Clinical presentation, management, and outcome of TIAN in CNS lymphoma treated with CD19-CAR T-cell therapy
Abstract
Abstract 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.
Article Details
Authors (21)
Leon D. Kaulen
1Department of Neurology and European Center for Neurooncology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
Maria Martinez-Lage
6Massachusetts General Hospital, Harvard Medical School, Department of Pathology, Division of Neuropathology, Boston, United States
Jeremy S. Abramson
1Department of Medical Oncology, Massachusetts General Hospital, Boston, MA
Philipp Karschnia
Sofia Doubrovinskaia
1Department of Neurology and European Center for Neurooncology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
Ganesh M. Shankar
7Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Bryan D. Choi
Christopher M. Ramundo
7Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Felix Ehret
6Massachusetts General Hospital Cancer Center, Division of Neuro-Oncology, Boston, United States
Jeffrey A. Barnes
5Hematology and Oncology Division, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Areej El-Jawahri
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Ephraim P. Hochberg
5Hematology and Oncology Division, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
P. Connor Johnson
Department of Medicine, Massachusetts General Hospital, Boston
Jacob D. Soumerai
5Hematology and Oncology Division, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Scott R. Plotkin
Tracy T. Batchelor
Wolfgang Wick
Marcela V. Maus
Yi-Bin Chen
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Matthew J. Frigault
3Massachusetts General Hospital, Boston, MA
Jorg Dietrich
3Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA