Radiotherapy for Relapse after Chimeric Antigen Receptor T Cell Therapy in Hematologic Malignancies

Abstract

<h3>Purpose/Objective(s)</h3> Approximately half of patients relapse following chimeric antigen receptor T-cell therapies (CAR T), a challenging clinical scenario without established treatment paradigms. Salvage radiotherapy (SRT) may be an important strategy for this population with rapidly growing, often systemic-refractory disease, particularly for localized relapses. Limited data are available regarding SRT utilization and outcomes. <h3>Materials/Methods</h3> We reviewed all hematologic malignancy patients treated with SRT for any intent post-CAR T from 2016–2022. Comprehensive SRT was defined as including all sites with PET avidity >liver max. Failure sites were classified as pre-existing (present pre-SRT) vs. new, and as in-field, marginal (within 1cm of), or distant with respect to SRT prescription dose region. Toxicities were graded by CTCAE v5.0. Progression free and overall survival (PFS/OS) were measured from SRT start by Kaplan Meier. Clinicodemographic associations with outcomes were assessed by Cox univariate proportional hazards. <h3>Results</h3> 44 patients with diffuse large B cell lymphoma (DLBCL; n=36), mantle cell lymphoma (n=4), multiple myeloma (n=3), and primary mediastinal B cell lymphoma (n=1) were included. Patients received axicabtagene (n=14), lisocabtagene (n=13), tisagenlecleucel (n=9), experimental CAR T (n=4), idecabtagene (n=3), and brexucabtagene (n=1). For 57%, SRT was the first post-CAR T therapy. SRT indications were palliative (n=25), definitive (n=10), bridging to allogeneic transplant (allo; n=5) or second CAR T (n=3), or consolidative (n=1). Most common SRT sites were abdominal/retroperitoneal (n=17), head/neck (n=8), and subcutaneous (n=8). At SRT, 11 (25%) had localized disease treated comprehensively; overall 39% of SRT was comprehensive. Median SRT dose was 30Gy (12–50.4). 34% received concurrent systemic therapy. SRT was well tolerated: 16% (n=7) had ≥ grade 2 (G2) acute adverse events (G3=1, no G4/5). Overall response rate (ORR) was 91% (41% complete) and 50%, within the SRT field and overall, respectively. With a median follow up of 35mo, 21 patients progressed. First failure sites were 67% pre-existing and 38% in field/marginal. For DLBCL patients, median PFS was 33mo in limited stage and 1.6mo in advanced (p=0.06). Median OS was 59.6mo and 2.7mo in localized and advanced DLBCL relapse (p<0.001). Median OS for RT as bridging to allo/CAR T, definitive therapy, and palliation was unreached, 59.6mo, and 2.6mo (p=0.001). Receipt of ≥30Gy and comprehensive SRT were associated with improved OS (p<0.001) while max tumor diameter and extranodal disease pre-SRT were associated with shorter OS (p=0.03). <h3>Conclusion</h3> SRT has promising and diverse utility after CAR T. Prolonged survival can be achieved with SRT bridging to allo/second CAR T or even with definitive SRT in the setting of limited relapse and when it is feasible to irradiate all active disease to a definitive dose.