儿童患者CAR-T治疗后严重神经毒性的输注前危险因素

Neurotoxicity is a common and potentially life-threatening complication after chimeric antigen receptor T-cell therapy (CART) for pediatric B-cell acute lymphoblastic leukemia (B-ALL). The only consistently demonstrated clinical risk factor for severe neurotoxicity in prior studies is high, preinfusion bone marrow disease burden (DB). To better prognosticate this syndrome, we sought to identify preinfusion clinical, laboratory, and imaging risk factors for the development of severe neurotoxicity, stratified by DB. We determined the incidence of severe neurotoxicity (defined as Grade ≥3 neurologic event[s]) in children and young adults treated with investigational anti-CD19 or anti-CD22 CART products across eight clinical trials or with commercial tisagenlecleucel. We comprehensively examined the association of putative clinical, laboratory, and imaging factors with the development of severe neurotoxicity. The occurrence of a seizure was included as a secondary outcome. Severe neurotoxicity was observed in 45/442 (10%) patients and was more frequent in the high DB (26/107, 24%) than the low DB (17/312, 5%) cohort. In the high DB cohort, history of a prior transient neurologic insult was associated with severe neurotoxicity (adjusted odds ratio, 5.73; 95% CI, 1.63, 21.7; P = 0.007). In the low DB cohort, no studied risk factors were robustly associated with severe neurotoxicity. Risk factors associated were different in the high and low DB cohorts. Patients with high DB and a previous history of transient neurologic events had a higher risk of severe neurotoxicity. Although the frequency of severe neurotoxicity was much lower in low DB patients, low DB patients accounted for 40% of severe neurotoxicity cases. Future studies should consider patients with high or low DB separately.