10114-CS-10 Current Status and Future Perspectives of Tirabrutinib in the Treatment of Primary CNS Lymphoma

Abstract Primary central nervous system lymphoma (PCNSL) is a subtype of diffuse large B-cell lymphoma (DLBCL) localized to the brain, spinal cord, or eyes at onset. Most PCNSLs are classified into the MCD/C5 molecular subtype, characterized by activating mutations in MYD88 and CD79B, which lead to constitutive activation of NF-κB signaling via Bruton’s tyrosine kinase (BTK). This pathophysiological background has prompted the development of BTK inhibitors as targeted therapies. Tirabrutinib (TIR), a second-generation BTK inhibitor, was approved in Japan in 2020 for relapsed or refractory (r/r) PCNSL based on a domestic phase I/II clinical trial. While the drug demonstrated promising activity, about one-third of patients showed no response, and the median progression-free survival (PFS) was approximately six months, indicating limited efficacy as monotherapy. To improve outcomes, various clinical strategies to enhance the therapeutic effects of TIR are under investigation. Currently, an observational study and follow-up trials of TIR monotherapy have been conducted for r/r PCNSL. Furthermore, several clinical trials are exploring its integration into frontline treatment, either as part of induction therapy or maintenance therapy for newly diagnosed PCNSL. These efforts reflect the need to optimize the therapeutic positioning of TIR in both relapsed and newly-diagnosed settings. In this presentation, we summarize the current status of tirabrutinib in PCNSL, including recent clinical trial developments and institutional experience. We also discuss the limitations of TIR and future perspectives for its role in personalized and combination treatment strategies.