Brain inflammation in CD19 CAR T cell treatment-related neurotoxicity
Juliane Gust1*, Olivia Finney2, Rebecca Gardner1,2
1Seattle Children’s, 2Ben Towne Center for Childhood Cancer Research
Neurologic symptoms are frequently observed in patients who have received CAR T cells for hematologic malignancies, but systematic characterizations of the clinical syndrome have so far been unavailable. We now present the first comprehensive analysis of neurotoxicity in a large cohort of pediatric patients treated with CAR T cells directed against CD19.
In a prospective consecutive case series, we analyzed the clinical courses of 43 children enrolled in a phase I CD19 CAR T trial for acute lymphoblastic leukemia. Neurologic symptoms were graded daily by CTCAE criteria for 28 days after CAR T cell infusion, and prospective blood and CSF samples were collected prior to treatment and on day 21.
51% of the patients had acute neurologic symptoms, most frequently delirium, headache, and decreased level of consciousness. The vast majority of these resolved without sequelae. Peak of symptoms was on day 8 after treatment. Risk factors for neurotoxicity included severe cytokine release syndrome, prior CNS radiation, and preexisting headache disorder. There was no effect of preconditioning regimen or any other treatment related factors. CSF protein rose transiently, while CSF cell counts rose after treatment and stayed persistently elevated in patients with neurotoxicity. These patients also had significantly higher IL-6 levels and CAR T cell numbers in the CSF on day 21 compared to patients without neurotoxicity, whereas blood CAR T cells and serum IL-6 levels were the same in both groups.
These results confirm a similar rate of neurotoxicity compared with prior reports, and provide the first comprehensive description of this novel syndrome in a pediatric population. Our data suggest that some patients are more susceptible to CNS inflammation that is uncoupled from systemic inflammation. This will serve as a basis for further investigation into the biology of CNS toxicity and utility of targeted therapies such as steroids and cytokine blockade.
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