Response-adapted chimeric antigen receptor T cell (CAR-T)-sparing consolidation radiotherapy in high-risk large B-cell lymphoma (LBCL): Results of the prospective RESTART protocol.

Early relapse remains a major limitation of chimeric antigen receptor T cell (CAR-T) in relapsed or refractory large B-cell lymphoma (LBCL), particularly for high-risk disease or suboptimal early response. The prospective RESTART protocol evaluated a risk-adapted integration of radiotherapy (RT) with CAR-T. Patients were assigned to RT-dominant (Pathway A) or systemic bridging (Pathway B) based on disease distribution and biology. A key innovation was response-adapted consolidation RT for patients with Deauville score (DS) 4-5 at 1-month post-infusion, or DS 3 and baseline high-risk lesions (≥5 cm and/or maximum standard uptake value [SUVmax] ≥15). Consolidation RT was delivered 6-8 weeks post-infusion using CAR-T-sparing techniques to minimise circulating blood dose. Among 190 patients, 55 (29%) received RT. Local control within irradiated volumes was 89%, including 92% following consolidation RT. At a median follow-up of 12.4 months, the 1-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 57% and 71% respectively. Patients receiving consolidation RT, despite high-risk features, achieved a 1-year PFS of 54% and OS of 95% with no evidence of excess systemic relapse due to a negative effect on CAR-T. This protocol demonstrates that response-adapted, CAR-T-sparing consolidation RT is feasible and associated with favourable outcomes in high-risk LBCL.