A novel application of deep learning (DL)-based MRI with liquid biomarkers for immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR) T-cell therapy.

Abstract

2516 Background: ICANS is a complication of CAR T-cell therapy, yet risk factors and quantitative diagnostic criteria, particularly neuroimaging criteria, remain incompletely characterized. We implemented a novel application of a deep learning (DL)-based MRI approach alongside clinical and liquid biomarkers to better characterize neurotoxicity after CAR T-cell therapy. Methods: We analyzed all patients with non-Hodgkin lymphoma (NHL) or acute lymphoblastic leukemia (ALL) who underwent CAR T-cell therapy at UCSD with a commercial product from 2018-2024. ICANS was graded as per American Society for Transplantation and Cellular Therapy (gr1-4). Variables included stage, performance status, and prior receipt of high-dose methotrexate (HD MTX), intrathecal (IT) chemotherapy, central nervous system (CNS) involvement, CNS-directed radiotherapy (CNS RT), and extracranial RT. Labs obtained pre-infusion, 3 days post-infusion, and during ICANS (or 7 days post-infusion for those without ICANS) were evaluated. Available post-infusion brain MRIs were processed with a 3D U-Net convolutional neural network to quantify T2 FLAIR hyperintensity volumetrics. Linear mixed regression models accounting for zero inflation assessed longitudinal DL-derived FLAIR. Multivariable regression models assessed factors associated with ICANS. Results: Of 163 patients (89% NHL, 11% ALL), 52 had IT chemotherapy, 27 had HD MTX, 24 had prior CNS disease, and 22 had prior CNS RT. Most (106) received axicabtagene ciloleucel (34 tisagenlecleucel, 23 brexucabtagene autoleucel) and most had CRS (133, 82%). ICANS occurred in 73 (45%) at a median of 7 days post-infusion (39 gr1-2, 34 gr3-4). Post-infusion, 21 patients had ³1 brain MRI (93 MRIs total). Baseline factors associated with ICANS were lactate dehydrogenase (LDH; odds ratio [OR] 1.03 p = 0.002) and prior IT chemotherapy (OR 2.5 p = 0.01). There was a trend toward association of gr3-4 ICANS with HD MTX (OR 2.8 p = 0.07). Post-infusion, CRS grade was associated with ICANS (OR 2.8 p < 0.001). LDH (1.02 p = 0.004) and C-reactive protein (OR 1.2 p < 0.001) were elevated during ICANS. Patients with ICANS had significantly greater FLAIR (intercept 23.8 cm³ p < 0.001) and there was increased FLAIR over time across all patients (b = 3.3 cm³ p = 0.05). There was a trend toward association between higher ICANS grade and DL-derived FLAIR (p = 0.09). Conclusions: Here, we demonstrate a novel application of DL-based MRI quantification of ICANS post-CAR T-cell therapy. This metric, along with clinical features, emerged as potential quantitative biomarkers of ICANS. These findings warrant further investigation and have informed a prospective study, including standardized brain MRI pre- and post-infusion, to develop a comprehensive phenotype of neurotoxicity following CAR T-cell therapy.