Introduction:

Chimeric antigen receptor (CAR) T-cells have improved outcomes of patients (pts) with relapsed/refractory Non-Hodgkin Lymphoma (R/R NHL). However, 20% to 40% of those pts did not benefit from CAR-T therapies according to real-world study. Glofitamab, a CD20xCD3 bispecific antibody, was proven viable as salvage therapy following CAR-T treatment failure in the LYSA study, but its potential role as a CAR-T bridging therapy to improve patients' prognosis has yet to be investigated. Here we report the efficacy and safety of glofitamab bridging CAR-T therapies in pts with R/R NHL.

Methods:

Pts with R/R NHL who underwent leukapheresis received pre-treatment with obinutuzumab prior to the first dose of glofitamab. Based on disease progression status, pts received glofitamab monotherapy or glofitamab combined with gemcitabine + oxaliplatin/ BTK inhibitor/ methotrexate regimens prior to CAR-T infusion. Response rates are evaluated after bridging therapies and CAR-T therapies based on Lugano criteria. Adverse events were assessed according to American Society for Transplantation and Cellular Therapy consensus.

Results:

As of May 2025, 10 NHL pts who received glofitamab bridging CD19 CAR-T therapy in Wuhan Union Hospital were enrolled, among which 8 pts had a biopsy proven diffuse large B-cell lymphoma (DLBCL) whereas others had mantle cell lymphoma (n=1) and Burkitt lymphoma (n=1). The median age was 61.5 years (range: 20-79) and 70% of pts had Ann Arbor stage III/IV. Median lines of prior therapies was 2 (range: 2-5; ≥3 prior therapies: 60%) with two cases of autologous hematopoietic stem cell transplantation and 1 case of CAR-T therapy. All pts were refractory to their last line of therapy, including two with primary central nervous system lymphoma (PCNSL), two with secondary CNS involvement, one with bulky extramedullary disease (>7 cm), and four harboring TP53 mutations.

During glofitamab bridging therapy, grade 1 cytokine release syndrome (CRS) occurred in 4 pts and grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient. Viral infections developed in 4 pts. The overall response rate (ORR) was 66.7% (6/9 pts), with a complete metabolic response (CMR) rate of 22.2% (2/9 pts), excluding one patient unevaluable for response.

The median interval between first glofitamab dose and CAR-T infusion was 31 (25-67) days. Seven pts (70%) experienced grade 1 CRS and 1 pts with PCNSL experienced grade 2 ICANS. Four pts experienced grade 3 infection. 100% pts responded to CAR-T therapies and 80% (8/10 pts) achieved CMR with PET-CT/PET-MRI at day+30 post-infusion. All subjects exhibited peripheral blood CAR-T expansion detectable via flow cytometry, reaching a median peak level of 13.57 CAR-T cells/μL (range: 3.2-403.4) at median peak time of day+11. CAR-T persistence (>50 copies/μg DNA by ddPCR) was sustained in 80% pts at month 1. At a median follow-up of 6.0 months (range: 4-15.5), all pts remained treatment-free except one receiving regular glofitamab maintenance therapy. Disease relapse occurred in one patient at 3.5 months, while others were under active surveillance.

Conclusion:

Glofitamab bridging therapy prior to CAR-T demonstrated promising efficacy in pts with high-risk NHL, without significant safety concerns or detrimental impact on CAR-T cell kinetics. This study provides preliminary evidence for redefining therapeutic paradigms in non-Hodgkin lymphoma, particularly PCNSL, supporting further investigation through expanded validation cohorts and longitudinal outcomes assessment.

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2025
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