Radiation Therapy as a Bridging Strategy for CAR T Cell Therapy With Axicabtagene Ciloleucel in Diffuse Large B-Cell Lymphoma

Abstract

Purpose: Axicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel. Methods and Materials: Between December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with “double hit” lymphoma and 6 of 12 with may be required for lymphoma control during manufacture. In our case series, no significant toxicities were identified during bridging radiation and no patient experienced in-field progression of disease before CAR T infusion. These data suggest radiation is a well-tolerated and effective bridging therapy, warranting further prospective study for optimization. disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6–36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1–12.0 months). Results: No significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL). Conclusions: Radiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy.

Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma

“…In the RT field. 6 In the current study, median dose was 35 Gy, with a smaller median fraction size of 2.5 Gy, without an apparent impact of dose on PFS. For DLBCL patients treated with salvage RT, doses .40 Gy may improve local control.…”

“…Often oncologists address this dilemma with bridging therapy (BT; commonly referred to as therapy administered after apheresis and before CAR T-cell infusion), which may include steroids, chemotherapy, targeted therapy, or radiation therapy (RT). 5,6 However, the ZUMA-1 trial that led to axi-cel approval did not permit the administration of BT other than dexamethasone. 1 It is unclear if BT adversely affects outcome.…”

“…7 Although the long-term durability of RT response for chemotherapy-refractory LBCL is moderate, in the bridging setting, RT can effectively address burdensome disease and may improve outcomes when coupled with cellular therapy. 6,[8][9][10] RT has been shown to enable presentation of tumor-associated antigens for the priming of antigen-specific T cells, facilitate homing of antigenspecific T cells, and augment effector function and proliferation of native and adoptively transferred T cells. 11 Preclinical data in a pancreatic adenocarcinoma model suggest that RT conditioning may promote susceptibility to CAR therapy and decrease antigennegative tumor relapse.…”

Understanding and Managing Large B Cell Lymphoma Relapses after Chimeric Antigen Receptor T Cell Therapy

“…This has been described in cell lines and solid tumors. Recently, the outcomes of 8 patients who were treated with radiation therapy while waiting for CAR T cell manufacturing showed that the approach is a safe and effective method of obtaining local disease control, suggesting that post-CAR T radiation similarly might be safe [68]. Data supporting the role of radiation therapy in hematologic malignancies before CAR T cell therapy are limited.…”

Don't Get Stuck on the Shoulder: Radiation Oncologists Should Get Into the CAR With T-Cell Therapies

“…In the current issue of the International Journal of Radiation Oncology, Biology, Physics, Sim et al retrospectively report their experience using radiation therapy to help bridge 12 patients who were planned for axi-cel as they awaited availability of their personalized CAR T-cell products. 7 Although ZUMA-1, the registrational trial for axi-cel, did not permit bridging therapy, the authors point out that bridging is commonly used with commercial standard of care axi-cel. 5,8 The majority of the patients in their series were in desperate condition, with 2 to 5 (median 2) prior lines of therapy, 8 out 12 with bulky (10 cm) disease, and 6 of 12 with double hit lymphomas.…”