Patient-Level Disease Burden as a Predictor of 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

Abstract

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) is a safe and effective treatment strategy in bridging patients with relapsed/refractory large B-cell lymphomas (R/R LBCL) to CAR T-cell therapy. However, the optimal implementation of bridging RT (bRT) remains poorly understood, particularly in respect to achieving durable local control (LC) and improving patient outcomes. We sought to identify factors associated with lesion LC and patient survival in patients treated with bRT. <h3>Materials/Methods</h3> Performed a retrospective analysis of R/R LBCL patients receiving CAR T-cell infusion at our institution between 12/2017 and 6/2021. Clinical outcomes were compared with our previously published cohort of 63 unirradiated (nonRT) patients. Categorical results were compared using Fisher's exact test. Time-to-event analysis was estimated using Kaplan-Meier method and compared with log-rank. <h3>Results</h3> Forty-five patients underwent bRT prior to CART. Compared with our previous nonRT cohort, bRT patients had substantially worse disease burden as measured by median metabolic tumor volume (MTV) (463 v. 186cc), the presence of any lesion ≥ 5 cm (87 v. 67%), and the presence of any necrotic lesion (50 v. 28%). Despite the worse prognosis, we observed similar DFS when compared to the prior lower-risk, nonRT cohort (12-month DFS 46 v. 51%). Nearly half of bRT patients maintained a complete and durable response at a median follow-up of 11.6 months. Furthermore, bRT patients experienced fewer local only failures (n=2/22, 9%) compared to our nonRT cohort (n=13/26, 36%; p = 0.03). A trend towards decreased any local failure (64% vs 86%) and an increased distant only failure (36% vs. 14%; both p = 0.06) was observed in our bRT cohort compared to our historical benchmark. Forty patients with 98 irradiated lesions underwent lesion-level analysis. Patients received bRT to a median of 2 lesions (range 1-9) with a median EQ2D (a/b=10) dose of 31.2Gy. In-field progression was observed in 11/40 (28%) of patients and 23/98 (24%) of lesions. In-field progression was strongly correlated within patients with multiple irradiated lesions, with 83% exhibiting uniform outcomes across all treated lesions (i.e., either all local control or failure among irradiated lesions). At the patient level, the presence of any in-field progression was strongly correlated with total disease burden using both the previously reported MTV threshold of 150cc (9 v 34%) and the bRT cohort's median MTV of 463cc (14 v. 42%; both p < 0.05). <h3>Conclusion</h3> Patients receiving bRT prior to CAR T-cell therapy for R/R LBCL with high MTV appear to exhibit comparable outcomes to patients with far lower disease burden who did not undergo irradiation, supporting a potential role of bRT in high-risk patients to improve clinical outcomes. In-field progression of irradiated lesions occurred in a quarter of bRT patients and is strongly correlated with total disease burden. Future prospective trials are needed to optimize RT strategies to improve outcomes in patients undergoing CART therapy.