Abstract
Introduction Despite evidence supporting the importance of remission prior to CAR-T therapy in relapsed/refractory large B-cell lymphoma (rrLBCL), standardized bridging strategies are lacking. Glofitamab, a CD3/CD20 bispecific antibody, has shown promise for this purpose. Though potentially synergistic with immunotherapy, prolonged use may lead to T-cell exhaustion. We hypothesize that short-term glofitamab bridging before anti-CD19 CAR-T therapy achieves high response rates without impairing CAR T-cell fitness.
Methods A retrospective analysis was conducted on patients who underwent glofitamab bridging (GLO; Oct 2023–Jan 2025) versus non-glofitamab bridging (noGLO; Sep 2021–Sep 2023) prior to CAR-T cell therapy at the University Hospitals of Cologne and Essen. Response was assessed according to Lugano criteria (Deauville Score, DS) and by metabolic tumor volume (MTV) prior to CAR T-cell re-infusion and at week 4 and 12 after CAR T-cell therapy. of peripheral blood was performed in patients prior to initiation of bridging therapy, immediately prior to CAR-T infusion and at days 9 and 21 after CAR-T cell treatment. Glofitamab levels in patient sera were measured via Enzyme-linked immunosorbent assay (ELISA), CAR-T expansion was determined by PCR analysis of CAR-copies in cell pellets derived from peripheral blood. CAR-T cell immunophenotyping was performed by flow cytometric analysis of peripheral blood mononuclear cells (PBMCs). Statistical analysis of results was performed using Welch's 2-tailed t-tests and Benjamini-Hochberg-correction for multi-hypothesis testing.
Results Besides GLO patients were older (median 64 vs. 54 years), further clinical characteristics were similar in both groups (GLO n=27; noGLO n=41). The median prior treatment lines were two in GLO and one in noGLO, while the median time to CAR-T infusion was similar in both groups (GLO: 51 days, noGLO: 48 days).
23/27 (85%) patients received glofitamab as monotherapy; four with simultaneous radiotherapy. NoGLO patients were treated with rituximab-based immunochemotherapy (30/41, 73%), tafasitamab-lenalidomide (6/41, 15%), high dose melphalan (3/41, 5%), or ibrutinib (3/41, 7%).
The median metabolic tumor volume (MTV) pre-bridging was 70 mL (2-1201mL; GLO) vs. 197 mL (4-2653mL; noGLO). Bridging led to overall response in 18/26 (69%) of GLO vs. 20/39 (51%) of noGLO patients. The median MTV-reduction among responders was 99% (32-100%; GLO) vs. 81% (8-100%; noGLO). At three months post-CAR-T, complete remission was seen in 12/20 (60%) GLO and 17/42 (40%) noGLO patients. The 90-day progression-free survival was 78% (GLO) vs. 70% (noGLO).
During bridging therapy Grade 3–4 cytopenia occurred in 1/27 (4%) GLO and in 7/25 (35%) noGLO patients. Neutropenic fever occurred in 5/25 (25%) noGLO patients and did not occur in GLO patients during bridging. In GLO patients, CRS grade 1–2 occurred in 7/27 (26 %), with one case of ICANS grade 2 and one infection; no grade 3–4 CRS/ICANS occurred. One GLO patient died prior to CAR-T infusion due to progressive disease.
Using flow cytometry comparing different CAR-T cell subsets between GLO and noGLO patients did not show significant differences. However, when we analyzed CAR-T cell subset-specific expression of activation and exhaustion markers via flow cytometry we detected a significant elevation of exhaustion markers like TIGIT and TIM3 in terminally differentiated and effector memory CAR-T cells in GLO compared to noGLO patients. Increased exhaustion of CAR-T cells was in-line with declining, but measurable glofitamab concentrations in patient sera at day 9 and day 21 post CAR-T infusion. MRD analysis, analyses of serum-cytokines and myeloid populations, and subgroup analyses will be presented at the conference.
ConclusionDespite the retrospective nature of our analysissuggest glofitamab as an effective and safe bridging therapy prior to CAR-T cell therapy. When compared to conventional chemotherapy bridging approaches, the risk-benefit profile seems to be beneficial for Glofitamab bridging with high CR rates after CAR T-cell therapy and an overall very good tolerability. However, data from prospectively controlled trials are warranted to confirm these findings.
