329 - Phase II Trial of 'Re-Priming' Radiation Therapy for Relapsed/Refractory Non-Hodgkin Lymphoma Patients in Incomplete Response after Chimeric Antigen Receptor T-cell (CAR-T) Therapy
Presenter(s)
K. A. Kumar1, M. Kozak1, R. Ravella2, P. Ramakrishnan Geethakumari3, F. Awan4, T. A. Aguilera5, T. D. Chiu6, E. Yilmaz4, H. Wolfe4, O. K. Öz6, A. Kandathil3, W. Chen7, F. Fuda3, C. Ahn8, P. Iyengar2, N. B. Desai1, and R. D. Timmerman1; 1Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 2Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 3UT Southwestern, Dallas, TX, 4Department of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 5Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, 6University of Texas Southwestern Department of Radiation Oncology, Dallas, TX, 7University of Texas Southwestern Medical Center, Dallas, TX, 8Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
Purpose/Objective(s): In patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) treated with CD19-directed CAR-T, only ~40% achieve complete response (CR) by day 30 PET/CT evaluation. Of those who do not, the large majority (~70%) ultimately fail, providing an ideal target for early therapeutic intervention to ‘re-prime’ CAR-T. Preclinical and early clinical studies suggest potential synergy and immune augmentation when combining RT with CAR-T. Here we report the preliminary phase II results of a prospective phase I/II clinical trial hypothesizing that early salvage focal RT to poor responding sites of disease after CAR-T in R/R NHL patients is safe (phase I) and will improve conversion to CR by day 90 post-CAR-T PET/CT from 29% (historical control) to 58% (phase II).
Materials/Methods: We opened a single-arm open-label phase I/II prospective clinical trial at our institution for R/R NHL patients treated with CD19-directed CAR-T with incomplete response on day 30 post-CAR-T PET/CT scan (defined as Lugano >=4). RT was initiated by day 45 and completed by day 60 post-CAR-T. Hypofractionated regimens (i.e. 5 fractions) directed only to residual FDG-avid disease were recommended to minimize lymphopenia and potentially result in a more favorable immune microenvironment. The primary endpoint is overall metabolic CR rate on day 90 post-CAR-T PET per Lugano 2014 classification, and secondary endpoints include local and systemic response rates, duration of response, progression free and overall survival.
Results: Between April 2021 and June 2024, 14 patients were enrolled. All patients had <=5 sites of residual FDG-avid disease on day 30 post-CAR-T PET/CT with no prior RT to these sites. Patients were treated to the “definitive” dose of RT (40-50 Gy EQD2) as determined safe by the roll in phase I component of the trial, most commonly 30 Gy in 5 fractions. At day 90 post-CAR-T PET/CT, the rate of metabolic CR was 50% (7/14). 1-year PFS and OS were 29% and 50%. No grade 3+ radiation related toxicities were observed. The 1-year local PFS was 60%, with 4/14 (29%) local failures noted, of which 2 occurred marginally just outside the prescription dose region.
Conclusion: Early salvage focal “definitive” dose RT to sites of incomplete response on day 30 post-CAR-T PET/CT for R/R/ NHL patients was safe and resulted in 50% conversion to metabolic CR by day 90 post-CAR-T PET/CT. While this did not meet the pre-specified hypothesis of doubling the metabolic CR rate, this data suggests that focal RT as early salvage to limited sites of residual disease after CAR-T may be a reasonable strategy for select patients. Further studies are needed to better understand the biologic impact of RT after CAR-T and prognostic factors that may help improve patient selection.