.
• Venetoclax carried higher risks of hospitalization, cytopenias, immune suppression, and intravenous immune globulin requirement.
• Cardiovascular and infectious complication rates were largely similar between cohorts.
The results from a recent global retrospective cohort study showed that venetoclax-based regimens were associated with lower 1-year all-cause mortality, but higher risks of hospitalization, cytopenias, and immune suppression compared with BTKi-based regimens in adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Fayaz and colleagues presented the results to their study at the Lymphoma, Leukemia, and Myeloma Congress 2025 in New York City, NY.
As targeted therapies reshape first-line and relapsed settings, real-world data remain essential to contextualize efficacy and safety outside clinical trials. The investigators evaluated comparative mortality, healthcare utilization, hematologic toxicity, and immunologic outcomes to inform therapy selection.
Fayaz and colleagues used deidentified electronic health records data from the TriNetX Network to identify adults aged 18 years or older with CLL/SLL who initiated either a venetoclax-based regimen without prior BTKi exposure (n = 1,704) or a BTKi-based regimen without prior venetoclax (n = 1,704). Propensity score matching (1:1) aligned baseline characteristics, including prior stem cell transplant. Outcomes occurring 1 day to 1 year after treatment initiation were assessed via Kaplan–Meier analyses, hazard ratios, and log-rank testing.
Study Findings
At 1 year, venetoclax-treated patients demonstrated significantly lower all-cause mortality compared with those receiving BTKi therapy (HR 0.78; 95% CI 0.63–0.98; P = .029). However, venetoclax was associated with higher risks of hospitalization (HR 1.46; 95% CI 1.11–1.94; P = .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 = .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 = .051), and intravenous immune globulin requirement (HR 1.97; 95% CI 1.44–2.70; P < 0.001).
Outpatient ambulatory visit risk was significantly lower with venetoclax (HR 0.39; 95% CI 0.21–0.73; P = .002), while emergency department visit rates were similar between groups. No significant cohort differences emerged for anemia, septic shock, pneumonia, CMV infection, candidemia, aspergillosis, intracerebral hemorrhage, GI bleeding, end-stage renal disease/hemodialysis, acute heart failure, or stroke. Myocardial infarction occurred less frequently among venetoclax recipients (HR 0.51; 95% CI 0.29–0.90; P = .019), although absolute event rates were low.
Clinical Implications
According to the authors, these real-world findings offer important context for clinicians choosing between venetoclax- and BTKi-based therapy. The lower mortality associated with venetoclax must be weighed against its higher risk of cytopenias, hospitalization, and immunosuppression. The similarities in cardiovascular and infectious complications across groups, along with reduced myocardial infarction risk with venetoclax, may further inform individualized treatment plans.
Expert Commentary
“These findings offer important context for clinicians selecting CLL therapy in practice and highlight the need for individualized treatment and monitoring strategies,” the researchers concluded.
Reference
Khan F, Ahmed MA, Mohammed M, Alam Z. One-year real-world outcomes of venetoclax versus BTK inhibitor–based regimens in CLL: insights from a global, propensity-matched EHR study. Presented at: Lymphoma, Leukemia, and Myeloma Congress 2025; October 14–17, 2025; New York, NY. Accessed December 10, 2025. https://www.hmpgloballearningnetwork.com/node/347759