Prophylactic steroids can prevent CAR T-cell toxicity

Prophylactic use of steroids and/or an IL-6 inhibitor can reduce the likelihood of severe adverse events in patients receiving axicabtagene ciloleucel (Yescarta) for large B-cell lymphoma (LBCL), a cohort analysis from the ZUMA-1 trial finds.

Writing in the British Journal of Haematology, the researchers noted that cytokine release syndrome (CRS) and neurologic events (NEs) were the adverse events (AEs) most commonly associated with anti-CD19 CAR T-cell therapy.

Cohort six of the multicentre ZUMA-1 trial therefore specifically looked at management of these adverse events with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention.

Overall, 40 Patients with relapsed or refractory LBCL received dexamethasone 10 mg orally on the day of CAR T-cell therapy and each of the two following days. Corticosteroids and tocilizumab were also started earlier at lower grades of CRS and neurologic events than in the trial 1 and 2 cohorts. All cohort six patients received at least one dose of corticosteroids.

The incidence rates of grade 3 or higher CRS were 13%, 2% and 0% in cohorts 1 + 2, 4 and 6 respectively, results showed.

“The fact that no cases of grade 3 or higher CRS occurred among patients treated with prophylactic corticosteroids is encouraging, as is the progressively shorter median CRS duration (8, 7 and 4 days, in cohorts 1 + 2, 4 and 6 respectively) and delayed time to CRS onset (median 2, 2 and 5 days, in cohorts 1 + 2, 4 and 6 respectively,)” the researchers wrote.

The incidence of grade 3 or higher NEs in cohort 6 (13%) was comparable to that of cohort 4 (17%), and both rates were numerically lower than in cohorts 1 + 2 (28%), they said, noting that the median duration of NEs in cohort 6 was numerically longer than that reported in the other cohorts.

The authors acknowledged that the prolonged use of high-dose corticosteroids for NE treatment is thought to affect CAR-T cell expansion and therefore clinical outcomes of treated patients.

However, their findings showed that corticosteroid prophylaxis and early corticosteroid and/or tocilizumab intervention did not appear to compromise axicel efficacy, they said.

“The use of prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention for toxicity management resulted in no cases of grade 3 or higher CRS, delayed CRS onset, and generally similar NE toxicity without adversely affecting CAR-T cell pharmacokinetics or efficacy outcomes for axi-cel-treated patients,” they concluded.

The authors noted that the ZUMA safety management cohorts were not designed or powered for comparisons with each other or with the pivotal cohorts. Differences in baseline characteristics and cohort sizes should be considered when making comparisons, they advised.

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