Radiotherapy Is an Excellent Bridging Strategy in Large B-Cell Lymphoma Patients Selected for CAR T-Cell Therapy
Authors: Niezink Anne , van Doesum Jaap , Beijert Max , Nijland Marcel , Langendijk Hans , Busz Dianne , Crijns Anne P.G. , Huls Gerwin A. , Van Meerten Tom 
Published: November 2021

Abstract
Purpose/Objective
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential curative treatment regime in patients with Large B-cell Lymphoma (LBCL) who have refractory or relapsed disease after two lines of systemic therapy. CAR T-cells are generated from autologous T-cells in specialized laboratories and the planning of the apheresis and manufacturing slot to the final infusion of the CAR T-cells into the patient may take up to 8 weeks for European centers, as the CAR T-cells are manufactured in the US. This logistic and time-consuming process might well be detrimental for patients with symptomatic and progressive disease.
In these cases, bridging therapy may be indicated, referring to therapy administered after apheresis until CAR T-cell infusion. Early reports on radiotherapy (RT) as a bridging strategy have shown feasibility, safety, and effectivity, but patient numbers were limited.
Here we present our experience with bridging therapy in patients selected for CAR T-cell therapy in a relatively large cohort. The current analysis focuses on the evaluation of safety and response rates.
Material and Methods
All patients treated with anti-CD19 CAR T-cell therapy are included in a prospective data registration program including data on patient and tumor characteristics, treatment, toxicity, and outcomes. All patients were treated with an anti-CD19 CAR containing a CD28 costimulatory molecule (Axi cel). For this analysis, patients with LBCL who underwent apheresis for CAR T-cell therapy were included. Bridging therapy consisted of steroids, chemotherapy, immunotherapy (systemic therapy; ST), RT, or a combination of these. Responses to bridging therapy were based on 18F-Fluordeoxyglucose PET (FDG-PET) before CAR T-cell infusion and Progression Free Survival (PFS), defined as time to clinical or FDG-PET based progression of disease, and Overall Survival (OS) are reported.
Results
In total, 49 patients underwent an apheresis procedure. Median follow-up after apheresis was 72 months. Sixteen of these patients (32.7%) did not receive bridging treatment, 19 (38.7%) underwent RT alone, 6 (12.2%) received ST alone and 8 (16.3%) received ST and RT. RT was given on bulky tumor or burdensome lesions, in most patients to a total dose of 20 Gy in 5 fractions (See figure). 81.5 percent of patients had an infield response to RT. 16 of 17 (94.1%) patients with multiple lesions, who received RT alone had out of field progression, compared to 75.0% in patients who received RT and ST and 60.0% after ST alone. No CTCAE v5.0 grade 2 or higher radiotherapy related toxicity was observed
Finally, 45 patients (91.8%) received CAR T-cells, while 3 patients did not because of rapid progression and 1 patient due to no residual disease. On day 28, two patients had died due to progression. Of the remaining 43 patients, FDG-PET evaluation showed progressive disease in 7 (16.3%) patients, stable disease in one patient (2.3%), partial response in 12 (27.9%) , and complete response in 23 (53.5%). The 2-year PFS of patients who did not receive bridging treatment was 47%, compared to 49% in patients bridged with RT alone and 31% in patients treated with ST or combined treatment. The 2-year OS was 63% versus 46%, and 34%, respectively.
Conclusion
Bridging the time between apheresis and CAR T-cell infusion is a critical phase in CAR T-cell therapy. Selection of bridging treatment type is based on prior treatment, tumor load and symptoms. RT is an excellent bridging option with a high local control rate and favorable toxicity profile and should be considered in this heavily pre-treated patient population.
Figure 1 Figure 1.

Disclosures
Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy.