Impact of systemic high-dose MTX and BTK inhibitors on outcomes in vitreoretinal lymphoma: A multicenter retrospective analysis

Abstract Background: Vitreoretinal lymphoma (VRL), a rare subtype of primary central nervous system lymphoma (PCNSL), poses significant therapeutic challenges due to its high risk of CNS progression and lack of standardized treatment. While intravitreal methotrexate (IV-MTX) remains a local cornerstone, the role of systemic prophylaxis—particularly high-dose MTX (HD-MTX) and Bruton's tyrosine kinase inhibitors (BTKi)—in preventing CNS relapse and improving survival requires further validation. Methods: We retrospectively analyzed 49 VRL patients, including 42 primary VRL (PVRL), 1 PCNSL with subsequent ocular involvement, and 6 concurrent PCNSL-VRL. Treatment heterogeneity was observed: 17 received IV-MTX alone, 24 received HD-MTX-based systemic therapy (±CD20 antibody± BTKi), and 26 received BTKi (19 combined with HD-MTX for CNS prophylaxis, 7 without). Outcomes included response rates, progression-free survival (PFS), CNS progression, and overall survival (OS). Results: The cohort (median age 56 years; 55.1% female) achieved an overall complete response (CR) rate of 63.4% and partial response (PR) rate of 34.1%. With a median follow-up of 748 days, the median PFS (mPFS) was 800 days (95% CI: 486–NR), and 2-year PFS was 52.4%. Crucially, patients receiving HD-MTX-based systemic therapy exhibited significantly prolonged PFS compared to non-recipients (p=0.0067). In contrast, BTKi use alone did not significantly impact PFS. Among 42 PVRL patients, 19 developed CNS progression. Interestingly, the CNS progression rate was markedly lower in HD-MTX-treated patients (16.7% vs. 65.2% in non-HD-MTX group; p=0.00294). While median OS was not reached, the projected 5-year OS was 50.2%. Factors including age, sex, bilateral involvement, and prior steroid use had no significant effect on PFS. Conclusion: This study underscores the critical role of HD-MTX-based systemic therapy in improving PFS and reducing CNS progression in VRL, supporting its integration for CNS prophylaxis. Although BTKi demonstrated clinical activity, its standalone use did not significantly enhance PFS, suggesting potential synergy when combined with HD-MTX. Prospective studies are warranted to optimize combinatorial strategies and validate the long-term survival benefit of CNS-directed systemic therapy in VRL.