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This study sought to assess whether there is a radiotherapy (RT) dose response for bulky tumors in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Patients with r/r DLBCL (age ≥18 years) treated with salvage- or palliative-intent RT (2008-2020) at a single institution were included. Course-level data were examined to assess in-field responses of index lesions. Courses used for either post-therapy consolidation, CNS or skin disease, and TBI conditioning were excluded. Index lesion size ≥7.5 cm was considered bulky. EQD2s (α/β = 10) were calculated to accurately compare biologic effective doses between conventional and hypofractionated (≥2.5 Gy/fraction) schemes. Post-treatment responses of index lesions were classified using Lugano Criteria. Objective response rates (ORR), defined as achieving either CR or PR, were compared between non-bulky and bulky tumors using Fisher's exact test. Freedom from local progression (FFLP) and overall survival (OS, patient-level data) from RT start date were recorded. Bulky disease impacts on FFLP and OS were assessed using Kaplan-Meier and multivariable-adjusted Cox proportional hazard regression analyzes. 151 r/r DLBCL patients underwent 183 RT courses (median follow-up time: 6 months, IQR: 2-17 months). Median age at RT was 67 years (IQR: 56-72 years) with a male/female ratio of 55%/45%. Non-bulky and bulky tumors were treated in 109 (60%) and 74 (40%) cases, respectively. Intent was classified as salvage or palliative in 68 (37%) and 115 (63%) cases, respectively. Median EQD2 was 33 Gy (IQR: 23-39 Gy) with hypofractionation used in 84 (46%) cases. Of those with post-RT imaging (n = 146, 80%), there was a trend towards lower ORR for bulky vs. non-bulky tumors (50% vs. 65%, p = 0.087; CR: 21% vs. 42%, PR: 29% vs. 23%, SD: 28% vs. 14%, PD: 22% vs. 22%). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs. >30 Gy: 27% vs. 64%, p = 0.014), whereas a lower EQD2 cut-off was sufficient for non-bulky tumors (<20 Gy vs. ≥20 Gy: 38% vs. 73%, p = 0.0076). In all courses, bulky tumors were significantly associated with shorter FFLP (median: 5.6 months vs. not reached, HR = 2.30, 95% CI: 1.24-4.26, p = 0.0079) and OS (median: 3.7 vs. 10.1 months, HR = 1.66, 95% CI: 1.06-2.58, p = 0.025). Amongst bulky tumors, there was a trend towards improved FFLP with RT regimens with higher EQD2s (20-30 Gy vs. <20 Gy - median: 4.2 vs. 2.3 months, HR = 0.38, 95% CI: 0.09-1.62, p = 0.19; >30 Gy vs. <20 Gy - median: not reached vs. 2.3 months, HR = 0.34, 95% CI: 0.11-1.01, p = 0.053). In this study, bulky r/r DLBCL tumors were associated with less favorable outcomes in salvage and palliative settings. If durable local control of bulky tumors is needed, RT regimens using higher EQD2s (>30 Gy) should be considered, including cases where shortened, hypofractionated courses are opted for such as during the SARS-CoV-2 pandemic, bridging to CAR-T cell infusion, or prior to allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

CD19-targeting chimeric antigen receptor T-cell (CART) therapy is an effective treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL). However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may limit applicability and typically require hospitalization for toxicity management. Bridging radiotherapy (RT) may be used to debulk tumor burden or maintain performance status prior to CART therapy infusion, but associations with CRS and ICANS remain unclear. We assessed associations of bridging RT with CRS and ICANS among a cohort of patients (pts) receiving commercial CART therapy. 94 pts receiving tisagenlecleucel (n=66) or axicabtagene ciloleucel (n=28) for r/rABL between April 2018 and June 2020 at a single institution were retrospectively identified. 22 pts (23%) received bridging RT (B-RT group) and 72 (77%) did not (NB-RT group). CRS was graded with ASTCT and ICANS with CTCAE v5.0. Grade ≥2 CRS (CRS2) and grade ≥2 ICANS (ICANS2) were compared between B-RT and NB-RT groups using Fisher exact test. Logistic regression was used to assess associations of patient characteristics, tumor bulk metrics (metabolic tumor volume [MTV], largest lesion max diameter [LLMD], and total lesion glycolysis [TLG]), and bridging therapy with CRS2 and ICANS2. B-RT group had better performance status (ECOG ≥1 41% vs 68%, p=0.027) and numerically but not significantly higher MTV (median 42.6mL vs 15.2, p=0.38), LLMD (median 5.8cm vs 3.5, p=0.12), and TLG (median 298.3 mL*SUV vs 60.8, p=0.22). Median B-RT dose was 31 Gy (IQR 20-40), most commonly in 2-2.5 Gy/fraction (n=17, 77%). Grade 1, 2, and 3 CRS occurred in 27 (29%), 19 (20%), and 5 (5%) pts, respectively. Grade ≥2 CRS occurred in 4/22 pts (18%) in B-RT group vs 20/72 pts (28%) in NB-RT group (p=0.16). Univariate analysis revealed associations between the following and CRS2: MTV (odds ratio [OR] 1.02 per 10 mL, p=0.025), LLMD (OR 1.12, p=0.01), largest lesion ≥5 cm (OR 2.98, p=0.046) and TLG (OR 1.02 per 100 mL*SUV, p=0.014), but not B-RT (OR 0.58, p=0.37), bridging systemic therapy (B-ST) (OR 1.33, p=0.56) or ECOG ≥1 (OR 1.33, p=0.56). Grade 1, 2, 3, and 4 ICANS occurred in 11 (12%), 6 (6%), 5 (5%), and 2 (2%) pts, respectively. Grade ≥2 ICANS occurred in 1/22 pts (5%) in B-RT group vs 12/72 pts (17%) in NB-RT group (p=0.29). Univariate analysis revealed associations between the following and ICANS2: MTV (OR 1.02 per 10 mL, p=0.048), TLG (OR 1.02 per 100 mL*SUV, p=0.017), and a trend for ECOG ≥1 (OR 3.98, p=0.085), but not B-RT (OR 0.24, p=0.18) or B-ST (OR 1.22, p=0.75). In this single-institution study, bridging RT was used for good performance status pts with bulky tumors and was associated with low rates of CRS and ICANS. An ongoing multi-institutional effort will help refine predictive models for these toxicity endpoints and further elucidate the role of bridging RT. [ABSTRACT FROM AUTHOR]

CD19-targeted chimeric antigen receptor (CAR) T cells have transformed the treatment of patients with relapsed or refractory CD19-positive hematologic malignancies. However, a significant subset of these patients either fails to respond or eventually relapses. Moreover, patients who are candidates for CART-19 therapy often have symptomatic disease that requires some form of treatment to support them during the manufacture period. An ideal bridging therapy would simultaneously both (1) sensitize the tumor to CART-19 attack to increase antitumor control and (2) debulk the disease during manufacture. Radiotherapy (RT) is an established curative and palliative cancer treatment regimen, with approximately half of cancer patients with solid tumors receiving RT sometime during their disease. Several reports have underscored the existence of threshold doses (and regimens) that are able to switch on different damage programs that profoundly affect responses to therapy by eliciting potent immune modulatory effects, prompting immunologically mediated tumor cell death. These effects have been attributed to multiple pathways, including the activation of the cGMP-cAMP Synthetase (cGAS), Stimulator of Interferon Genes (STING) pathway with Type I Interferons expression, and tumor associated antigen (TAA) cross priming with anti-tumor CD8+ T cell elicitation, ultimately inducing "abscopal" effects. By virtue of the immunomodulatory effects of RT, we hypothesize that RT could serve as a successful bridging strategy for CAR T-cell therapy. To investigate this hypothesis, we established the A20 Lymphoma CART-19 therapy mouse model in our lab and used it to perform preliminaries experiments. A20 cells were implanted into both flanks of the animals. Mimicking human immune adjuvant doses used in our institute for RT bridging, 20 days after tumor cell implantation, we radiated one of the two tumors using a dose of 8Gy divided in two fractions of 4Gy each. Twenty-four hours later 1 × 10ep6 CART-19 cells were infused intravenously. While the effects of RT in combination with CART-19 have similar impact on the tumor growth of the irradiated mass, a significant increase of the antitumor effects of the single therapy was observed on the non-irradiated tumor. FACS studies demonstrated heavy leukocyte infiltration with increased presence of infused CART-19 as well indigenous T cells. To investigate possible molecular mechanisms involved in the increased effects on the non-irradiated tumor, we performed a qPCR array and observed increased expression of genes linked to cross priming, including IFN type I and Batf3. A20 cells express the ectopic retroviral antigen gp70 with well characterized AH1 immune-dominant epitope. AH1 tetramer staining on infiltrating T cells demonstrated increased staining in tumor from mice treated with the combination. Overall these results suggest RT may serve as optimal debulking and bridging therapy for CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

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]

Purpose/objective(s): To identify the patient characteristics, treatment indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at a tertiary academic medical center.Materials/methods: A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010-2019. Follow-up was calculated from start of PBT until death or last follow-up. Treatment intent was retrospectively defined as curative treatment for localized disease, for isolated local recurrence, oligometastatic disease, durable local control, or palliation of symptoms. Durable local control was defined as treatment for durable control of otherwise incurable disease whereas palliation was defined as treatment for symptom palliation only. Acute (< 3 months) and chronic (> 3 months) toxicities were graded using the CTCAE v5.0. Chi-square test was performed to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with any acute toxicity.Results: During the study period, 299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Mean age was 66 years (19-94 years), with 58% male. The most common cancers were non-small cell lung cancer (27%), hepatocellular carcinoma (13%), and small cell lung cancer (6%). Eleven percent of patients were treated for symptom palliation; the remainder were treated for durable local control (57%), definitively (16%), for an isolated local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received PBT for re-irradiation. Concurrent systemic therapy was delivered to 47%. Median prescribed dose was 50 Gy (15-80 Gy). Mean treatment time was 34 days (1-189 days). Seven patients received split-course proton therapy for hepatocellular carcinoma. Median time from final fraction to death was 139 days (1-363 days). On average, patients spent 24% of the remaining days of life receiving PBT. Acute toxicity of any grade was noted in 85% of patients (31% G1, 53% G2, 15% G3). Fifty-two patients (17%) experienced chronic toxicity, the most severe of which was a tracheo-esophageal fistula (G4). In the chi-square test, breast and hematologic malignancy were associated with palliative intent (χ2 (1, N = 14) = 15.9, P < 0.001; (χ2 (1, N = 14) = 15.9, P < 0.001). In the simple logistic regression model, concurrent systemic therapy was positively associated with any acute toxicity (OR: 2.0, P = 0.05).Conclusion: The number of patients treated with PBT at the EOL was low compared to all-comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Nearly half received re-irradiation. Grade 3 or higher acute toxicity was moderate, and some patients spent a large portion of their remaining days on treatment. Thus, the incorporation of a prognostic indicator in clinical practice may further optimize use of PBT. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): CD19-directed CART therapy has emerged as a promising treatment for relapsed/refractory non-Hodgkin lymphoma. However, sustained efficacy is limited with durable complete response rates of 40% (Schuster & Locke, 2019). Salvage radiotherapy (SRT) is potentially an important strategy post-CART, but current data is limited to one series of 14 patients.Materials/methods: We retrospectively analyzed 21 patients who received SRT after commercial CART therapy between 8/2018 and 6/2020. Patients who relapsed after CART were divided into two groups: locoregional disease (LD, all relapsed disease encompassable within an RT field) and advanced disease (AD). SRT was defined as comprehensive (treated all sites of active disease) or focal. Post-SRT in-field objective response rates (ORR) were recorded according to Deauville or RECIST criteria with a response characterized as a complete response or partial response. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Acute RT toxicity was graded by CTCAEv5.Results: Median time from CART infusion to SRT was 4.0 months (m) (range, 0.6-11.6m). Within the LD group, 8/9 patients were treated with comprehensive SRT (median SRT dose 37.5 Gy, range 8-45 Gy, and number fractions 15, range 2-25 fractions). The in-field ORR was 8/9 (89%). For the AD group, 12/12 patients were treated with focal SRT (median SRT dose 20.8 Gy, range 8-30 Gy, and number fractions 5, range 1-12 fractions). 11/12 AD patients were treated with hypofractionated SRT (≥2.5Gy fractions). Three patients died prior to subsequent imaging with an ORR of 8/9 (89%) for the remaining evaluable patients. Distant progression occurred in 17/18 patients post-SRT (Table). Three-month PFS was 24% for the entire cohort, and 33% and 17% for the LD and AD groups, respectively (P = 0.258). Median OS was 7.4m for the entire cohort, and 21.1m and 2.4m for the LD and AD groups, respectively (P < 0.001). Grade 1 (G1) and G2 acute SRT toxicities occurred in 10 and 4 patients, respectively. No G3 or higher toxicities occurred.Conclusion: SRT post-CART therapy appears safe (no ≥G3 RT toxicities) in our series. SRT led to an ORR of 89% with only 1 observed local relapse. Patients with LD relapse post-CART had significantly improved survival compared with AD relapse. Unfortunately, prognosis remains poor as 17/18 patients with evaluable imaging progressed outside of the RT field. Thus, prolonged RT courses may not be warranted given the practical inevitability of out of field disease progression. Multi-institutional review of SRT following CART is warranted to further elucidate the impact of RT dose and fractionation on disease outcomes. [ABSTRACT FROM AUTHOR]