Radiotherapy in Combination with CD20×CD3 Bispecific Antibodies for B-Cell Lymphoma: Biological Rationale, Current Evidence, and Open Questions

Background/Objectives: CD20×CD3 bispecific antibodies (BsAbs) have changed the management of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. Whether and how radiotherapy (RT) can be safely and usefully combined with BsAb therapy remains undefined. This Perspective reviews the biological rationale and the available clinical evidence, distinguishing the established findings from the hypotheses. Methods: We conducted a targeted, non-systematic review of RT combined with CD20×CD3 BsAbs in B-cell lymphoma, searching PubMed/MEDLINE, the Cochrane Library, and ClinicalTrials.gov, supplemented by conference abstracts and a post hoc verification search. Given the immaturity and heterogeneity of the field, we used a narrative synthesis rather than a systematic search. Sources were classified as direct evidence, mixed/indirect (non-disaggregable) evidence, or registered trials without results; only the first category was used to support clinical claims. Results: Direct evidence comprises three case reports, a 7-patient lymphoma subgroup, and a 29-patient cohort with disaggregated CRS/neurotoxicity data. Additional mixed/indirect evidence comes from a 12-patient series. Three registered trials have not yet reported results. Five partially overlapping rationales are proposed: cytoreduction, the modulation of the tumour microenvironment, the management of tumour flare, the consolidation of residual disease, and urgent local control during BsAb step-up dosing. The potential antagonistic effects, including CD20 loss and T-cell depletion, have received comparatively little study. Whether RT-induced lymphopenia could blunt BsAb efficacy remains a key open question. Conclusions: The available evidence indicates only that RT has occasionally been delivered around BsAb therapy in small, non-comparative series, without a consistent toxicity signal. It does not establish the benefit, synergy, or optimal sequencing. Prospective studies are needed to define the role of RT in this setting.