Role of Radiotherapy for Patients With Refractory Lymphoma Receiving CAR T-Cell Therapy

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Although the role of radiotherapy in chimeric antigen receptor (CAR) T-cell therapy for lymphoma is still evolving, radiotherapy “would be an ideal bridging therapy” for patients with chemorefractory diffuse large B-cell lymphoma, stated George Mikhaeel, MD, Professor of Radiation Oncology and Consultant Clinical Oncologist at Guy’s Cancer Centre, London, at the 2019 American Society for Radiation Oncology (ASTRO) Annual Meeting in Chicago. “Radiotherapy still works when chemotherapy stops working,” Dr. Mikhaeel said. “It can hold the disease under control and also control symptoms.”

CAR T-cell therapy is the most important improvement in the therapeutic scene for diffuse large B-cell lymphoma in a long time.
— George Mikhaeel, MD

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Dr. Mikhaeel served as a discussant of the ASTRO science highlights session on hematologic cancers. Abstracts reviewed during that session found that radiotherapy may be used to safely stabilize patients before CAR T-cell therapy, increasing the efficacy and reducing the toxicity associated with the immunotherapy.

Improving Efficacy and Reducing Toxicity

“CAR T-cell therapy is the most important improvement in the therapeutic scene for diffuse large B-cell lymphoma in a long time,” Dr. Mikhaeel noted. “It is quite intensive treatment requiring delivery in specialized centers. It is toxic and expensive; and it doesn’t actually work in many patients—just about 40% or so have durable responses beyond 1 year.”

The manufacturing process takes several weeks, during which the disease can progress and patients may become unwell and unable to get the treatment. Bridging therapy could increase the percentage of patients benefiting from CAR T-cell therapy by stabilizing those who are symptomatic, are chemorefractory, or can no longer tolerate chemotherapy while they await CAR T-cell therapy. “That can be a long wait,” Dr. Mikhaeel explained. For instance, in England, the National Health Service funds the treatment through a national approval process, and the pathway of approval to manufacturing can take 6 to 10 weeks. During this time, many patients will experience disease progression. “This is where radiotherapy may play an important role,” he added.

Radiotherapy may play other roles in CAR T-cell therapy. “We are also starting to understand that cytokine-release syndrome, which is the main toxicity, is related to the bulk of the disease; by debulking the tumor with radiotherapy, you may reduce the cytokine-release syndrome,” Dr. Mikhaeel stated. “There is also the immunomodulatory effect of radiotherapy, which could potentiate the effect of CAR T cells and help their trafficking, persistence, expansion, and activity in the tumor.”

In a study of 31 patients with relapsed or refractory non-Hodgkin lymphoma,1 treated with either of two CAR T-cell therapies approved by the U.S. Food and Drug Administration—tisagenlecleucel (13 patients) or axicabtagene ciloleucel (18 patients)—there was no grade 3 or higher cytokine-release syndrome events nor neurotoxicity among patients who received radiotherapy up to 30 days before CAR T-cell therapy.

Conducted at the University of Pennsylvania, the study included 19 patients who received no radiotherapy, 7 patients who received radiotherapy at least 30 days before CAR T-cell infusion (nonbridging), and 5 who received induction radiotherapy up to 30 days before CAR T-cell infusion (bridging). “This was a mixed bag of patients,” Dr. Mikhaeel noted, with different treatments and techniques used and a range of doses. “The assortment was representative of the various ways refractory disease presents itself.”

No Survival Decrement

“There was no grade 5 cytokine-release syndrome nor neurotoxicity, no grade 4 cytokine-release syndrome, and the only grade 4 neurotoxicity was found in the cohort that did not receive radiotherapy. The radiated cohort did not have any of that,” Dr. Mikhaeel said.

The reduced toxicity among patients receiving induction radiotherapy up to 30 days before CAR T-cell infusion came “with no decrement in overall or progression-free survival,” the study abstract noted. “Induction radiotherapy may safely and effectively be used to clinically stabilize patients, and in conjunction with cytotoxic chemotherapy, for bridging and cytoreduction, facilitating the use of less toxic chemotherapy regimens to allow sufficient CAR T-cell expansion,” the authors concluded. They recommended additional studies to test these hypotheses.

Patterns of Recurrence

Another study looked at patterns of recurrence among patients with lymphoma treated with CAR T-cell therapy and what might predict those patterns.2 “A large number of patients relapse. Up to 60% of patients develop disease progression after CAR T-cell therapy,” Dr. Mikhaeel noted. “Where do they relapse? And is there a role for local treatment?”

The study included 26 patients who experienced disease progression after CAR T-cell therapy—22 with diffuse large B-cell lymphoma and 4 patients with transformed follicular lymphoma. “Disease burden and lesion-specific disease characteristics were quantified by pretreatment positron-emission tomography/computed tomography and compared with serial post-treatment images to characterize patterns of recurrence, including the timing and location of recurrent disease,” the researchers at Moffitt Cancer Center in Tampa, Florida, wrote. “Progression of existing pretreatment disease sites was considered a local failure, while the development of new, nonoverlapping disease sites was considered distant failure.”

‘Staggering’ Result

The result “is quite staggering,” Dr. Mikhaeel remarked: “A total of 96% of patients [25 of 26] had an element of local disease progression in their relapse.” Only one patient had disease progression in a new and distant site. Twelve patients (46%) had local disease progression alone, and 13 patients (50%) had local and distant disease progression.

Bridging radiotherapy [to CAR T-cell therapy] is feasible and safe. It seems to reduce CAR T-cell toxicity, although many questions remain.
— George Mikhaeel, MD

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Of the 243 distinct disease sites identified on pretreatment imaging, nearly half (47%) had progressed at the time of overall treatment failure. Nearly all patients who failed to respond to CAR T-cell therapy had recurrences at involved disease sites at 6 months. 

“Disease sites with high metabolic activity and lesions ≥ 2 cm2 in a cross-sectional area or ≥ 20 cc in metabolic volume are at increased risk of disease progression after CAR T-cell therapy. All necrotic lesions progressed at the time of failure,” the researchers noted. They concluded: “Patients with disease sites that have high-risk features may benefit from the addition of local treatment, such as involved-site radiotherapy, particularly those with large lesions, high maximum standardized update values, and clustered lesions.”

“That is an interesting and important finding,” according to Dr. Mikhaeel, “making a case perhaps for adding local treatment, not just for bridging, but also to help the long-term control of disease that is refractory and might relapse after CAR T-cell therapy with a high proportion.”

Future Role of Radiotherapy

So, what do these studies mean in terms of the future role of radiotherapy in CAR T-cell therapy? “We can say that bridging is feasible and safe,” said Dr. Mikhaeel. “It seems to reduce CAR T-cell toxicity. Many questions remain—the optimal timing, the volume, the dose/fractionation.” Additional questions center on understanding the other potential effects of radiotherapy, such as priming and lymphodepletion

DISCLOSURE: Dr. Mikhaeel reported no conflicts of interest.


1. LaRiviere MJ, Wright CM, Arscott WT, et al: Induction radiation prior to commercial chimeric antigen receptor T-cell therapy for relapsed/refractory non-Hodgkin lymphoma. Int J Radiat Oncol Biol Physics 105:S66, 2019.

2. Figura NB, Jain MD, Sim AJ, et al: Patterns of failure following chimeric antigen receptor T-cell therapy. Int J Radiat Oncol Biol Physics 105:S66-S67, 2019.