Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma

Abstract

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 10⁶ anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.

Keywords: CAR T; axi-cel; corticosteroids; large B-cell lymphoma; toxicity.

Fig 1

Protocol‐specified AE management in cohorts 1 + 2 and cohort 4 of ZUMA‐1. (A) Comparison of AE management in cohorts 1 + 2 and cohort 4 of ZUMA‐1. ‘Yes’ or ‘No’ indicates whether tocilizumab or corticosteroid was or was not administered, respectively. (B) Tocilizumab and corticosteroid guidelines for AE management in cohort 4 of ZUMA‐1. *Only in case of comorbidities or older age. ^†Only if no improvement with tocilizumab; use standard dose. ^‡If no improvement after three days. ^§Therapy to be tapered upon improvement of symptoms at investigator’s discretion. ^||Not to exceed 800 mg. AE, adverse event; CRS, cytokine release syndrome; HD, high dose; IV, intravenously; N/A, not applicable; NE, neurologic event; Mgmt, management.

Fig 2

ORR and duration of response. (A) ORR of patients in cohort 4 and rates of SD and PD. Response could not be evaluated in two patients: one patient died of pneumonia before the first assessment, and one patient had a positive result from positron emission tomography with suspected inflammation. (B) Kaplan–Meier curve of duration of response. CR, complete response; NE, not estimable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Fig 3

CAR T‐cell expansion and key soluble serum biomarker levels over time. (A) Median (Q1, Q3) blood levels of CAR T cells over time. (B) Median (Q1, Q3) levels of key soluble serum inflammatory biomarkers plotted against time. BL, baseline; CAR, chimeric antigen receptor; CRP, C‐reactive protein; GM‐CSF, granulocyte‐macrophage colony–stimulating factor; IFN, interferon; IL, interleukin; MCP‐1, monocyte chemoattractant protein‐1.