Background: First-line treatment for chronic lymphoid leukemia (CLL) has shifted from chemoimmunotherapy to targeted therapies, including Bruton's tyrosine kinase inhibitors (BTKis) and BCL-2 inhibitors. Acalabrutinib is a next-generation BTKi administered continuously, while venetoclax plus obinutuzumab is a time-limited regimen. Both are guideline-endorsed frontline therapies, yet direct real-world comparisons are lacking.

Methods: We performed a retrospective cohort analysis using the TriNetX Research Network, a global federated health data platform covering over 150 healthcare organizations. Adult patients (≥18 years) with CLL who initiated first-line treatment with acalabrutinib or venetoclax plus obinutuzumab between January 1, 2015, and April 15, 2025, were identified. Patients with TP53 mutations or incomplete baseline data were excluded. The primary endpoint was time to next treatment (TTNT); secondary outcomes included overall survival (OS), subgroup analyses of TTNT, and treatment-related adverse events. Propensity score matching (1:1) using age, sex, race, hemoglobin, platelet count, LDH, β2-microglobulin, and eGFR was performed to reduce confounding. Kaplan–Meier curves were used to estimate survival outcomes, and Cox proportional hazards models were used to calculate HRs.

Results: Among 115,624 CLL patients without TP53 mutations, 30,603 received first-line treatment during the study period. Of these, 2,097 received acalabrutinib and 682 received venetoclax plus obinutuzumab. Prior to matching, patients in the acalabrutinib group were older, while those in the venetoclax group exhibited more advanced disease and greater renal impairment. After 1:1 propensity score matching, 669 patient pairs were analyzed, with balanced demographic and clinical characteristics.

Median follow-up was 23.4 months in the acalabrutinib group and 20.5 months in the venetoclax–obinutuzumab group. At analysis, 37.4% of patients on acalabrutinib and 22.1% on venetoclax–obinutuzumab had initiated subsequent therapy. Median TTNT was 47.7 months for acalabrutinib and not reached for venetoclax–obinutuzumab (HR 1.84; 95% CI, 1.50–2.26; p < 0.0001). The estimated 4-year TTNT rates were 49.1% and 63.6%, respectively. Median OS was not reached for either group. The 4-year OS estimates were 81.7% for acalabrutinib and 88.4% for venetoclax–obinutuzumab (HR 1.84; 95% CI, 1.28–2.65; p = 0.0009). Subgroup analyses consistently favored venetoclax plus obinutuzumab across predefined clinical strata, including age, sex, Rai stage, and renal function. Differences were not statistically significant in patients with atrial fibrillation, diabetes, or cerebrovascular disease.

Safety: Cytopenias were the most frequently reported adverse events. Compared to acalabrutinib, venetoclax plus obinutuzumab was associated with higher rates of neutropenia (any grade: 54.3% vs. 33.3%, p < 0.001; grade 3/4: 35.2% vs. 20.2%, p < 0.001), thrombocytopenia (any grade: 45.9% vs. 31.9%, p = 0.003; grade 3/4: 15.1% vs. 10.6%, p = 0.022), and febrile neutropenia (7.1% vs. 3.4%, p = 0.003). Tumor lysis syndrome was more frequent in the venetoclax group (6.3% vs. 2.3%, p < 0.001). COVID-19 infection was also higher in this group (13.1% vs. 9.4%, p = 0.037). The rate of atrial fibrillation was 9.4% in the acalabrutinib group but did not significantly differ between regimens.

Conclusion: In this large, real-world matched cohort study of TP53 wild-type CLL patients, venetoclax plus obinutuzumab was associated with significantly longer TTNT and higher 4-year OS compared to acalabrutinib. Although venetoclax-based treatment was linked to higher incidences of neutropenia, infections, and tumor lysis syndrome, these events were generally manageable with appropriate supportive care.

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2025
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