Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma

Abstract

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 106 CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

Keywords: axi-cel; chimaeric antigen receptor-T cell; corticosteroids; cytokine release syndrome; large B-cell lymphoma; prophylaxis.

Conflict of interest statement

OOO: consultancy or advisory role for Kite, a Gilead Company, Pfizer, Spectrum Pharmaceuticals, Legend, and Bayer. KB: honoraria from Kite, a Gilead Company, Takeda, Roche, and Celgene; consultancy or advisory role for Kite, a Gilead Company, Takeda, Roche, and Sandoz; travel support from Roche. JM: honoraria from Kyowa and Seattle Genetics; consultancy or advisory role for Pharmacyclics, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol‐Myers Squibb, Kyowa, Alexion, Fosun Kite, Innovent, Seattle Genetics, and BeiGene; speakers’ bureau participation for Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, BeiGene, Verastem, AstraZeneca, Juno/Celgene/Bristol Myers Squibb, Genentech/Roche, and AbbVie; research funding from Bayer, Kite, a Gilead Company, Juno/Celgene/Bristol‐Myers Squibb, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium. SdG: honoraria from Gilead Sciences, AbbVie, and Janssen; consultancy or advisory role for Gilead Sciences, AbbVie, and Janssen. JMV: honoraria from Kite, a Gilead Company, AbbVie, Epizyme, Janssen, AstraZeneca, Verastem, Miltenyi, Loxo, Allogene, Wugen, Celgene, Roche, Genentech, and Karyopharm; consultancy or advisory role for AbbVie, Janssen, Kite, a Gilead Company, AstraZeneca, Verastem, Miltenyi, Loxo, Allogene, Wugen, Roche, Genentech, Karyopharm, and Morphosis; research funding from AstraZeneca, Bristol‐Myers Squibb, Incyte, Kite, a Gilead Company, Novartis, Seattle Genetics, Loxo, and Epizyme; travel support from Roche Pakistan. NLB: consultancy or advisory role for ADC Therapeutics, Roche/Genentech, and Seattle Genetics; research funding from ADC Therapeutics, Autolus, Bristol‐Myers Squibb, Celgene, Forty Seven, Genentech, Janssen, Kite, a Gilead Company, Merck, Millennium, Pharmacyclics, and Seattle Genetics. YL: consultancy or advisory role for Kite, a Gilead Company, Janssen, Novartis, Celgene, Bluebird Bio, Juno, Legend, Sorrento, Gamida Cell, and Vineti; research funding from Kite, a Gilead Company, Janssen, Celgene, Bluebird Bio, Merck, and Takeda. AD: consultancy or advisory role for Janssen and Kite, a Gilead Company. PAM: employment with Colorado Blood Cancer Institute Medical Group; consultancy or advisory role for, speakers' bureau participation for, and research funding from Kite, a Gilead Company. AHG: employment with Regional Cancer Care Associates/OMI; leadership role at and stock or other ownership in Cancer Outcome Tracking Analysis (COTA); consultancy or advisory role for AstraZeneca, Celgene, Gilead Sciences, Kite, a Gilead Company, and Xcenda; research funding from Acerta, AstraZeneca, Celgene, Constellation, Genentech‐Hoffmann La Roche, Infinity, and Infinity Verastem. MJK: honoraria from, consultancy or advisory role for, and travel support from Kite, a Gilead Company, Novartis, and Miltenyi; research funding from Roche, Takeda, and Celgene. CAJ: honoraria from Kite, a Gilead Company, Celgene, Novartis, Pfizer, Precision Biosciences, Nkarta, Lonza, and AbbVie; consultancy or advisory role for and travel support from Kite, a Gilead Company, Celgene, Novartis, Bristol‐Myers Squibb, Precision Biosciences, Nkarta, and Lonza; speakers' bureau participation for Axis and Clinical Care Options; research funding from Pfizer. UF: honoraria from Kite, a Gilead Company. MCM: consultancy or advisory role for Gilead Sciences, Janssen Cilag, and Servier; research funding and travel support from Celgene. CT: honoraria from Gilead Sciences, Novartis, Celgene, Roche, and Janssen; consultancy or advisory role for Celgene, Roche, Novartis, and Janssen; research funding from Roche; travel support from Novartis, Roche, Gilead Sciences, and Janssen. JMT: stock or other ownership in Genmab, Corvus, Marker Therapeutics, and Bluebird Bio; consultancy or advisory role for Kite, a Gilead Company, Celgene, Immune Design, and Celldex Therapeutics; research funding from Bristol‐Myers Squibb, Kite, a Gilead Company, Spectrum Pharmaceuticals, and Merck; travel support from Bristol‐Myers Squibb and Kite, a Gilead Company. PS: honoraria from and consultancy or advisory role for MorphoSys, Karyopharm, and Crispr; researching funding from Kite, a Gilead Company, Incyte, Amgen, Gamida Cell, Macrogenics, Cellectar, and Bristol‐Myers Squibb. IA: no relevant financial relationships to disclose. DT: consultancy or advisory role for Partner, Takeda, EUSA, Kite, a Gilead Company, Kyowa Kirin, and Magenta; speakers' bureau participation for Takeda and Kite, a Gilead Company; research funding from Bristol‐Myers Squibb, Kite, a Gilead Company, Genentech, Incyte, and Fate. JJK, JM, YZ, and LG: employment with Kite, a Gilead Company; stock or other ownership in Gilead Sciences. ZB: employment with Kite, a Gilead Company; stock or other ownership in OmniacPharmConsult Ltd. JMR: former employment with Kite, a Gilead Company. LJ: employment with Kite, a Gilead Company, and Trillium Therapeutics; stock or other ownership in and patents, royalties, or other intellectual property from Trillium Therapeutics. TvM: honoraria from Celgene; consultancy or advisory role for Kite, a Gilead Company.

© 2021 Kite, a Gilead Company. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1

Toxicity management in ZUMA‐1. *Only in case of comorbidities or older age. †Only if no improvement with tocilizumab, use standard dose. ‡If no improvement after 24 h. §If no improvement after three days. ||Only for grade 2 or higher NEs with concurrent CRS. AE, adverse event; CRS, cytokine release syndrome; HD, high dose; Mgmt, management; NE, neurologic event. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig 2

(A) Objective response rates (ORRs) and (B) duration of response (DOR) in patients achieving an objective response in ZUMA‐1 cohort 6. For patients who underwent stem cell transplantation before documented progression, DOR was censored at the date of stem cell transplantation. CR, complete response; NE, not estimable; NR, not reported; PR, partial response; SD, stable disease. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig 3

Levels of (A) blood chimaeric antigen receptor (CAR)‐T cells and (B) key soluble serum biomarkers over time. Dashed lines (A) and bars (B) represent the interquartile range. BL, baseline; CRP, C‐reactive protein; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; IFN, interferon; IL, interleukin; MCP‐1, monocyte chemoattractant protein 1.