Aggressive use of corticosteroids for the management of toxicities associated with chimeric antigen receptor (CAR) T-cell therapy may worsen survival in patients with large B-cell lymphoma (LBCL), according to a new retrospective study.
In the pivotal trial that led to approvals of the CAR T-cell therapy axicabtagene clioleucel (axi-cel) in Australia, the US, UK, and elsewhere, corticosteroids were used in 27% of patients for the management of severe cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS).
Outside of the trials, however, corticosteroid use has risen, and was used in as many as 55% of patients receiving the therapy.
“Corticosteroids likely mitigate toxicities by inhibiting the proliferation and/or inflammatory cytokine production from CAR T-cells and other immune cells,” wrote study authors led by Dr Paolo Strati, of MD Anderson Cancer Center in Houston, in Blood. “However, the magnitude of CAR T-cell expansion during the first month after infusion was shown to be associated with response and durability.”
Because of this, there was a concern that corticosteroid use could itself impact the efficacy of the treatment. The authors retrospectively examined 100 patients with relapsed or refractory LBCL treated with axi-cel at their centre between January 2018 and May 2019. Of those, 60 patients received corticosteroids for management of ICANS (37%), CRS (7%), or both (16%).
The median progression-free survival among 96 patients evaluable for efficacy was 8 months, but the use of a higher cumulative dose of corticosteroids was significantly associated with shorter PFS. The use or duration of corticosteroids did not appear to impact PFS.
When the analysis was restricted to only 74 patients with elevated baseline lactate dehydrogenase (LDH) – which was used as a marker of higher tumour burden – the association between higher dose and shorter PFS was maintained.
The median overall survival had not yet been reached, but the median OS was significantly shorter among those who received any corticosteroid, higher cumulative dose of corticosteroid, prolonged use for at least 10 days, or early use within 7 days of treatment initiation.
The associations between higher dose of corticosteroid (p < .001), prolonged use (p = .008), and early use (p = .01) and OS remained significant when limited to the patients elevated LDH.
The maintenance of the associations in patients with higher tumour burden suggests that the corticosteroid use itself may be worsening outcomes, rather than simply reflecting poorer disease outlook in general.
“We tried to assess whether the effect of corticosteroids was independent of the baseline factors and the evidence we presented suggests that corticosteroids have independent prognostic value,” the study’s senior author, Dr Sattva Neelapu, told the limbic. Still, he stressed that this was a retrospective study and therefore its interpretation is limited.
The analysis showed that no aspects of corticosteroid dose appeared to impact CAR T-cell amplification, but Dr Neelapu said there was still a mechanism that could explain the negative impact on outcomes. “Corticosteroids can dampen the effector function of CAR T cells besides potential effect on proliferation,” he said.
The authors concluded that until those mechanisms are understood better, use of corticosteroids in this setting should likely be used sparingly, with a focus on delaying their initiation and limiting the cumulative dose and duration, when possible.
“Moreover, evaluation of alternative interventions that could minimize the need for corticosteroids to mitigate CAR T-cell-associated toxicities is warranted,” they wrote.