Clinical activity and immune correlates of glofitamab combined with tislelizumab in relapsed/refractory follicular lymphoma: A translational study

Abstract

Abstract Background Patients with relapsed/refractory follicular lymphoma (R/R FL) refractory to anti-CD20 therapy face dismal outcomes and limited options. Preclinical evidence indicates that glofitamab-a CD20xCD3 T-cell-engaging bispecific antibody-induces PD-1/PD-L1 upregulation, creating a strong rationale for synergistic PD-1 blockade. We present the first clinical translation of glofitamab combined with tislelizumab (anti-PD-1) in this high-risk population. Methods In this single-center retrospective study (Feb 2024-May 2025), 12 consecutive R/R FL patients received a fixed-duration regimen: Cycle 1: Obinutuzumab 1,000mg (Day 1, CRS prophylaxis) followed by glofitamab step-up dosing (2.5mg→10mg→30mg on Day 8/15/22). Cycles 2-12: Glofitamab 30mg + tislelizumab 200mg every 3 weeks (maximum 12 cycles). Endpoints included ORR/CR (Lugano 2014), MRD negativity (<10⁻⁵ by next-generation flow cytometry in peripheral blood/bone marrow), progression-free survival (PFS), safety (CTCAE v5.0), and tumor genomic profiling (128-gene NGS panel). Results Patients (58.3% male) had a median age of 66 years (range: 56-78) and a median of three prior treatment lines (range: 2-9); all patients are anti-CD20 refractory. As of July 25, 2025, in 12 high-risk R/R FL patients, glofitamab combined with Tislelizumab achieved an 100% overall response rate (ORR; 12/12) with 83.3% complete remission (CR; 10/12) and responses remained ongoing at a median follow-up of 10.4 months. Critically, all CR patients (10/10) achieved minimal residual disease (MRD) negativity (<10^−5 by next-generation flow cytometry) in peripheral blood and bone marrow at response assessment. Treatment was well-tolerated with only grade 1-2 cytokine release syndrome (41.7%, 5/12) and no grade ≥3 immune-related adverse events. The most common AEs (>20%) were pyrexia (41.7%, 5/12), neutropenia (33.3%, 4/12), anemia (33.3%, 4/12), and decreased appetite (25%, 3/12). The most common Grade ≥3 AEs (>10%) were neutropenia (16.7%, 2/12). Genomic profiling revealed recurrent mutations in epigenetic regulators (CREBBP 58.3%, KMT2D 50%) and TNFRSF14 (41.7%), with all CR patients harboring alterations in CREBBP and/or KMT2D. Conclusion Glofitamab plus tislelizumab demonstrated transformative clinical activity in ultra-high-risk R/R FL, achieving 100% ORR and 83.3% CR with durable MRD-negative remissions in a population uniformly refractory to anti-CD20 therapy. The regimen's exceptional safety profile (no high-grade immune toxicity) and predictive role of CREBBP/KMT2D alterations support this fixed-duration, chemotherapy-free strategy as a paradigm shift, representing the first clinical validation of synergistic PD-1 blockade with T-cell-engaging bispecifics in FL.