Abstract
Introduction. CAR T-cell therapy is indicated for patients with diffuse large B-cell lymphoma as well as for mantle cell lymphomas, transformed indolent lymphomas, primary B-cell lymphoma, and follicular lymphoma. Regardless of histology, relapse after CAR T-cell infusion is usually considered an adverse prognostic factor. The LYSA group conducted a phase II trial (BiCAR), that included patients who were refractory or in their first relapse immediately after CAR T-cell therapy. This trial enrolled patients with large B-cell lymphoma (cohort 1) and, as an exploratory cohort, patients with other B-cell non-Hodgkin lymphoma histologies (cohort 2). We report the final analysis of cohort 2.
Patients and Methods. The cohort 2 of the BiCAR study included patients with non-DLBCL lymphoma such as transformed follicular lymphoma (t-FL), transformed marginal zone lymphoma(t-MZL), primary B-cell lymphoma (PMBL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Patients who showed no metabolic response (i.e., stable disease) or experienced progression/relapse at least one month (first assessment) after CAR T-cell infusion received obinutuzumab (1000 mg) three days prior (Day -3, D-3) to the first glofitamab dose. Intravenous glofitamab was administered with a rapid step-up dosing schedule on D1 (2.5 mg), D3 (10 mg), and D8 (30 mg) of Cycle (C) 1, and at 30 mg on D1 of C2–11 (21-day cycles). Response was assessed according to Lugano criteria after cycle 2 (C2), C4, C6, C9, C11, and every 3 months for 2 years. All analyses were exploratory, and there was no specific hypothesis testing. Therefore, the sample size was not based on formal calculations.
Results. All patients in the BiCAR trial completed their follow-up on May 21, 2025. The median follow-up duration was 37.2 mo (95% CI: 32.1-37.7). Twenty patients were enrolled, and 19 patients (12 males/7 females) received at least one dose of treatment and were available for analysis: FL (n=6), MCL (n=5), t-FL (n=4), t-MZL (n=2), PMBL (n=1), and t-WM (n=1). The median age was 66 years (range 42–76), and 16 out of 19 patients were Ann Arbor stages III/IV. Prior CAR T-cell therapies included tisa-cel (n=8), axi-cel (n=5), brexu-cel (n=5), or investigational CAR T-cell (n=1). One patient was refractory (no response to CAR T-cell), while 18 were in relapse or progression. Among them, 6 patients (33%) relapsed or progressed between 1-3 months, 10 (55%) between 3-6 months, and 2 (11%) after more than 6 months following CAR T-cell infusion. The median overall survival (mOS) was 29.2 months (95% CI: 6.2-NA), with a 3-year overall survival (3y-OS) of 47.4%. The median progression-free survival (mPFS) was 3.9 months (95% CI: 1.1-NA), with a 3-year PFS of 42.1%. The overall best response rate according to the central review was 57.9% (95% CI: 33.5-79.7), including 52.6% of patients achieving complete remission (CR). The median duration of response (DOR) was not reached (95% CI: 3.6-NA), with a 3-year DOR of 72.7%. The median duration of CR (mDOCR) was not reached (95% CI: 2.8-NA), with a 3-year mDOCR of 77.8%. Three patients experienced cytokine release syndrome (CRS), with one patient at grade 1 and two at grade 2; one patient experienced neurotoxicity (NE) at grade 2. No grade 3 or higher events for CRS or neurotoxicity were observed. Neutropenia grade ≥ 3 was observed in 9 patients (47.5%), thrombocytopenia grade ≥ 3 in 5 patients (26.3%), and anemia grade ≥ 3 in 1 patient (5.3%). Fourteen patients (73.7%) experienced adverse events (AEs) grade ≥ 3, mainly infections (8 patients, 42.1%).
Conclusion. This exploratory cohort showed that for patients with non-hodgkin lymphoma other than DLBCL who are refractory or relapse immediately after CAR T-cell therapy, glofitamab is a feasible and effective option.
