Pre-existing cognitive impairment is associated with reduced long-term survival following chimeric antigen receptor T-cell therapy for non-Hodgkin's lymphoma

Abstract Introduction: CAR T therapy has revolutionized treatment landscape for patients with relapsed refractory (R/R) non-Hodgkin's lymphoma (NHL), leading to long-term survival for a significant portion of patients including those with advanced age, multi-morbidity, and suboptimal performance status. However, many patients still relapse after CAR T therapy and often require additional treatments. We have previously shown in a small cohort of older patients with NHL that pre-CAR T geriatric assessment and consultation could identify prognostically important impairments in various health domains. In this retrospective study, we focus on the impact of pre-existing cognitive impairment on CAR T therapy outcomes in a larger, contemporary cohort of patients with NHL. Methods: The single instituion cohort includes patients with a diagnosis of R/R NHL after ≥1 line of therapy who received axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, or tisagenlecleucel. CAR T therapy eligibility criteria, clinical care, and monitoring of CRS and ICANS follows standard institutional guidelines. Cognition is assessed using Montreal Cognitive Assessment (MoCA), with a score < 26 out of 30 defined as impaired. Overall patient characteristics are summarized using descriptive statistics. Overall survival (OS) is defined from infusion until death or end of follow-up, whereas progression-free survival (PFS) is defined from infusion until progression, death, or end of follow-up in the absence of an event; patients who received subsequent treatment for NHL before or in absence of post-CAR T relapse are censored at next treatment start. Survival endpoints are estimated using Kaplan Meier methodology and compared using log-rank tests. Cox proportional hazards models are used to evaluate univariable and multivariable associations between outcomes and baseline characteristics. The study has been approved by MSK institutional review board and conducted in accordance with the Declaration of Helsinki. Results: From January 1st, 2020 to December 31st, 2024, 179 out of 375 patients receiving CAR T therapy for NHL had pre-infusion MoCA and were included in this analysis. There were no significant differences in baseline patient, disease, and treatment characteristics between the groups of patients with and without MoCA except for age and KPS as expected, since MoCA is commonly used as a part of geriatric assessment for older patients. Based on the cutoff score, sixty-eight patients (38%) were cognitively impaired while the remaining 111 were cognitively intact. There were no significant differences in baseline patient, disease, and treatment characteristics between the groups of patients with and without cogntive impairment except for history of seizure. With a median follow-up of 21 months (IQR: 12.2-31.2), cognitively intact patients had significantly superior OS compared to cognitively impaired patients (univariable HR 0.57, 95% CI 0.34–0.95, p = 0.032). Importantly, we find a similar association of cognitive impairment with OS in multivariable analysis (HR 0.57, 95% CI 0.33–0.96, p = 0.034), after adjusting for two other significant variables: LDH pre-lymphodepletion (HR for normal LDH: 0.31, 95% CI 0.18–0.52, p < 0.001) and KPS (HR for KPS ≥90: 0.48, 95% CI 0.23–0.99, p = 0.047). Cognitive impairment is not associated with PFS, non-relapse mortality (NRM), or the development of CRS or ICANS. We next examine possible mechanisms by which cognitive impairment affects survival. We find that the NRM of the overall cohort is quite low with a non-significant difference of 5 events among 68 cognitively impaired, and 6 events among 111 cognitively intact patients. Interestingly, significantly more cognitively intact patients received additional treatments post-relapse, 87%, than cognitively impaired patients, 67%. Conclusions: In this contemporary, large, single-institution cohort study, we show that pre-exisiting cognitive impairment prior to CAR T therapy is associated with significantly reduced OS independent of other well-established risk factors. While the underlying mechanism may be multifactorial, cognitive impairment, as a marker of frailty among older patients, may contribute to these patients' decreased ability to tolerate additional, post-relapse therapy. We are currently planning a multi-center validation study, and conducting a prospective, pilot interventional study to target cognitive impairment during CAR T therapy.

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