Change in Patients' Perceived Cognition Among Chimeric Antigen Receptor T-Cell Therapy Recipients at Day 360
Authors: Barata Anna , Hoogland Aasha I. , Kommalapati Anuhya , Logue Jennifer M , Hyland Kelly A. , Eisel Sarah L. , Small Brent J. , Welniak Taylor , Irizarry-Arroyo Nathaly , Rodriguez Yvelise , Jayani Reena , Booth-Jones Margaret , Oswald Laura B. , Gonzalez Brian D. , Kirtane Kedar , Jain Michael D. , Mokhtari Sepideh , Chavez Julio C. , Lazaryan Aleksandr , Shah Bijal D. , Locke Frederick L. , Jim Heather S. L. 
Published: November 2021

Abstract
Introduction: Chimeric antigen receptor (CAR) T-cell therapy can lead to durable responses in patients with relapsed/refractory hematologic malignancies. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in up to 64% of patients. There is concern that ICANS places patients at risk for longer-term cognitive impairment. This study examined changes in patients' perceived cognition from prior to CAR T-cell therapy to days 90 and 360 in patients diagnosed with non-Hodgkins lymphoma, as well as CAR T-cell therapy-specific risk factors (e.g., ICANS, cytokine release syndrome [CRS]) and non-specific risk factors (e.g., age, education) associated with changes in cognition.
Methods: Patients' perceived cognition was assessed at baseline and at days 90 and 360 with the Everyday Cognition Questionnaire (ECog), that provides scores for global cognition (which includes subscales for memory, language, visuospatial abilities, planning, organization, divided attention), and satisfaction with cognition. Quality of life was scored using the Patient-Reported Outcomes Measurement Information System-29. Frailty was examined with the hand grip strength test. Cognitive reserve was examined with the Weschler Test of Adult Reading. Clinical variables were extracted from medical records. Demographic variables were self-reported by participants. Percentages of patients reporting clinically significant worsening, clinically significant improvement, and unchanged cognition over time were calculated. Piecewise mixed models were used to examine average change in perceived cognition from baseline to day 90 and from day 90 to day 360, as well as to explore potential risk factors of average change in global cognition. Risk factors included demographic (i.e., age, education) and clinical factors (i.e., grade&gt;2 CRS, grade&gt;2 ICANS, disease response at days 90 and 360, baseline grip strength, baseline cognitive reserve) as well as baseline quality of life variables (i.e., fatigue, physical function, pain, depression, anxiety).
Results: A total of 118 participants provided data (mean age 61, 59% male, 86% diagnosed with large B-cell lymphomas, 87% received axicabtagene ciloleucel). At day 90, relative to baseline, 17% of participants reported worsened global cognition, 10% improved global cognition, and 73% no change in global cognition (Figure 1). At day 360, relative to baseline, 28% reported worsened global cognition, 11% improved global cognition, and 61% no change in global cognition (Figure 1). Piecewise mixed models indicated that from baseline to day 90, there were no changes on average in global cognition or in any cognitive domain (ps&gt;.05). In contrast, from day 90 to 360, participants reported, on average, worsened global cognition (p=.01), language (p=.04), visuospatial abilities (p=.04), divided attention (p=.03) and satisfaction with cognition (p=.01). At baseline, greater fatigue, anxiety and depression were associated with worse concurrent perceived cognition (p&lt;.01). From baseline to day 90, physical functioning was associated with worsening cognition such that participants with better baseline physical functioning reported better perceived cognition at day 90 relative to participants with worse baseline physical functioning (p=.05). No other risk factors (e.g., CRS, ICANS) were associated with changes in global cognition from baseline to day 90 or from day 90 to day 360 (ps&gt;.05). Post-hoc analyses indicated no differences in cognition by disease status at day 360 (ps&gt;.05).
Conclusions: Results suggest that perceived cognition worsens on average beyond day 90, with patients reporting worse baseline physical functioning being at risk of worse perceived cognition by day 90. Results should be incorporated when preparing patients about what to expect when receiving CAR T-cell therapy. Further research is needed regarding objective neurocognitive performance after CAR T-cell therapy.
Figure 1 Figure 1.

Disclosures
Barata: Grifols: Current holder of individual stocks in a privately-held company; Almirall: Current holder of individual stocks in a privately-held company. Gonzalez: SureMed Compliance Equity: Consultancy; Elly Health, Inc.: Consultancy. Kirtane: Oncternal Therapeutics: Current holder of individual stocks in a privately-held company; Seattle Genetics: Current holder of individual stocks in a privately-held company; Myovant Sciences: Current holder of individual stocks in a privately-held company; Veru: Current holder of individual stocks in a privately-held company. Jain: Kite/Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Mokhtari: Kite: Consultancy. Chavez: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Speakers Bureau; AstraZeneca: Research Funding; Merck: Research Funding; Novartis: Consultancy; Epizyme: Speakers Bureau; BeiGene: Speakers Bureau; Kite/Gilead: Consultancy; Adaptive: Research Funding; Karyopharm Therapeutics: Consultancy; MorphoSys: Speakers Bureau; Abbvie: Consultancy. Lazaryan: Kadmon: Consultancy; Avrobio: Membership on an entity's Board of Directors or advisory committees; Humanigen: Membership on an entity's Board of Directors or advisory committees. Shah: Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Jim: Kite pharma: Research Funding; Merck: Consultancy; Janssen Scientific Affairs: Consultancy; RedHill Biopharma: Consultancy.