Outcomes with a fixed duration combination of bruton tyrosine kinase inhibitors and venetoclax in chronic lymphocytic leukemia: A systematic review and meta-analysis

Abstract

Abstract Introduction: Single agents, such as Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors, are being widely used in the treatment of chronic lymphocytic leukemia (CLL), but neither of these is curative. Continuous therapies present a risk of drug resistance and disease progression in CLL. We report outcomes with a targeted, fixed-duration combination of BTK inhibitors and venetoclax in CLL patients. Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (inception to June 2025) was conducted using MeSH terms for “Chronic Lymphocytic Leukemia,” “Venetoclax”, and “Fixed Duration BTK inhibitors.” After screening and excluding review articles, meta-analyses, and studies without a patient population of interest, ten studies reporting the outcomes with a fixed-timed combination of BTK inhibitors and venetoclax were selected for inclusion from a total of 436 references. For outcomes reported in two or more studies, a meta-analysis was conducted using a random-effects model. Results were expressed as prevalence estimates with 95% confidence intervals (CIs). Some characteristics were described systematically. Results: A total of 1,163 patients from six Phase II, two Phase III, one Phase II RCT, and one Phase Ib study were included in this review and analysis. The median age was 62,5 years (range, 24-78), with the majority being male (65%, n = 752). Baseline ECOG status was 0 in 59% (n = 335/567), and 1-2 in 41% (n = 232/567). TP-53 mutation was reported in 23% (n = 192/822) of the patients, whereas one RCT excluded patients with TP-53 mutation (n = 291). BTK inhibitors used in the studies included ibrutinib (67%, n = 775), acalabrutinib (31%, n = 363), and pirtobrutinib (2%, n = 25). Anti-CD 20 antibody was added in 188 patients, Obinutuzumab in 163 (87%), and Rituximab in 25 (13%) patients. The treatment duration ranged from 5 weeks to 15 months. The pooled rates for overall response (OR) and complete response (CR) were 95% (95% CI, 0.91-0.98, p < 0.0001, I2= 75.2%) and 51% (95% CI, 0.440.58, p = 0.0003, I2= 72,4%), respectively. The pooled rates for partial response (PR) and peripheral blood minimal residual disease (MRD) negativity were 46% (95% CI, 0.39-0.53, p = 0.1847, I2= 37.9%) and 72% (95% CI 0.60-0.83, p < 0.0001, I2=93.2%), respectively. The pooled rate for progressive disease (PD) was 4% (95% CI, 0.0-0.14, p = 0.0008, I2= 82%). The pooled rates for overall survival (OS) and progression-free survival (PFS) were 94% (95% CI, 0.91-0.96, p = 0.0463, I2= 51%%) and 87% (95% CI, 0.80-0.92, p < 0.0001, I2= 82.6%), respectively. The pooled rates for grade 3 or neutropenia and infections were 36% (95% CI, 0.25-0.48, p < 0.0001, I2= 93.3%) and 14% (95% CI, 0.07-0.24, p < 0.0001, I2= 92%), respectively. The pooled drug discontinuation rate was 8% (95%CI 0.05-0.11, p = 0.003, I2=65.6%) and the pooled mortality rate was 7% (95% CI 0.02-0.14, p < 0.0001, I2=85.7%). Conclusion: The fixed-duration combination of BTK inhibitors and venetoclax shows very promising response rates compared to either of these agents as monotherapy. This necessitates the continuation of high-quality trials to consolidate these findings.