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Anti-CD19 chimeric antigen receptor T-cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B-cell non-Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life-threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre-existing sites of disease present pre-CART. Radiation therapy stands as a promising peri-CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease-free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post-CART disease alters the pattern of relapse and improves local recurrence-free and progression-free survivals. Salvage radiotherapy for relapsed post-CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri-CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART., (© 2023 Wiley Periodicals LLC.)

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

Purpose: The optimal approach to incorporate radiation therapy (RT) in conjunction with chimeric antigen receptor (CAR) T-cell therapy (CART) for relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (bNHL) remains unclear. This study documented the RT local control rate among patients who received bridging radiation therapy (BRT) before CART and compares it with those who received salvage radiation therapy (SRT) after CART. This article further reports on a promising way to use SRT for post-CART disease and identifies predictors for RT in-field recurrence., Methods and Materials: We retrospectively reviewed 83 patients with r/r bNHL who received CART and RT, either as BRT pre-CART infusion (n = 35) or as SRT post-CART infusion (n = 48), between 2018 and 2021. RT was defined as comprehensive (compRT; ie, treated all sites of active disease) or focal (focRT). Limited disease was defined as disease amenable to compRT, involving <5 active disease sites., Results: At time of RT, patients who received BRT before CART had bulkier disease sites (median diameter, 8.7 vs 5.5 cm; P = .01) and were treated to significantly lower doses (median equivalent 2-Gy dose, 23.3 vs 34.5 Gy; P = .002), compared with SRT post-CART. Among 124 total irradiated sites identified, 8 of 59 (13%) bridged sites and 21 of 65 (32%) salvaged sites experienced in-field recurrence, translating to 1-year local control rates (LC) of 84% and 62%, respectively (P = .009). Patients with limited post-CART disease (n = 37) who received compSRT (n = 26) had better overall survival (51% vs 12%; P = .028), freedom from subsequent progression (31% vs 0%; P < .001), and freedom from subsequent event (19% vs 0%; P = .011) compared with patients with limited disease who received focSRT (n = 11)., Conclusions: BRT followed by CART appears to be associated with improved LC compared with SRT in r/r bNHL. Nonetheless, SRT offers a promising salvage intervention for limited (<5 sites) relapsed post-CART disease if given comprehensively., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Analyze the pattern of disease failure after anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) for non-Hodgkin lymphoma, assess the local control rate of bridging radiotherapy (bRT) and characterize in-field recurrences., Methods: We retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020. Baseline characteristics and treatment outcomes were compared between patients who received bRT and those who did not (noRT)., Results: Of the 118 patients included, 14 (12%) received bRT, while 104 (88%) did not. bRT group had more localized and extranodal disease. bRT was delivered with a median dose of 20 Gy (range: 15-36) in 5 fractions (range: 3-24). Pattern of failure analysis revealed that progression involving pre-existing sites was the predominant pattern of failure in both the bRT and noRT groups (86% and 88%, respectively). Median duration of response was 128 days (range: 25-547) for bRT group and 93 days (range: 22-965) for noRT group (p = 0.78). In the bRT group, only 2/15 sites irradiated had infield recurrence and where characterized by bulky disease, SUV max >20, elevated LDH at the time of CART infusion, and extranodal involvement. The bRT 1-year LC was 86%. Median duration of local response was 257 days (range: 25-630) for radiation-bridged sites., Conclusion: Majority of progressions after CART infusion involve pre-existing sites. Bridging RT prior to CART provides excellent in-field local control and durable response. Patients with bulky disease, SUV max >20, elevated LDH, and extranodal involvement are likely at higher risk of in-field recurrence after bRT and may benefit from higher curative doses of bRT., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Proton therapy (PT) is a highly conformal type of radiation therapy that can target the tumor while sparing dose to surrounding normal tissues. This study reviews a single institution's experience managing patients with non-Hodgkin lymphoma (NHL) treated with PT. Eleven patients with NHL were treated with PT from January 2008 to January 2014 on an institutional review board-approved outcomes tracking protocol, and included patients with indolent orbital lymphoma (n = 4), primary mediastinal B-cell lymphoma (n = 3), plasmablastic lymphoma (n = 2) and natural killer (NK) T-cell lymphoma (n = 2). The median follow-up was 38 months. The 2-year rate of local control was 91%, with one patient with NK T-cell lymphoma having recurrence in-field. Toxicities were limited to grade 2 at highest, during follow-up. PT is a feasible and effective treatment for NHL. Early outcomes are favorable. Longer follow-up and more patients are needed to confirm our findings.

Hodgkin lymphoma and non-Hodgkin lymphoma are common hematologic malignancies with such a favorable prognosis that many survivors live decades after combined chemotherapy and radiotherapy. These survivors, however, are at risk of developing late treatment adverse effects from collateral damage, including secondary malignancies, cardiac toxicities, and ischemic heart diseases. Recent efforts have successfully reduced the radiation dose and treatment field without compromising cure rates. Proton therapy has the potential of further lowering the treatment-related toxicity owing to its ability to deposit a high dose only at the target. Although this finding has been supported by several current dosimetric studies, its utilization in the management of lymphoma has been limited during the past 5 years because of the paucity of facilities and the difficulty of obtaining insurance coverage. With diligent follow-up, the clinical impact of proton therapy will be established to improve the therapeutic ratio and to reduce late treatment-related morbidity.

Purpose: To compare the efficacy and toxicity of external-beam radiotherapy (EBRT) to sites of bulky lymphadenopathy in patients with chemotherapy-refractory low-grade non-Hodgkin's lymphoma (NHL) immediately before receiving Bexxar (tositumomab and (131)I) vs. in patients receiving Bexxar alone for nonbulky disease., Methods and Materials: Nineteen patients with chemotherapy-refractory NHL were treated with Bexxar at our institution (University of Florida, Gainesville, FL) from 2005 to 2008. Seventeen patients had Grade 1-2 follicular lymphoma. Ten patients received a median of 20 Gy in 10 fractions to the areas of clinical involvement, immediately followed by Bexxar (EBRT + Bexxar); 9 patients received Bexxar alone. The median tumor sizes before EBRT + Bexxar and Bexxar alone were 4.8 cm and 3.3 cm, respectively. All 5 patients with a tumor diameter >5 cm were treated with EBRT + Bexxar. A univariate analysis of prognostic factors for progression-free survival (PFS) was performed., Results: The median follow-up was 2.3 years for all patients and 3.1 years for 12 patients alive at last follow-up. Of all patients, 79% had a partial or complete response; 4 of the 8 responders in the EBRT + Bexxar group achieved a durable response of over 2 years, including 3 of the 5 with tumors >5 cm. Three of 9 patients treated with Bexxar alone achieved a durable response over 2 years. Actuarial estimates of 3-year overall survival and PFS for EBRT + Bexxar and Bexxar alone were 69% and 38% and 62% and 33%, respectively. The median time to recurrence after EBRT + Bexxar and Bexxar alone was 9 months. Having fewer than 4 involved lymph-node regions was associated with superior PFS at 3 years (63% vs. 18%). There was no Grade 4 or 5 complications., Conclusions: Adding EBRT immediately before Bexxar produced PFS equivalent to that with Bexxar alone, despite bulkier disease. Hematologic toxicity was not worsened. EBRT combined with Bexxar adds a safe and effective therapeutic treatment for managing recurrent low-grade follicular NHL., (Copyright © 2012 Elsevier Inc. All rights reserved.)