Investigating Treatment Kinetics and Local Response during and after Bridging Radiotherapy Prior to CAR-T Cell Therapy for Lymphomas

Introduction: Bridging radiotherapy (BR) prior to chimeric antigen receptor T-cell (CAR-T) therapy for non-Hodgkin Lymphoma (NHL) provides effective cytoreduction and durable response rates. Lymphomas can exhibit rapid responses to radiotherapy, but reliable predictors of BR response, and optimal dosing to mitigate toxicity of combined modality treatment, are unknown.

Methods: We evaluated patients with relapsed or refractory NHL who underwent CAR-T apheresis, BR, and CAR-T infusion at our institution from 2019-2024 and had evaluable PET/CT imaging following CAR-T. We collected information on patient demographics, clinicopathologic characteristics including histology and disease bulk, pre-BR metabolic tumor volume (MTV) of the irradiated site, radiotherapy dose and fractionation, and disease outcomes from the medical record. Post-CAR-T treatment response was assessed on PET/CT. We evaluated volumetric response to radiation by contouring visible gross tumor volume (GTV) on available cone beam CT from image-guided radiotherapy (IGRT) during the first five fractions of radiotherapy. Using spider plots and waterfall plots, a threshold for “rapid early response” (RER) to BR was defined to be a volume shrinkage of at least 10% within five radiation fractions. We compared demographics, disease, and treatment characteristics between patients with and without RER using chi-squared tests for categorical variables and non-parametric Kruskal-Wallis tests for continuous variables. We evaluated one-year progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. One-year cumulative incidence of local failure was estimated with a cumulative incidence function with death as a competing risk. All analyses were performed using R software.

Results: Thirty patients with NHL underwent CAR-T apheresis, BR, and CAR-T infusion and had evaluable post-treatment PET/CT imaging. Diffuse Large B-cell Lymphoma (DLBCL) was the most common histology (n=21) followed by Mantle Cell Lymphoma (MCL, n=7). The median age of the cohort was 67.5 years and there was a slight male predominance (57%). Approximately half of patients had disease refractory to first-line chemotherapy, and 77% of patients received BR to bulky disease. The most common regimens were 30 or 33 Gy in 10 fractions (n=5) and 20 or 20.5 Gy in 5 fractions (n=11). Twenty-five of thirty patients experienced a complete response (CR) as their best response at the irradiated site following CAR-T, and five patients experienced a partial response (PR). Approximately one-third (8/23) of patients with available IGRT experienced a “rapid early response” (RER) to BR. Patients with RER versus without RER were younger (59 vs 72 years, p=0.049), with a trend toward higher numeric MTV (305 vs 87 mL, p=0.06) but were equally likely to have received radiotherapy to bulky disease (75 vs 87%, p=0.9). MCL histology was more common among patients with RER compared to those without RER (50 vs 13%), while DLBCL was less common (37.5 vs 80%). There was a trend toward lower median equivalent dose in 2-Gy fractions (EQD2) in the RER vs no RER cohort (22.9 Gy vs 25.6 Gy, p=0.1), even when limited to only patients with DLBCL (22.4 Gy vs 27 Gy). With a median follow-up of one year, all four local recurrences within radiotherapy treatment volumes have occurred in patients without RER. One-year PFS and OS for the cohort were 65% and 81%, respectively, and the incidence of local failure was 16%.

Conclusions: Based on our findings, we have formulated recommended BR doses ranging from an EQD2 of 15 Gy to 37 Gy based on histologic and clinical features, including an algorithm for adaptive radiotherapy dose and fraction reduction for patients exhibiting RER on IGRT with a goal of minimizing adverse effects of combined radiotherapy and CAR-T. Future directions include evaluating biomarker responses to BR and identifying the effect of BR on the immune microenvironment, investigating the role of concurrent systemic therapies such as steroids or Polatuzumab during BR, and assessing the safety and efficacy of adaptive and personalized BR in a prospective clinical trial.

Marar:Bristol Myers Squibb: Consultancy. Advani:Seattle Genetics: Research Funding; Cyteir: Research Funding; Regeneron: Research Funding; Autolus: Honoraria, Other: DSMB/Advisory Boards; Gilead: Research Funding; Merck: Other: Steering committee, DSMB/Advisory Boards, Research Funding; ADCT: Honoraria, Other: DSMB/Advisory Boards; BeiGene: Honoraria, Other: DSMB/Advisory Boards, Research Funding; Roche/Genentech: Honoraria, Other: Steering committee, DSMB/Advisory Boards, Research Funding. Alizadeh:Forty Seven: Other: stock; CiberMed: Consultancy, Other: Scientific Co-founder; Gilead: Consultancy; Roche: Consultancy; Pharmacyclics: Consultancy; Foresight: Consultancy, Other: Scientific Co-founder; CARGO Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Consultancy; Adaptive Biosciences: Consultancy; BMS: Research Funding. Miklos:Adaptive Biotechnologies: Research Funding; Fosun Kite Biotechnology: Honoraria; Juno Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy, Other: Travel Support, Research Funding; Galapagos: Consultancy; Miltenyi: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Patents & Royalties; Adicet: Research Funding; 2SeventyBio: Research Funding; Allogene: Research Funding. Dahiya:Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding; Kite-Pharma-Gilead: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy.