Glofitamab in combination with CD19 CAR-T therapy for high-risk relapsed/refractory large B-cell lymphoma

Abstract

Abstract Introduction Relapsed or refractory large B-cell lymphoma (r/r LBCL) is associated with poor prognosis, particularly among patients with high-risk features who frequently relapse or fail treatment after CD19 CAR-T therapy. Glofitamab, a CD20×CD3 bispecific antibody, has demonstrated potent T-cell–mediated antitumor activity in r/r LBCL. An immunotherapy-driven approach combining glofitamab with CD19 CAR-T therapy has not yet been systematically evaluated in patients with high-risk r/r LBCL. Methods We conducted a phase 2 single-arm trial in adults with high-risk r/r LBCL. Patients underwent leukapheresis, followed by obinutuzumab pretreatment and bridging therapy with glofitamab (step-up dosing in cycle 1, then 30 mg IV on day 1 of cycle 2). After lymphodepletion with fludarabine and cyclophosphamide, patients received CD19 CAR-T infusion. Responses were first assessed at day 28. Patients with partial response, stable disease, or investigator-assessed clinical benefit despite progression at this time point were eligible for up to four additional cycles of glofitamab. The primary endpoint was complete response (CR) rate. Here we report initial results from this study. Results At the cut-off date of 1 May 2025, 26 patients had received CD19 CAR-T infusion. The CR rate at initial assessment was 65.4% (17/26). Of the 9 patients who did not achieve CR, 1 discontinued due to disease progression, and 8 proceeded to glofitamab consolidation. Following consolidation, the CR rate increased to 90.9% (20/22; 4 patients not yet evaluated). Among the 8 consolidation patients, 4 had completed 4 cycles, with 3 achieving CR and 1 relapsing, while the other 4 remain on treatment awaiting evaluation. The relapse was characterized by a CD19⁻CD20⁻ phenotype. Treatment was well tolerated, with no grade ≥3 cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS). The most common adverse events were grade 1–2 CRS and hematologic toxicities. Conclusions Glofitamab plus CD19 CAR-T therapy achieved a high CR rate with favorable safety in high-risk r/r LBCL. These findings support a chemotherapy-free, immunotherapy-driven approach to improve outcomes in this high-risk population.