Incorporating radiation with anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory non-Hodgkin lymphoma: A multicenter consensus approach

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. Radiation can be incorporated with anti-CD19 chimeric antigen receptor T-cell therapy (CART) in the bridging, consolidation, and salvage setting. Prior to CAR T-cell infusion, patients with limited pre-CART disease are encouraged to receive comprehensive bridging radiation to a definitive dose, if possible, while those with diffuse pre-CART disease are encouraged to receive focal low dose/short course of bridging radiation. Post CAR T-cell infusion, patients with limited residual fluorodeoxyglucose activity/disease on Day +30 and patients with limited relapsed post-CART disease are encouraged to receive comprehensive consolidative and salvage radiation, respectively. However, patients with diffuse relapsed post-CART disease are likely to proceed with a subsequent line of systemic therapy +/- palliative radiation. CT, computed tomography scan; EQD2, equivalent 2 Gy dose using an alpha/beta ratio of 10; FDG, fluorodeoxyglucose.image