Outcomes of Salvage Radiotherapy in Relapsed/Refractory Large B-Cell Lymphoma Patients Following CAR T-Cell Therapy Failure: A Multicenter Pooled Analysis

Introduction: While CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can lead to durable remission in many patients with relapsed/refractory large-B cell lymphoma (LBCL), the majority will develop relapsed or refractory disease, necessitating effective salvage strategies. Therefore, we aim to evaluate the long-term outcomes of salvage radiation therapy (RT) compared to other therapeutic strategies for patients with LBCL following CAR T-cell therapy failure. Methods: We conducted a multi-institutional retrospective study in a database of 352 consecutive LBCL patients who received axicabtagene ciloleucel or tisagenlecleucel CAR T-cell therapy following ≥2 prior therapies and subsequently received salvage therapies post-CAR T relapsed/refractory disease [RT alone, systemic therapy (ST) alone, or combined modality therapy (CMT)]. All three categories were defined at the time of the first salvage therapy following CAR T failure. A separate analysis was conducted for patients who were treated with comprehensive versus focal RT; only the first RT course was included in this analysis for patients receiving >1 salvage RT course. Comprehensive RT was defined as RT to all sites of disease, while focal RT was defined as RT to a subset of disease sites. In-field response for salvage RT was evaluated using post-RT imaging and/or clinical assessment. Biologically effective dose (BED) was calculated using an α/β ratio of 10. Survival measures were computed using the Kaplan-Meier method, with comparisons via log-rank test. Results: A total of 128 patients with post-CAR T relapsed LBCL received salvage therapies (RT, 24 patients; CMT, 16 patients; ST, 88 patients). The median follow-up after CAR T-cell infusion was 14.2 months [interquartile range (IQR): 6.3-41.0 months], and the median follow-up after post-CAR T salvage therapy was 7.1 months (IQR: 3.0-24.0 months). Analysis of patterns of failure revealed that the majority of patients (n=96, 75%) had a component of failure in previously involved sites pre-CAR T. The 2-year and 3-year overall survival (OS) rates post-CAR T were 41% and 37%, respectively. The median progression-free survival (PFS) post-CAR T was 3.1 months (95% CI: 3 months-3.8 months). Patients progressing within 6 months of CAR T infusion (n=93) showed inferior OS compared to those progressing later (n=35) (median OS of 10.7 vs. 42.0 months; p = 0.0008). The median OS was significantly higher in patients relapsing post-complete remission (n=61) than in those with refractory disease post-CAR T (n=67) (24.4 vs. 12.3 months; p = 0.03). There was no significant difference in OS or PFS post-salvage therapy start date based on the class of salvage therapy. A total of 101 sites were irradiated in 55 patients who received any salvage RT post-CAR T failure. The median dose/fractionation were 30 Gy (range, 4-50.4 Gy) and 10 fractions (range, 1-28 fractions). The 3-year in-field PFS was 62%. Seventeen sites experienced local recurrence with a median time to in-field progression of 3.5 months (IQR: 2.4-9.8 months). The median out-of-field PFS was 2.6 months (95% CI: 1.7 months - 7.5 months). There was a non-significant trend of higher in-field PFS for sites that received high-dose RT (BED10≥ 39 Gy) as compared to sites that received low-dose RT (BED10<39 Gy) (median in-field PFS: not reached vs. 11.4 months, p= 0.09). The 2-year OS and PFS rates for patients who received comprehensive RT (n=30) vs. focal RT (n=25) were 55% vs. 10% (p<0.0001), and 36% vs. 5% (p=0.001), respectively. On multivariable analysis from the salvage therapy start date, advanced-stage disease, elevated LDH, and shorter time interval from CAR T infusion to salvage therapy were independently associated with inferior OS, while response to last line of therapy (complete or partial response) was associated with superior OS. For PFS from the salvage therapy start date, advanced-stage disease and elevated LDH were independent factors associated with a shorter PFS. Conclusions: Salvage RT is associated with excellent in-field control after CAR T-cell therapy failure. Patients suitable for comprehensive RT exhibit superior survival outcomes compared to those receiving focal RT. High tumor burden at the time of salvage therapy is associated with worse outcomes. Analysis of the dose-response relationship may be limited by the number of local failures and selection bias; therefore, larger cohorts are needed to confirm our findings.