Hyper-fractionated radiotherapy bridging CAR-T overcome early relapse for aggressive B-cell CNS lymphoma

Background: Relapsed/refractory (R/R) primary/secondary central nervous system (CNS) lymphoma has poor prognosis and limited treatments. Chimeric antigen receptor T-cell (CAR-T) therapy shows promise but has high early relapse/death rates. Hyper-fractionated radiotherapy (HFRT) enables rapid cytoreduction and immune modulation, potentially enhancing CAR-T efficacy as a bridging approach. Methods: This prospective pilot study enrolled patients with relapsed or refractory primary or secondary B-cell CNS lymphoma treated at Peking Union Medical College Hospital. All patients received HFRT (30 Gy in 1.5 Gy twice-daily fractions for 10 consecutive days), followed by lymphodepletion and subsequent CAR-T cell infusion. Clinical response, survival outcomes, and toxicities were evaluated according to standard criteria. Results: 9 R/R CNS lymphoma patients were enrolled. The median follow-up time was 17 (4-34) months after CAR-T infusion. At 1 month follow-up, 6/9 (66.7%) patients achieved complete remission (CR), 1/9 (11.1%) had partial remission (PR) and 1/9 (11.1%) had disease progression (PD) in brain. 7/9 (77.8%) patients had CR at 3 months. 7 patients have been followed up for more than 6 months and remained CR. The 1-year PFS was 87.5% and the 1-year OS was 77.8%. The median PFS and OS were not reached. At Grade ≥3 CRS and ICANS each occurred in one patient (11%). Seven (78%) experienced grade 3–4 myelosuppression, and one patient died of mixed pulmonary infection. Conclusions: Whole-brain HFRT as bridging strategy helps maintain long-term CAR-T response in CNS lymphoma with favorable safety. (NCT05514327)