Dr Plastaras saw the results as complimentary to several recent studies that have shown encouraging results bridging CAR-T patients with radiation therapy in other hematological malignancies. One study by Dr Pinnix and her colleagues compared different bridging approaches in nearly 150 relapsed/refractory large B-cell lymphoma (LBCL) patients who underwent leukapheresis for a planned axi-cel infusion.2 In that study, patients bridged with radiation had improved 1-year progression free survival compared with those bridged with systemic therapy, most of which received cytotoxic chemotherapy. A smaller study suggested that radiation is safe as a bridging therapy to axi-cel in patients with highly aggressive diffuse LBCL.3

Radiation may be effective in temporizing life-threatening lymphoma during the CAR-T manufacturing process for patients who have relapsed or progressed on systemic therapies, since the mechanisms underlying resistance to those therapies tend to be different than those underlying resistance to radiation, Dr Plastaras said. The most notable advantage may be for patients with chemorefractory disease, Dr Pinnix added, noting studies suggesting that patients with relapsed/refractory LBCL have an overall response rate (ORR) greater than 80% with radiation therapy.4

She added that radiation can rapidly palliate painful or symptomatic sites of disease, and targeted, contemporary approaches can limit exposure of normal tissue in the process. Radiation comes with challenges, however, such as deciding at which dose and how much lymphoma to radiate, Dr Plastaras noted. “That’s an open clinical question whether patients do better if you radiate all of their disease vs less than all of their disease . . . These are the types of clinical questions that we want to answer through research.”


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To Dr Plastaras, his data warrant further investigation into the hypothesis that radiation could decrease the severity of cytokine release syndrome (CRS) upon receipt of CAR-T cells by decreasing the volume of malignant cells. Some studies have reported an association between high tumor burden and the severity of CRS.5 “If patients go into CAR T-cell therapy with a smaller amount of lymphoma that’s active, then there will be a less sort of cataclysmic reaction to the lymphoma by the CAR T cells, and all of the cytokines that get released should hopefully be less.”

To find out, he’s collaborating with other members of the International Lymphoma Radiation Oncology Group on a larger, multi-institutional retrospective review of patients on commercially available CAR-T therapies to investigate the effect of bridging with radiation on disease control and on subsequent toxicities under CAR-T therapy, Dr Plastaras said. The second goal will be to investigate whether bridging with radiation can “modify the risk [of CRS] based on the amount of disease you have.”

“If bridging RT resulted in effective tumor debulking, this could be a mechanism by which the incidence or severity of CRS or [immune effector cell-associated neurotoxicity syndrome] could be reduced,” added Dr Pinnix.

References

  1. Wright C, Anstadt E, Baron J et al. Impact of radiotherapy on hospitalization burden surrounding chimeric antigen receptor T-cell therapy in patients with relapsed/refractory non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2020;108(2):supplement E51-E52. doi:10.1016/j.ijrobp.2020.02.590
  2. Pinnix CC, Gunther JR, Dabaja BS et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv. 2020;4(13):2871-2883. doi:10.1182/bloodadvances.2020001837
  3. Sim AJ, Jain MD, Figura NB et al. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-Cell lymphoma. Int J Radiat Oncol Biol Phys. 2019;105(5):P1012-1021. doi:1016/j.ijrobp.2019.05.065
  4. Tseng YD, Chen Y, Catalano PJ et al. Rates and durability of response to salvage radiation therapy among patients with refractory or relapsed aggressive non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2015;91(1):223-231. doi:10.1016/j.ijrobp.2014.09.041
  5. Maziarz RT, Schuster S, Ericson S, et al. Cytokine release syndrome and neurotoxicity by baseline tumor burden in adults with relapsed or refractory diffuse large B-cell lymphoma treated with tisagenleucleucel. Hematol Oncol. 2019;37(S2):307. doi:10.1002/hon/117_2630