Forecasting immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor t-cell therapy

Abstract

BackgroundImmune effector cell-associated neurotoxicity syndrome (ICANS) is a clinical and neuropsychiatric syndrome that can occur days to weeks following administration chimeric antigen receptor (CAR) T-cell therapy. Manifestations of ICANS range from encephalopathy and aphasia to cerebral edema and death. Because the onset and time course of ICANS is currently unpredictable, prolonged hospitalization for close monitoring following CAR T-cell infusion is a frequent standard of care.MethodsThis study was conducted at Brigham and Women’s Hospital from April 2015 to February 2020. A cohort of 199 hospitalized patients treated with CAR T-cell therapy was used to develop a combined hidden Markov model and lasso-penalized logistic regression model to forecast the course of ICANS. Model development was done using leave-one-patient-out cross validation.ResultsAmong the 199 patients included in the analysis 133 were male (66.8%), and the mean (SD) age was 59.5 (11.8) years. 97 patients (48.7%) developed ICANS, of which 59 (29.6%) experienced severe grades 3–4 ICANS. Median time of ICANS onset was day 9. Selected clinical predictors included maximum daily temperature, C reactive protein, IL-6, and procalcitonin. The model correctly predicted which patients developed ICANS and severe ICANS, respectively, with area under the curve of 96.7% and 93.2% when predicting 5 days ahead, and area under the curve of 93.2% and 80.6% when predicting the entire future risk trajectory looking forward from day 5. Forecasting performance was also evaluated over time horizons ranging from 1 to 7 days, using metrics of forecast bias, mean absolute deviation, and weighted average percentage error.ConclusionThe forecasting model accurately predicts risk of ICANS following CAR T-cell infusion and the time course ICANS follows once it has begun.Cite Now

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“…Newly emerging biomarkers of neuronal toxicity such as neurofilament [ 128 , 129 ] may become useful in the prompt identification and treatment of patients with ICANS, but their utility remains to be assessed. The development of models to predict who is at high (or low) risk would help the community better tailor patient therapy and potentially predict who could safely be discharged home after treatment with cell therapies [ 93 ]. While we continue to develop expertise in the context of the clinical use of CAR T cells and bispecific antibodies targeting CD19-positive cells, we have less clinical expertise with new targets such as BCMA.…”

“…Features associated with an increased likelihood of developing ICANS include a high baseline tumor burden [ 90 ], greater CAR T cell expansion [ 85 ], an earlier and more severe systemic inflammatory response called cytokine release syndrome (CRS) (with high peak ferritin and C-reactive protein levels) [ 91 , 92 , 93 ], and chimeric receptors with a CD28 co-stimulatory signaling domain [ 85 , 94 , 95 ]. CD19-targeted CAR T cells have thus far been associated with more neurotoxicity than CD20, CD22, or B-cell maturation antigen (BCMA)-targeted CAR T cells [ 95 , 96 ].…”

A systematic framework for predictive biomarkers in immune effector cell-associated neurotoxicity syndrome

“…Rubin and colleagues demonstrated the promise of a combined risk model for ICANS that assembles markers across each of the three major categories ( 39 ). Amidi et al ( 70 ) recently expanded on this approach. Notably, neither study integrated vascular factors, neurologic injury, key cytokines, or type of cellular therapy agent in their respective models, holding promise these further additions may improve generalizability.…”