Phase II Trial of Hypofractionated Radiotherapy and Immunochemotherapy in Primary Refractory Diffuse Large B‐Cell Lymphoma: Preliminary Results and Insights from Digital Spatial Profiling

This open-label, single-arm phase II study assessed the safety and efficacy of sequential hypofractionated radiotherapy (RT) followed by zimberelimab and R-GemOx (rituximab, gemcitabine, oxaliplatin) in patients with primary refractory diffuse large B-cell lymphoma (DLBCL). Fourteen patients were enrolled between June 2022 and December 2023, with 13 included in the analysis. RT doses of 36 and 24 Gy were delivered to the gross and target volumes in 12 fractions, followed by zimberelimab and R-GemOx. The overall response rate within the irradiated field was 92.3%, and a complete response (CR) was achieved by 61.5% of patients; however, 38.5% experienced disease progression. Treatment-related toxicities were manageable, primarily comprising mild leukocytopenia. Digital spatial profiling revealed 53 differentially expressed genes in CD20-rich lymphoma regions and 93 in CD3-rich T cell regions in non-CR patients. Reactome analysis identified key immune system pathways. T cell infiltration correlated with treatment efficacy, and multiplex immunohistochemistry validated immune pathways as potential therapeutic targets. This study demonstrated the promising role of RT combined with immunochemotherapy in refractory DLBCL and suggests immune pathways as critical targets to improve treatment outcomes.