Neurocognitive Outcomes over the First 3 Months after Chimeric Antigen Receptor T-Cell (CAR T) Therapy: Preliminary Findings from a Longitudinal Study

Abstract

Introduction People treated with systemic therapies for cancer may exhibit changes in neurocognitive functioning over time, affecting domains such as memory, processing speed, and executive functioning. There is a need for prospective data regarding neurocognitive outcomes among patients treated with Chimeric Antigen Receptor T-Cell (CAR T) therapy. The purpose of this study was to investigate the trajectory of neurocognitive performance and self-reported cognitive functioning over the first 3 months of CAR T therapy. Methods As part of a larger cohort study of patients treated with CAR T, neurocognitive outcomes were assessed prior to starting CAR T and again at 1- and 3- months post-CAR T. Neurocognitive performance was measured using standardized neuropsychological tests including measures of verbal memory (Hopkins Verbal Learning Test-Revised (HVLT-R) - immediate recall, delayed recall, retention), processing speed (Trail-making Test - Part A (TMT-A)) and executive functioning (Trail-making Test Part B (TMT-B), Controlled Oral Word Association Test (COWAT)). Raw test scores were converted to z-scores (Mean 0, SD 1) based on norms adjusted for age, sex, and education, where applicable. Impairment on individual tests was defined by a z score ≤ -1.64. Participants were categorized as showing overall impairment if they had at least two tests with a z-score of ≤ -1.5 or a z-score ≤ -2.0 on one test. Self-reported cognitive functioning was measured using the Functional Assessment of Cancer Therapy - Cognition, Perceived Cognitive Impairment score (FACT-Cog3 PCI) and the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire C-30, Cognitive Functioning scale (EORTC QLQ-C30 CF). Demographic and clinical data were collected through self-report and patient records. Frequencies of impairment were determined at each time point, with clinically significant changes on individual test scores in the first month determined based on z-score changes of ≥1.0 or minimal clinically important differences for self-report questionnaires. Linear mixed models were generated to estimate the trajectory of neurocognitive performance and self-reported cognitive functioning over time from baseline to 3 months. Results Neurocognitive outcomes were available for 37 participants at baseline, with follow-up data available for 29 patients at 1 month and 17 patients at 3 months. Participants were 54% male, had a mean age 58.4 years (sd 11.3) and a mean 15.5 years (sd 3.2) education. All patients had a diagnosis of non-Hodgkin lymphoma (53% diffuse large B-cell lymphoma (DLBCL), 31% transformed DLBCL from follicular lymphoma). Immune effector cell-associated neurotoxicity syndrome (ICANS) affected 32% of patients (5% Grade 4, 3% Grade 3, 8% Grade 2, 16% Grade 1). Cytokine release syndrome (CRS) affected 97% of patients (3% Grade 3, 76% Grade 2, 19% Grade 1). Frequency of overall impairment at each time point was 10/37 (27%) at baseline, 12/29 (41.4%) at 1 month, and 3/17 (17.6%) at 3 months. At each time point, impairment was most common on tests of executive functioning and memory. Based on individual test score changes between baseline and 1 month, rates of decline on individual tests of neurocognitive performance ranged from 11.5% (TMT-A) to 34.6% (COWAT). Decline on self-reported cognitive functioning was observed for 14.3% (FACT-Cog PCI) and 28.6% (EORTC QLQ-C30 CF) of participants. Based on mixed models (Table 1), there was a statistically significant decline in estimated mean z-scores on a test of executive function (COWAT: -0.52, 95% CI -0.89-(-0.16), p=0.007) at 1-month compared to baseline. At three months, there was a statistically significant improvement in estimated mean z-scores on memory (HVLT-R immediate recall: 0.56, 95% CI 0.11-1.01, p=0.017) and executive functioning (TMT-B: 0.87, 95% CI 0.17-1.57, p=0.019; COWAT: 0.68, 95% CI 0.19-1.16, p=0.009) compared to baseline. Conclusions Impairment is present in a subgroup of patients prior to starting CAR T therapy. Patients may demonstrate declines on performance-based measures and report worsening cognitive symptoms in the first month after CAR T therapy, but also improved performance in some domains by three months. Enrollment and long-term follow-up of patients in this study is ongoing. Future analyses will explore differences in trajectories among subgroups, such as those who have experienced ICANS and CRS.