Introduction Bispecific antibodies (BsAbs) targeting CD20 and CD3 have demonstrated promising efficacy in treating relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL). However, treatment failure due to disease progression or primary resistance remains a significant challenge. Evidence on clinical outcomes following BsAb failure is scarce, especially in real-world settings. To address this gap, we evaluated post-failure treatment patterns, survival outcomes, and clinical factors associated with resistance to BsAb treatment.

Methods We conducted a retrospective study of NHL patients aged ≥18 years treated with CD20/CD3 BsAb monotherapy (glofitamab, mosunetuzumab, or epcoritamab) at Princess Margaret Cancer Centre between January 2020 and December 2024. Patients were identified via the institutional Cancer Registry. Lymphomas were classified as aggressive (diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, high-grade B-cell lymphoma, and transformed lymphoma) or indolent (follicular lymphoma, marginal zone lymphoma). Treatment patterns, response (per Lugano 2014 Criteria), and survival outcomes were analyzed using descriptive statistics, Kaplan-Meier survival analysis, and Cox proportional hazards modeling.

Results Among 50 patients treated with BsAbs, 31 had aggressive and 19 had indolent NHL. In the indolent group, 11 (57.9%) received glofitamab and 8 (42.1%) mosunetuzumab. In the aggressive group, 22 (71.0%) were treated with glofitamab, 8 (25.8%) with mosunetuzumab, and 1 (3.2%) with epcoritamab. BsAbs were administered via clinical trials (n=41), compassionate use (n=7), or standard care (n=2). Prior CAR-T was more common in aggressive group (32.3% vs. 0%), which also had more males (61.3% vs. 26.3%). No significant differences were found in prior therapy lines (median 2; P=0.780) or autologous stem cell transplant history (12.9% vs. 21.1%; P=0.459). Cytokine release syndrome occurred in 32 patients (64%): 29 with grade 1–2 and 3 with grade 3. Immune effector cell-associated neurotoxicity syndrome occurred in 4 patients, all grade 1. Two patients discontinued BsAbs due to infections.

Over a median follow-up of 23.0 months (range 2.0–75.0), 23 patients experienced progression—17 (55%) in the aggressive and 6 (32%) in the indolent group. At the time of progression, the median age was 68 years, with 69.6% of patients aged ≥60. High-risk features were prevalent, including elevated LDH (87%), stage III/IV disease (87%), IPI 4-5 (48%), and ECOG ≥2 (30%), similarly distributed across subtypes. Post-progression treatments in aggressive group included CAR-T therapy (n=3), BsAb re-treatment (n=1), chemotherapy (n=2), radiation (n=4), clinical trial (n=1), palliative care (n=5), or observation (n=1). Treatments in the indolent group included CAR-T therapy (n=2), allogeneic transplantation (n=1), chemotherapy (n=1), radiation (n=1), and palliative care (n=1).

In aggressive lymphoma, the median PFS and OS were 21.0 and 31.0 months, respectively (1-year PFS: 54.4%, 1-year OS: 69.4%), while both were not reached in the indolent group (1-year PFS: 82.5%, 1-year OS: 94.7%) (PFS: P =0.046; OS: P=0.033, log-rank test). Post-progression, the median OS was 11 months overall. Patients with indolent lymphoma had a median OS of 41 months and a 1-year OS rate of 83.3%, compared to 7 months and 28.2%, respectively, in those with aggressive lymphoma, showing a trend toward statistical significance (P=0.070). Aggressive histology was independently associated with a higher risk of progression (Hazard ratio 3.93; 95% CI, 1.72–8.97; P=0.001).

Eighteen deaths occurred during the study, including 15 among patients with disease progression. Of these, 12 deaths due to disease progression occurred exclusively in the aggressive group, while 3 infection-related deaths occurred in the indolent group.

Conclusion

This study highlights the divergent outcomes following BsAb failure in NHL. Patients with aggressive histology had poor prognosis and limited durability, whereas those with indolent lymphoma showed encouraging post-progression survival. These findings suggest that BsAb failure does not uniformly indicate poor prognosis across all subtypes, highlighting an unmet need for subtype-specific approaches and prospective studies to guide effective post-BsAb strategies, particularly in high-risk aggressive NHL.

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2025
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