Neurotoxicity following CD19/CD28 zeta CAR T-cells in children and young adults with B-cell malignancies

Background. Neurotoxicity is an established toxicity of CD19 CART-cell therapy; however, there is little information on neurotoxicity in children, adolescents, and young adults (CAYA) receiving CD19/CD28 zeta CART-cells for B-cell malignancies. Methods. We analyzed neurotoxicity of CD19/CD28 zeta CART-cells in CAYA treated on a phase I study (NCT01593696). Assessments included daily inpatient monitoring, caregiver-based neuro-symptom checklist (NSC), exploratory neurocognitive assessments, clinically-indicated imaging, CSF analysis, and systematic cytokine profiling, outcomes of which were associated with cytokine release syndrome (CRS) and treatment response postinfusion. Patients with active CNS leukemia were included. Results. Amongst 52 patients treated, 13 patients had active CNS leukemia at infusion. Neurotoxicity was seen in 11/52 (21.2%) patients, with an incidence of 29.7% (11/37) in patients with CRS. Neurotoxicity was associated with the presence and severity of CRS. Those with neurotoxicity had higher levels of peak serum IL-6, IFN gamma, and IL-15. Additionally, CNS leukemia was effectively eradicated in most patients with CRS. Pilot neurocognitive testing demonstrated stable-to-improved neurocognitive test scores in most patients, albeit limited by small patient numbers. The NSC enabled caregiver input into the patient experience. Conclusions. This is the first systematic analysis of neurotoxicity utilizing a CD19/CD28 zeta CAR construct in CAYA, including in those with active CNS involvement. The experience demonstrates that the neurotoxicity profile was acceptable and reversible, with evidence of anti-leukemia response and CNS trafficking of CART-cells. Additionally, neurocognitive testing, while exploratory, provides an opportunity for future studies to employ systematic evaluations into neurotoxicity assessments and validation is needed in future studies.