Critically Ill Patients Treated for Chimeric Antigen Receptor-Related Toxicity: A Multicenter Study*

Abstract

To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. DESIGN: Retrospective cohort study SETTING: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. PATIENTS: Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. INTERVENTIONS: Demographics, toxicities, specific interventions, and outcomes were collected. RESULTS:One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cellassociated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cellassociated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progressionfree survival. CONCLUSIONS:This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cellassociated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.

Chimeric Antigen Receptor T Cells, the Shock of the New*

“…Although there can be a tendency toward therapeutic nihilism when oncology patients are admitted to the ICU, this is often misplaced, and indeed, we must guard against premature discontinuation of organ support (2). In this respect, the report by Gutierrez et al (4) is encouraging on first reading. The outcomes for patients with CAR-T toxicity are excellent, with an ICU mortality of 8.6%, 74% achieving discharge to home, and no apparent impact of severe toxicity on longer term outcomes.…”

“…The latter example sounds a note of caution, as when a large placebo-controlled trial was conducted, adrenaline only improved survival at the cost of increased severe neurologic disability (11). The observation by Gutierrez et al (4) that patients receiving higher doses of steroids had lower overall and progression-free survival should also give us pause for thought. As an observational association it is possible that the use of higher doses of steroids simply reflects more aggressive primary disease or more severe toxicity, resulting in the mortality effect seen.…”

“…This approval was unusual in that it was not based on prospective, randomized controlled trials but rather retrospective, observational data from its use in IEC trials, supported by underpinning human and animal biology data (5). Given the impressive resolution rates of CRS symptoms in patients receiving tocilizumab, it has rapidly become the standard of care for such patients, as evidenced by its use in 80% of cases reported by Gutierrez et al (4). Many centers use corticosteroids as second-line therapy for CRS, given the concerns regarding their ability to impair CAR-T therapeutic response (9).…”

“…In this issue of Critical Care Medicine , Gutierrez et al (4) report on the experience of ICU management of CAR-T toxicity across nine U.S. immune effector cell (IEC) therapy centers, including many of those that have pioneered this therapy and have the greatest experience. Gutierrez et al (4) report that CAR-T toxicity sufficient to warrant ICU admission was common, occurring in one third of recipients.…”

“…In this issue of Critical Care Medicine , Gutierrez et al (4) report on the experience of ICU management of CAR-T toxicity across nine U.S. immune effector cell (IEC) therapy centers, including many of those that have pioneered this therapy and have the greatest experience. Gutierrez et al (4) report that CAR-T toxicity sufficient to warrant ICU admission was common, occurring in one third of recipients. In common with previously published reports (5), patients presented with the sterile systemic inflammatory response syndrome termed “cytokine release syndrome” (CRS) or the neurologic impairment termed “immune cell–associated neurotoxicity syndrome” (ICANS) or less commonly with both.…”