CNS Bridging Radiotherapy Achieves Rapid Cytoreduction Prior to CAR T Cell Therapy for Aggressive B-Cell Lymphoma

• Bridging radiotherapy for chemorefractory CNS lymphoma achieves rapid cytoreduction prior to CAR T-cell therapy

• CNS bridging radiotherapy is associated with a favorable CNS response profile and CAR T associated neurotoxicity profile

CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma where it can improve CAR T outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction prior to CAR T for CNSL (CNS-BRT). We identified CNSL patients with non-Hodgkin B-cell lymphoma who received CNS-BRT prior to commercial CAR T. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CAR T. Twelve patients received CNS-BRT, and the median follow up among survivors is 11.8 months (IQR: 8.5 - 21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten patients with CNSL had progressive disease at the time of CNS-BRT. 1/12 patients experienced grade ≥ 3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95% confidence interval: 62.0 - 86.0) mean reduction in lesion size from baseline (p = 0.014) at a median of 12 days from BRT completion and prior to CAR T infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CAR T.