In-Field Failures in Patients Undergoing Bridging Radiotherapy for CD19-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Recurrent/Refractory Large B-Cell Lymphomas.

Purpose/objective(s) The majority of patients with relapsed or refractory large B-cell lymphomas (R/R LBCL) treated with CAR-T cell therapy experience disease progression. We previously identified that most relapses include local failures at PET avid sites that were present prior to CAR T cell infusion. We hypothesize that targeting unfavorable lesions with bridging radiation (RT) may prevent local failure. Materials/methods We retrospectively identified R/R LBCL patients treated with bridging RT between T cell apheresis and CAR T-cell infusion at a single institution. Patterns of failure were analyzed descriptively and time-to-event analysis was estimated using Kaplan-Meier. Results From 12/2017-11/2020, 30 patients underwent bridging RT prior to CAR T. Median age of patients was 63 (range 24-79) and the majority were male (n = 19). At a median follow-up of 22.8 months, 12-month disease free survival was 52% and 12-month overall survival was 57%. Eighteen patients (60%) achieved a durable response. Of the 12 patients with treatment failure, 8 (67%) experienced progression within the RT field as part of their relapse. On baseline PET/CTs of the 30 patients, we identified 403 individual pretreatment lesions, of which 53 were irradiated as bridging therapy before CAR T infusion. The median SUVmax and metabolic tumor volume (MTV) for the irradiated lesions were 16.7 (interquartile range [IQR] 8.8-24.3) and 67.7cc (IQR 8.6-269.4 cc), respectively. Using an alpha/beta of 10, the median equivalent 2 Gy dose (EQD2) administered was 24 Gy (IQR 13-32.5 Gy), with the most common regimens being 37.5 Gy in 15 fractions (n = 10) and 30 Gy in 10 fractions (n = 10). Of the 53 irradiated lesions, nine (16.9%) experienced an in-field failure, translating to 12- and 24-month in-field local control rates of 79.0% and 74.3%, respectively. Nearly all in-field failures (8/9, 89%) initially experienced a response (complete or partial) in the first month prior to progressing on subsequent imaging, demonstrating true progression of disease. Seven of the nine in-field failures had a baseline lesion MTV > 50cc. However, no lesion that received at least 37.5Gy or 39Gy EQD2 failed (n = 11). Conclusion In patients receiving bridging RT prior to CAR T cell therapy for R/R LBCL, treatment failure was characterized by high rates of genuine in-field relapse after an initial partial or complete response. In a smaller number of patients, no lesion that received a higher dose of RT demonstrated an in-field failure. This calls into question the potential synergistic effects of bridging RT and CAR T therapy at low RT doses in some patients and suggests the need for significant dose-escalation to achieve adequate local control.