Clinical presentation, management, and outcome of TIAN in CNS lymphoma treated with CD19-CAR T-cell Therapy.

Abstract

Tumor inflammation-associated neurotoxicity (TIAN) was recently proposed as a unique complication of immunotherapy in brain tumor patients. Here, we report a first comprehensive characterization of TIAN in CNS lymphoma (CNSL) patients treated with CD19-directed chimeric antigen receptor T-cells (CD19-CAR). TIAN occurred in 10/56 (17.9%) CNSL with clinical onset at a median 3.5 days (range: 1-9) after CD19-CAR infusion. It was less frequently associated with cytokine release syndrome (60% vs 100%, p = 0.009) than immune effector cell-associated neurotoxicity syndrome (ICANS). Although symptoms were usually transient and fully reversible, TIAN was associated with a fatal outcome in one patient. Larger CNS tumor volume at baseline allowed the identification of patients at risk for TIAN (AUC: 0.847, p = 0.002). Maximizing Youden J statistics, a discriminatory tumor volume threshold >3.4cm3 was determined, which carried 87.5% sensitivity and 80.5% specificity. TIAN correlated with higher overall response rates to CD19-CAR (90% vs 52%, p = 0.036) and improved progression-free survival (Hazard ratio: 0.22; 95%-Confidence interval: 0.07-0.61, p = 0.006) on multivariate Cox proportional hazard regression. Post-mortem histopathological evaluation of a TIAN lesion revealed a dense macrophage population with central necrosis and peripheral reactive gliosis, accompanied by loss of white matter and intracytoplasmic myelin in foamy macrophages. Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to pre-existing CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management.