Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy

Abstract

IMPORTANCE Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.OBJECTIVE To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. DESIGN, SETTING, AND PARTICIPANTSThis single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion. MAIN OUTCOMES AND MEASURESThe primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria. RESULTSTwo hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26). CONCLUSIONS AND RELEVANCEThe score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

CRP and ferritin in addition to the EASIX score predict CAR-T–related toxicity

“…2,5,7,8 Likewise, CRP and ferritin levels measured on the day of CAR-T-cell infusion or shortly thereafter were also associated with increased risk of severe CRS and ICANS. 1,5,6 Time (days) In preclinical models, the development of CRS has been shown to be secondary to both CAR T-cell expansion and to subsequent activation of the immune microenvironment, leading to a cytokine storm, including peak levels of in IL-1, IL-6, and other proinflammatory molecules. 19,20 Of interest, in patient-derived samples, 4 these chemokine levels associated not only with higher CAR-T-cell expansion, but also with endothelial activation.…”

“…Different studies have reported on several biomarkers, including lactate dehydrogenase (LDH), as the surrogate marker of tumor burden, and C-reactive protein (CRP) and ferritin as general inflammatory markers, all 3 of whichare associated with severe CRS and/or ICANS. 2,[4][5][6][7][8] However, their individual predictive power is limited, and novel biomarkers are strongly needed.…”

Management of a patient with mantle cell lymphoma who developed severe neurotoxicity after chimeric antigen receptor T-cell therapy in ZUMA-2

“…Patients underwent leukapheresis with optional bridging therapy, followed by conditioning chemotherapy (cyclophosphamide 500 mg/m 2 /day; fludarabine 30 mg/m 2 /day) on days −5 to −3, as previously reported. 4 KTE-X19 was infused at a target dose of 2×10 6 CAR T cells/kg on day 0. 4 CRS was graded per Lee et al 15 National Cancer Institute Common Terminology Criteria for Adverse Events, V.4.03, was used to grade the severity of adverse events, including NE and symptoms of CRS.…”

Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies

“…Lately, Rubin et al developed a model for predicting neurotoxicity after anti-CD19 CAR T cell therapy with axicabtagene ciloleucel for RR NHL. In this scoring system, the following factors were considered: age (≥52 versus <52 years), maximum CRP (≥8.95 versus <8.95 mg/dl), maximum ferritin (≥641 versus <641 ng/ml), minimum white blood cell (WBC) count (<790 versus ≥790/ml), time point of CRS onset (prior to versus after day 3), histologic subtype of lymphoma (aggressive versus indolent), temperature (≥38.5°C versus <38.5°C), presence of CRS of any grade, and use of tocilizumab prior to day 5 (105). This is a valuable instrument for triaging and resource allocation, and development of such a predictive model for MM patients is highly warranted.…”