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Presence of MYC, BCL2 , and/or BCL6 translocations (i.e., double/triple-hit lymphoma [DHL/THL]) among patients with large cell lymphoma (LCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy. This retrospective, multi-institutional, international cohort included 211 patients with LCL and known DHL/THL status, who received RT in the relapsed/refractory (r/r) setting. Only the first RT course was included. Separate analyses were conducted for curative versus palliative intent. Response was defined as a radiographic or clinical complete or partial response (PR). Primary chemorefractory disease was defined as less than a PR to initial chemotherapy. Predictors for response and local recurrence (LR) were evaluated using Cox regression analysis. LR analyses and estimates were restricted to patients treated with curative intent to ensure adequate follow-up (median 39.6 months among surviving patients). Patients were heavily pretreated prior to RT (25% stem cell transplant, 8.5% CART, 41% >2 lines of therapy); 49% were irradiated with curative intent. Most patients (90% curative, 100% palliative) had macroscopic disease at RT. Response rates were similar among those with versus without DHL/THL pathology: 71.4% vs 81.2% (curative), 54.5% vs 64.7% (palliative). DHL/THL was not associated with response on univariate analysis in either the curative (HR 1.03, 95% CI 0.58-1.84, p=.91) or palliative setting (HR 1.42, 95% CI 0.73-2.76, p=.29). In contrast among patients irradiated with curative intent, presence of DHL/THL pathology was associated with increased LR risk (HR 2.38, 95% CI 1.15-4.92, p=.02), controlling for primary chemorefractory disease and radiation biologically effective dose (BED10). LR at 6 and 12 months was 21% and 30% among non-DHL/THL and 41% and 45% among DHL/THL, respectively. R/R LCL is radioresponsive. Though presence of DHL/THL pathology does not appear to impact RT response , it is associated with increased LR risk, suggesting that it may influence radiation sensitivity. These findings require confirmation in other cohorts. [ABSTRACT FROM AUTHOR]

To report an ILROG multi-institutional analysis of bridging radiotherapy (BRT) prior to CD19-targeting chimeric antigen receptor T-cell (CAR T) therapy for relapsed/refractory aggressive B-cell lymphomas (BCL). Weretrospectively reviewed 115 patients (pts) with diffuse large BCL (n = 101, 88%), primary mediastinal BCL (n = 11, 10%), mantle cell lymphoma (n = 2, 2%), and T-cell/histiocyte rich large BCL (n = 1, 1%) who received BRT prior to commercial CAR T from 2018-2020 across 6 institutions. BRT toxicities were graded per CTCAE v5.0, cytokine release syndrome (CRS) per ASTCT, and immune effector cell-associated neurotoxicity syndrome (ICANS) per either ASTCT or CTCAE v5.0. Progression-free survival (PFS) and overall survival (OS), measured from CAR T infusion, were estimated using the Kaplan-Meier method. PFS was modeled using Cox regression with stepwise variable selection. BRTwas given prior to axicabtagene ciloleucel (axi-cel; n = 82, 71%), tisagenlecleucel (tisa-cel; n = 31, 27%), or brexucabtagene autoleucel (n = 2, 2%). Median age was 62 years with median of two prior lines of therapy. Most pts had advanced stage III/IV disease at leukapheresis (n = 87, 76%), elevated pre-leukapheresis LDH (n = 73, 63%), and bulky disease (n = 55, 50%) (1 lesion ≥7.5 cm). 78 pts (68%) had extranodal disease, 12 (10%) had central nervous system (CNS) involvement, and 36 (31%) had bone involvement. Systemic bridging therapy was given to 42 pts (37%). Median intervals from leukapheresis to BRT start and from BRT completion to CAR T infusion were 5 days (IQR -6, 11) and 12 days (IQR 9, 23), respectively. BRT was delivered to 163 total sites; most commonly the abdomen/pelvis (n = 58, 50%), head/neck (n = 34, 30%), thorax (n = 20, 17%), extremity/soft tissue (n = 20, 17%), and CNS (n = 13, 11%). Median biologically effective dose was 31.3 Gy (IQR 24, 39). Most common regimen was 30 Gy in 10 fractions (n = 27, 17%). 40 pts (35%) received comprehensive BRT (to all active lesions). There were no grade ≥3 BRT toxicities. Grade ≥3 CRS occurred in 9 pts (8%), including 8/82 (10%) after axi-cel and 1/31 (3%) after tisa-cel. Grade ≥3 ICANS occurred in 23 pts (20%), including 22/82 (27%) after axi-cel and 1/31 (3%) after tisa-cel. Median follow up was 26.9 months. 1- and 2-year OS rates were 60% and 49%. 1- and 2-year PFS rates were 41% and 35%. Comprehensive BRT associated with superior PFS (HR 0.34, 95% CI 0.19-0.62, p<0.001) in a multivariable model with age ≥60, ECOG ≥2, advanced stage, CNS disease, pre-leukapheresis LDH, and axi-cel. In this multi-institutional study, pts receiving BRT prior to CAR T therapy for BCL frequently had bulky disease yet experienced favorable PFS and OS. There were no serious toxicities attributable to BRT, and the rates of CRS and ICANS are comparable to those after CAR T alone. Comprehensive BRT associated with superior PFS. [ABSTRACT FROM AUTHOR]