A Prospective Clinical Trial of Boom-Boom Radiation As Bridging Therapy for Patients with Large B-Cell Lymphoma Undergoing Treatment with Lisocabtagene Maraleucel (Liso-cel) Therapy

Introduction: Many patients receiving chimeric antigen receptor T-cell (CAR T)-cell therapy for aggressive B-cell non-Hodgkin lymphoma will fail to respond or relapse. Bridging therapy, administered between pheresis and infusion, is used to control disease prior to CAR T-cell infusion. The impact of bridging therapy has been difficult to determine as majority of data is retrospective with bridging therapy heterogeneously employed. Low dose radiation, 2 Gray administered in 2 fractions (Boom-Boom), has demonstrated efficacy and exceptionally low toxicity in palliation of localized B-cell lymphoma. Pre-clinical experiments have demonstrated that Boom-Boom radiation administered prior to CAR T-cell therapy successfully enhances CAR T cell efficacy, suggesting potential engagement of novel immunotherapeutic mechanisms. We hypothesized that Boom-Boom radiation would be safe and effective as bridging therapy prior to liso-cel infusion.

Methods: We performed an investigator-initiated, pilot feasibility study of Boom-Boom bridging radiation therapy prior to liso-cel infusion. Eligible patients included adults aged 19+ with a diagnosis of aggressive B-cell non-Hodgkin lymphoma eligible to receive liso-cel under commercial indication at the University of Nebraska Medical Center. Subjects received Boom-Boom (2 x 2 Gy) radiation to disease sites approximately 7-10 days prior to liso-cel infusion. No other bridging therapy aside from steroids was allowed after lymphocyte pheresis. The primary endpoint was feasibility, defined as the percentage of subjects receiving boom-boom radiation that go on to receive CAR T-cell infusion. Based on prior clinical trial data for TRANSCEND and TRANSFORM, we set a feasibility threshold at 70% for enrolled subjects to receive boom-boom and CAR T-cell therapy.

Results: The trial is ongoing and this data represents an interim analysis. Twenty subjects enrolled and underwent lymphocyte pheresis. Eighteen subjects received Boom-Boom radiation and liso-cel infusion, with 2 subjects removed for advanced disease requiring alternative therapy. The study is meeting prespecified feasibility criteria with 18/18 (100%) subjects who received Boom-Boom proceeded to liso-cel infusion, and 18/20 (90%) subjects enrolled and intended for liso-cel received Boom-Boom and liso-cel. The median age was 70 (range 23-84), 13 (65%) subjects were male, 100% were Caucasian and 1 subject (5%) was Hispanic. The median distance for subjects to our center was 93 miles (range 11-448 miles), and 11/20 (55%) subjects reside in rural counties. Two subjects were diagnosed with high-grade B-cell lymphoma, 1 with grey zone lymphoma, and 17 with DLBCL. Fourteen subjects (14/21, 67%) had an LDH above the upper limit of normal. Thirteen subjects (13/20, 65%) had extranodal disease, 13/20 (65%) had advanced stage disease, 11/20 (55%) were refractory to frontline therapy, and 13/20 (65%) were refractory to most recent line of therapy. Eighteen subjects (18/20, 90%) received liso-cel as second-line therapy.

Seventeen subjects receiving per-protocol therapy were evaluable for response. One subject experienced grade 5 CRS toxicity and was not evaluable. The overall response rate to Boom-Boom and liso-cel was 14/17 (83%), and all (14/14,100%) were complete responses. One subject had stable disease and 2 subjects experienced progressive disease as best response. Landmark analysis including all subjects performed at D100 indicated a progression-free survival rate at 76%, duration of response at 69%, and overall survival at 88%.

Eighteen subjects were evaluable for safety. Cytokine release syndrome was observed in 7 subjects and was G1 in 4, G2 in 2, and G5 in 1. ICANS toxicity was observed in 5 subjects and G3+ in 3/5. Two subjects died due to intestinal perforation and septic shock prior to D100.

Conclusion: This is the first prospective trial to report results of radiation therapy as bridging therapy prior to CAR T-cell therapy. Despite inclusion of a high risk, refractory population, the CR rate for evaluable patients is encouraging at 83%, and it is noteworthy that all responses were CRs. Use of low-dose radiation therapy as bridging was safe and feasible as 90% of consented subjects received therapy per protocol. No new safety signals for radiation toxicity, CRS, ICANS, were observed. The study is ongoing and updated data on tumor burden, response, and survival will be featured at presentation.