Background: Fixed-duration treatment regimens have emerged as a paradigm shift in first-line chronic lymphocytic leukemia (CLL) management. By aiming to maximize disease control while minimizing long-term toxicity and treatment burden, time-limited approaches particularly those centered around venetoclax (Ven) offer an attractive alternative to continuous BTK inhibitor therapy and traditional chemoimmunotherapy (CIT). We performed a meta-analysis to assess the efficacy and safety of ven-based fixed-duration therapies in treatment-naïve CLL patients.

Methods: A systematic literature search of PubMed and Scopus was conducted up to June 2025 to identify prospective clinical trials evaluating fixed-duration ven-based regimens in first-line CLL. “Chronic Lymphocytic Leukemia”, “TKI”, “Venetoclax”, and “fixed-duration” were the keywords used. Eligible studies included randomized controlled trials (RCTs) and high-quality single-arm phase II studies that reported on efficacy and safety outcomes were selected. Fixed duration was defined as any protocol-defined treatment course with planned discontinuation. PRISMA guidelines were followed to conduct this systematic review. Outcomes reported are progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and treatment-related adverse events (AEs). Comparisons were drawn between ven-based regimens including doublets [Ven+Obinutuzumab (Obi), Ven+Ibrutinib (Ibr), Ven+Acalabrutinib (Acala)] and triplets (BTKi + Ven + Obi) and CIT comparators such as chlorambucil+Obi or fludarabine (Flu)-based combinations. Pooled data were extracted at 1 and 2 years and R software was used to run meta-analyses.

Results: In 2 RCTs of Ven + Ibr N=734, the odds ratio (OR) of ORR, PFS at 1 year and 2 years were 1.69 (CI 1.06; 2.70), 4.21 [confidence Interval (CI) 0.08; 208.87] and 8.39 (CI 4.87; 14.47), respectively. In 2 RCTs of Ven + Obi N = 890, the OR of ORR, PFS at 1 year and 2 years were 2.77 ( CI 1.41; 5.43), 1.69 (CI 0.95; 3.0) and 3.23 (CI 2.21; 4.73), respectively. In 1 RCT of Ven + Acala N = 581, the OR of ORR, PFS at 1 year and 2 years were 4.25 ( CI 2.53; 7.13), 2.28 (CI 1.21; 4.31) and 1.95 (CI 1.24; 3.06), respectively. In 1 RCT of Ven + Acala + Obi N = 576, the OR of ORR, PFS at 1 year and 2 years were 4.17( CI 2.48; 7.0), 1.42 (CI 0.81; 2.49) and 1.79 (CI 1.15; 2.80), respectively. In 1 RCT of Ven + Obi + Ibr N = 460, the OR of ORR, PFS at 1 year and 2 years were 9.77 ( CI 2.24; 46.60), 3.40 (CI 1.22; 9.43) and 5.38 (CI 2.55; 11.36), respectively.

In single arm studies Ven + Acala N=291, ORR, PFS 1 year, and PFS 2 years were given as 93% (CI 89-95%), 95% ( CI 92-97%), and 88% (CI 84-91%), respectively. Ven + Obi N=229, ORR, PFS 1 year, and PFS 2 years were given as 95% (CI 92-98%), 97% ( CI 94-99%), and 92% (CI 88-95%), respectively. Ven + R N=237, ORR, PFS 1 year, and PFS 2 years were given as 96% (CI 92-98%), 96% ( CI 92-98%), and 92% (CI 88-95%), respectively. Ven + Acala + Obi N=358, ORR, PFS 1 year, and PFS 2 years were given as 96% (CI 82-99%), 97% ( CI 72-100%), and 89% (CI 82-94%), respectively. Ven + Obi + Ibr N=272, ORR, PFS 1 year, and PFS 2 years were given as 95% (CI 90-98%), 97% ( CI 94-99%), and 96% (CI 93-98%), respectively. Flu cyclophosphamide rituximab/bendamustine rituximab N=519, ORR, PFS 1 year, and PFS 2 years were given as 88% (CI 56-98%), 91% ( CI 86-94%), and 80% (CI 77-84%), respectively.

Grade ≥3 neutropenia occurred in 45–55% of Ven-treated patients, versus 60–65% in CIT or triplet arms (p < 0.01). Febrile neutropenia was less frequent in Ven-based therapies (5–9%) compared to CIT (12–15%). . Cardiovascular AEs were more common in Ibr-containing arms, including hypertension (14–18%) and atrial fibrillation (6–9%) (p < 0.05).

Conclusion: Ven+Obi consistently showed superior PFS and ORR compared to CIT, positioning it as a frontline standard for time-limited therapy. While the Ven+Ibr combination offered similar durability, it introduced higher cardiovascular toxicity, requiring patient-specific consideration. The addition of a third agent did not yield meaningful clinical benefit in PFS but increased myelosuppression, underscoring the need for regimen personalization. More double blinded randomized clinical trials are needed to confirm these results.

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2025
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