Glofitamab-based combinatorial therapy demonstrates high efficacy in primary refractory and early relapsed DLBCL: Real-world evidence of durable responses and immune modulation in high-risk subgroups

Abstract

Abstract Background: Glofitamab, an innovative CD20xCD3 bispecific T-cell engager, has emerged as a groundbreaking therapeutic option for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), receiving FDA approval for patients who have failed ≥2 prior lines of therapy. This immunotherapeutic agent mediates potent antitumor activity by redirecting endogenous T cells to eliminate CD20-expressing malignant B cells, demonstrating remarkable clinical efficacy even in high-risk subgroups. Current evidence remains insufficient regarding glofitamab's efficacy in primary refractory and early relapsed (≤12 months post-first-line therapy) DLBCL - clinically distinct subgroups characterized by particularly aggressive disease biology and critically unmet therapeutic needs Methods: This real-world study include glofitamab in 12 DLBCL patients (primary refractory n=9; early relapsed n=3) receiving planned 12-cycle therapy. Glofitamab was combined with polatuzumab vedotin, PD-1 inhibitors, GemOx, BTKi, or radiotherapy per clinical practice. Primary endpoints included overall response rate (ORR) and complete response (CR) rate by Lugano criteria. Secondary endpoints assessed progression-free survival (PFS), duration of response (DOR), and CRS/ICANS graded by ASTCT criteria. Mechanistic analyses included serial immune profiling of T/NK-cell subsets and serum cytokine monitoring. Results: At the data cut-off (July 25, 2025), among 12 treated patients (median 5 cycles, range 1–12), 75% (9/12) were primary refractory and 25% (3/12) early relapsed. Histologic/molecular subtypes included DLBCL DEL (58.3%, 7/12), DLBCL NOS (16.7%, 2/12), HGBCL (8.3%, 1/12), CD5+ DLBCL (8.3%, 1/12), and TP53-mutated (16.7%, 2/12). Median age was 56 years (range 37–79); 91.7% (11/12) had stage III/IV disease, with median IPI 3 (41.7% IPI 3, 33.3% IPI 4).All were heavily pretreated (median 3 prior lines, range 2–7; 83.3% Pola-exposed, 16.7% CAR-T–experienced). At median 7.0-month follow-up (range 1.0–16.5), evaluable patients (9/12) demonstrated 100% ORR and 55.5% CMR (median time: 2 cycles). CMR rates were 57.1% in primary refractory (4/7) and 50% in early relapsed disease (1/2), with subtype-specific responses noted. The safety profile remained consistent with prior analyses. Grade ≥3 AEs occurred in 58.3% (7/12) of patients. Dose interruptions of glofitamab were required in 50% (4/12) (due to CRS [n=1] and pulmonary infections [n=3]), with 8.3% (1/12) discontinuing due to pulmonary infection. Median dose intensity was maintained at 100% for GEMOX and POLA.Cytokine release syndrome (CRS) occurred in 33.3% (4/12) (Gr 3, n=1), all during Cycle 1 (no ICANS reported). Tocilizumab was administered in 8.3% (1/12). Neurologic AEs (NAEs) were reported in 83.3% (10/12) (Gr 3/4, n=7), most commonly neutropenia (83.3%), hypoalbuminemia (58.3%), frailty (58.3%), low immunoglobulinemia (58.3%), anemia (41.7%), and pulmonary infection (25.0%). Grade 3 NAEs included neutropenia (58.3%), pulmonary infection (16.7%), and CRS (8.3%). This study analyzed immune function changes during 12 treatment cycles. Early treatment cycles (1-6) were associated with modest declines in immunoglobulin levels (IgG/IgM/IgA) and low infection risk. Beyond cycle 6, severe lymphopenia (lymphocytes <0.5×10⁹/L) emerged in 33.3% (4/12), correlating with increased pulmonary infections, necessitating vigilant monitoring. Glofitamab induced robust T/NK-cell expansion, with 91.7% (11/12) showing elevated CD3+/CD4+/CD8+/NK-cell counts. Clinically meaningful expansions (>1-fold) occurred in 50.0% (6/12) for CD3+/CD4+/NK cells and 58.3% (7/12) for CD8+ cells. Notably, this activation persisted without exhaustion through 6 cycles, including in CAR-T–pretreated (n=2) and bendamustine-exposed (n=2) subgroups, suggesting sustained modulation of the tumor immune microenvironment. Conclusions: Glofitamab exhibits clinically significant activity in primary refractory and early relapsed DLBCL through potent T/NK-cell engagement, inducing durable responses across high-risk subtypes. Real-world data support combinability with Polatuzumab Vedotin, PD-1 immune checkpoint inhibitor, GemOx, BTKi, or radiotherapy, warranting proactive toxicity monitoring. These findings establish glofitamab as a transformative backbone therapy for resistant DLBCL, addressing critical unmet needs via its unique immune-redirecting mechanism.