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.

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While selective BRAF inhibitors have demonstrated improved outcomes in patients with metastatic BRAF V600E mutant melanoma, management of brain metastases prior to and during therapy presents challenges. Stereotactic radiosurgery (SRS) is an effective treatment for melanoma brain metastases, but there is limited safety and efficacy data on the use of SRS during BRAF therapy. An analysis was performed of patients with metastatic melanoma and brain metastases treated with SRS while on vemurafenib. MRI scans were reviewed post-SRS to evaluate local control (LC) as well as distant control. We identified 80 metastatic melanoma brain lesions treated in 24 patients. The median planning target volume was 0.28 cm(3) (range 0.05-4.19 cm(3)), and lesions were treated to a median dose of 24 Gy (range 15-24 Gy). The median follow up was 5.1 months (range 2-25.2 months). Eight (10 %) lesions showed progression at a median of 6.1 months (range 2-20.1 months) following SRS. Kaplan-Meier LC estimates at 6 and 12 months were 92 and 75 %, respectively. Fourteen (58 %) patients were noted to have distant brain failure at a median of 3.4 months (range 1.9-16.1 months) following treatment with SRS. Median overall (OS) from the date of SRS was 7.2 months (range 1.5-26.8 months) with a median of 11.9 months (range 1.5-28.5 months) since the date of brain metastases diagnosis. There was no evidence of increased toxicity with the combination of SRS and vemurafenib. SRS to brain metastases appears to be both safe and effective for patients treated concurrently with BRAF inhibitors.

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Following surgical resection for brain metastases, fractionated stereotactic radiotherapy (FSRT) has been used as an alternative to single dose treatment for large cavities and to reduce risks of late toxicity. The purpose of this study was to evaluate the outcomes of patients treated with FSRT to the post-operative bed for both radioresistant and radiosensitive brain metastases. Between December 2009 and May 2013 a total of 65 patients with newly diagnosed brain metastases were treated with resection followed by FSRT. Patients were treated to a total dose of 20-30 Gy in five fractions. Median planning target volume (PTV) was 16.88 cm(3) (range 4.87-128.43 cm(3)). The median follow-up for all patients was 8.5 months (range 1.1-28.6 months) with a median of 12.9 months for living patients. One and two year Kaplan-Meier estimates of local control were 87.0 and 70.0 %, respectively. Local control at 1 year was 85.6 and 88.0% for radioresistant and radiosensitive tumors, respectively (p = 0.44). A PTV ≥17 cm(3), was associated with local failure, HR 8.63 ((1.44-164.78); p = 0.02). One and two year distant control rates were 50.9 and 46.2%, respectively with six patients (9.2%) experiencing leptomeningeal disease. OS rates at 1 and 2 years were 65.2 and 47.5%, respectively. Survival was significantly associated with recursive partitioning analysis class (p = 0.001) and graded prognostic assessment score (p = 0.005). One case of radionecrosis was noted on follow-up imaging. FSRT in five fractions offers excellent local control in both radiosensitive and radioresistant tumors with minimal toxicity.

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