Multicenter Real‐World Analysis of Glofitamab in Relapsed/Refractory Primary <scp>CNS</scp> Lymphoma: Clinical Activity, <scp>CNS</scp> Penetration, and <scp>ctDNA</scp> Dynamics

Therapeutic options for relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) are limited, and the clinical activity and central nervous system (CNS) pharmacology of CD20 × CD3 bispecific antibody glofitamab remain poorly defined. This multicenter real-world study evaluated the efficacy, CNS penetration, and molecular response dynamics of glofitamab in 16 adults with R/R PCNSL treated with glofitamab monotherapy. Paired plasma and cerebrospinal fluid (CSF) samples were analyzed to assess CNS drug penetration. Serial CSF circulating tumor DNA (ctDNA) profiling was performed during glofitamab monotherapy, and chimeric antigen receptor T (CAR-T) cell kinetics were examined in patients receiving CAR-T consolidation. Glofitamab monotherapy achieved an interim overall response rate of 75%, including 50% complete responses. Median progression-free survival was 15.4 months, and median overall survival was not reached. In several patients, glofitamab was used as a bridge to subsequent CAR-T and/or autologous stem cell transplantation (ASCT), which may have influenced long-term outcomes. Glofitamab was detectable in the CSF of 60% of patients, with CSF/plasma ratios up to 0.44%. Longitudinal ctDNA analysis demonstrated that early molecular clearance was associated with radiographic response, while persistent or re-emergent ctDNA preceded clinical progression. The safety profile of glofitamab monotherapy was manageable, with most adverse events being Grade 1-2. Two patients (11%) experienced Grade ≥ 3 neurotoxicity and recovered after corticosteroid treatment. Two additional patients developed fatal immune effector cell-associated neurotoxicity syndrome following CAR-T consolidation. Glofitamab demonstrates early clinical activity and measurable CNS penetration in R/R PCNSL. Serial CSF ctDNA profiling may aid treatment monitoring, warranting prospective validation.