Frontline Bruton tyrosine kinase inhibitors are associated with improved response and PFS in primary CNS lymphoma.

High-dose methotrexate (HD-MTX)-based immunochemotherapy remains the standard for primary CNS lymphoma (PCNSL), yet relapse rates are high and outcomes suboptimal. While Bruton's tyrosine kinase inhibitors (BTKi) demonstrate efficacy in trials, their comparative benefit against conventional regimens in heterogeneous real-world populations remains undefined. We conducted a retrospective study of 131 newly diagnosed patients stratified by frontline induction therapy (BTKi-based, n=85; conventional, n=46), utilizing multiple imputation (m=50) and inverse probability of treatment weighting (IPTW) to balance baseline covariates. In the primary pooled multiple-imputation IPTW analysis, BTKi-based therapy was associated with improved PFS (HR 0.57, 95% CI 0.32-1.00; P=0.048) and a higher complete response rate (OR 5.50, 95% CI 2.25-13.47; P<0.001). The objective response rate was also higher (OR 2.59, 95% CI 1.05-6.36; P=0.038). The overall survival difference was not statistically significant (HR 0.65, 95% CI 0.31-1.38; P=0.263), which may reflect multifactorial confounding inherent in this retrospective comparison. These findings suggest that integrating BTKi into frontline regimens is associated with a favorable PFS profile and improved response in newly diagnosed PCNSL, while definitive OS conclusions cannot be drawn.