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

Tumor inflammation-associated neurotoxicity (TIAN) was recently proposed as a unique complication of immunotherapy in patients with brain tumor. Here, we report a first comprehensive characterization of TIAN in patients with central nervous system (CNS) lymphoma (CNSL) treated with CD19-directed chimeric antigen receptor (CD19-CAR) T cells. TIAN occurred in 10 of 56 (17.9%) patients with CNSL, with clinical onset at a median 3.5 days (range, 1-9) after CD19-CAR T-cell infusion. It was less frequently associated with cytokine release syndrome (60% vs 100%; P = .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 1 patient. Larger CNS tumor volume at baseline allowed the identification of patients at risk for TIAN (area under the curve, 0.847; P = .002). Maximizing Youden J statistics, a discriminatory tumor volume threshold of >3.4 cm3 was determined, which carried 87.5% sensitivity and 80.5% specificity. TIAN correlated with higher overall response rates to CD19-CAR T cells (90% vs 52%; P = .036) and improved progression-free survival (hazard ratio, 0.22; 95% confidence interval, 0.07-0.61; P = .006) on multivariate Cox proportional hazard regression. Postmortem 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 preexisting CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management.