Introduction Bruton Tyrosine Kinase inhibitors (BTKi) combined with anti-CD20 monoclonal antibodies have emerged as chemotherapy-free alternatives to traditional chemoimmunotherapy (CIT) in the first-line management of Chronic Lymphocytic Leukemia (CLL). However, the comparative efficacy of these regimens remains under evaluation. This systematic review and meta-analysis aimed to assess the efficacy of BTKi + anti-CD20 antibody combinations versus CIT in treatment-naïve CLL patients.Methods A comprehensive literature search was conducted through March 2025 across PubMed, Embase, CENTRAL, ClinicalTrials.gov, and major hematology/oncology conference abstracts (ASH, ASCO, EHA), using keywords such as “BTK inhibitor AND anti-CD20 AND CLL AND randomized”, without language restrictions. We screened titles/abstracts and full texts, extracting data into a standardized spreadsheet, including trial characteristics, BTKi agent, antibody used, CIT regimen, sample sizes, and response outcomes. Discrepancies were resolved by consensus.

Binary outcomes for overall response rate (ORR), complete response (CR), and partial response (PR) were pooled using a random-effects model to derive risk ratios (RR) with 95% confidence intervals (CI). Subgroup analyses were conducted comparing obinutuzumab-based versus rituximab-based BTKi combinations. Statistical analyses were performed using RevMan and Stata.Results Four randomized controlled trials enrolling a total of 1,479 treatment-naïve CLL patients (828 assigned to BTKi + anti-CD20 therapy; 651 to CIT) were included in the analysis.

  • Overall Response Rate (ORR): BTKi + anti-CD20 combinations significantly improved ORR compared with CIT (RR 1.16; 95% CI: 1.12–1.21; p < 0.00001).

  • Complete Response (CR): No significant difference was observed overall (RR 1.10; 95% CI: 0.47–2.60; p = 0.83). However, subgroup analysis showed:

    • Obinutuzumab-based regimens: Higher CR rates vs. CIT (RR 2.39; 95% CI: 1.74–3.28)

    • Rituximab-based regimens: Lower CR rates vs. CIT (RR 0.53; 95% CI: 0.41–0.69)

Partial Response (PR): No meaningful difference overall (RR 1.15; 95% CI: 0.84–1.57; p = 0.39), but:

  • Rituximab-based BTKi regimens: Higher PR rates than CIT (RR 1.52; 95% CI: 1.37–1.69)

  • Obinutuzumab-based regimens: Trend toward lower PR compared to CIT (RR 0.87; 95% CI: 0.73–1.05)

Conclusion BTKi plus anti-CD20 antibody therapy significantly enhances overall response rates compared with CIT in the first-line treatment of CLL. The depth of response is influenced by the choice of anti-CD20 antibody: obinutuzumab-based regimens are associated with higher complete response rates, while rituximab-based combinations tend to yield partial responses. These findings support the selection of obinutuzumab-based BTKi combinations to maximize response depth in frontline CLL treatment.

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2025
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