CAR T-Cell Therapy May Spare Older Patients’ Memory More Than Younger Ones

Chimeric antigen receptor T-cell therapy has transformed the outlook for patients with large B-cell lymphoma whose disease has stopped responding to conventional treatments, but a persistent question has shadowed its success: what does this powerful immunotherapy do to the brain? A new longitudinal study published in Supportive Care in Cancer suggests the answer may depend more on age than clinicians expected. Contrary to the researchers’ own hypothesis, older patients did not fare worse cognitively after receiving axicabtagene ciloleucel, one of the most widely used CAR T-cell products. Instead, it was younger adults who showed unexpected vulnerability, particularly in memory, while older patients demonstrated greater recovery of cognitive abilities over the first year after infusion.

The research team, led by Aasha I. Hoogland of the Moffitt Cancer Center, pooled data from two longitudinal studies of patients treated with axicabtagene ciloleucel, restricting their analysis to people diagnosed with large B-cell lymphoma. In total, 155 participants completed neuropsychological assessments before conditioning therapy began and again at 30, 90, and 360 days after infusion. Sixty-nine of them, or 45 percent, were aged 65 or older. The sample was predominantly male and White, and participants ranged in age from 19 to 82, with a mean age of 61. Each assessment covered a battery of validated tests measuring attention, executive function, verbal ability, immediate verbal memory, delayed memory, and visuospatial abilities, which were averaged into domain scores and an overall total neuropsychological performance score.

The technical design of the study matters for interpreting its findings. Raw test scores were standardized as T-scores using age-adjusted population norms, so performance was judged against what would be expected for a person’s age. Impairment on any given test was defined as scoring two or more standard deviations below the mean, and overall cognitive impairment was flagged when a participant scored two standard deviations below the mean on one test or 1.5 standard deviations below on two tests. To track change over time, the researchers used random-effects mixed models with linear and quadratic terms for time, an approach that estimates within-person trajectories and tolerates the unequal assessment intervals and missing data that are inevitable in a population of seriously ill cancer patients.

The starting point was sobering but not surprising. Before infusion, 48 percent of older adults showed overall neurocognitive impairment compared with 34 percent of younger adults, a statistically significant difference. Older participants also performed worse than younger participants on every neurocognitive domain at baseline. Yet by one year after infusion, that gap had dissolved entirely. There were no statistically significant differences between the age groups in immediate verbal memory or delayed memory at the 360-day mark, and the overall rates of impairment no longer differed between the groups after treatment.

The most striking result emerged in the memory domains. Immediate verbal memory and delayed memory improved significantly over time in older adults, with p-values below 0.01, but remained stable in younger adults. The improvement in immediate verbal memory among older patients was large enough to be clinically meaningful, exceeding the five-point threshold the researchers set to reflect a medium effect size. This pattern is the reverse of what the team predicted. In neuropsychology, a lack of expected improvement between repeated test administrations, often called an absence of practice effects, is itself considered a signal of cognitive abnormality. The fact that younger patients showed no such improvement, while older patients did, hints at a genuine post-treatment cognitive vulnerability in the younger group that could not be explained by disease status, cytokine release syndrome, neurotoxicity, or the number of prior therapies.

The raw impairment counts reinforce that interpretation. Among younger adults with normal cognitive scores before infusion, 30 percent developed newly onset impairment by day 30, 41 percent by day 90, and fully half by day 360. Among older adults who started with normal cognition, the corresponding figures were 15, 32, and 35 percent. Persistent impairment at one year was evaluable in a subset of patients, and 61 percent of younger adults with new impairment who completed the final assessment still met impairment criteria, compared with 50 percent of older adults. These numbers suggest that the burden of new cognitive deficits after CAR T-cell therapy falls disproportionately, if unexpectedly, on the young.

The clinical context helps explain why this question is urgent. Subgroup analyses of the pivotal ZUMA-1 trial showed that patients aged 65 and older achieved high response rates to axicabtagene ciloleucel, with 92 percent clinical responses and 75 percent complete responses, and the ZUMA-7 trial found that older patients given the therapy lived significantly longer, 21.5 versus 2.5 months, with better objective response rates than standard care at the time. Real-world data echo those results. But the same trials revealed that older patients were more likely to experience severe neurologic events, grade 3 or higher, than younger patients. Severe acute neurotoxicity, however, is a different phenomenon from the subtle, measurable cognitive changes tracked by neuropsychological testing, and until now little was known about how age shapes those longer-term trajectories.

The exploratory analyses of clinical risk factors added further nuance. Older adults who had received four or more prior lines of therapy showed the greatest improvements in overall neuropsychological performance and verbal ability, a finding that challenges the so-called multiple hit hypothesis, which holds that each successive cancer treatment accumulates cognitive damage. By 12 months post-infusion, these older, heavily pretreated patients demonstrated clinically meaningful gains relative to younger patients with the same treatment history. Conversely, older adults with active disease at three months, meaning they had not responded to the CAR T-cell infusion, showed rapid deterioration in visuospatial ability and performed significantly worse than younger patients with active disease at every post-infusion timepoint. The researchers caution, however, that only four older adults in each of these subgroups provided neurocognitive data at 12 months, so these subgroup findings have limited statistical power and require replication.

The authors situate their results within a broader literature on cognition after cellular therapy. A meta-analysis of cognitive function after hematopoietic cell transplantation, another cellular therapy for blood cancers, similarly found a lack of expected practice effects over time in a population with a median age of 43. Prior work from the same Moffitt group had shown that older age was associated with worsening verbal memory and fluency after transplantation, making the current reversal in CAR T-cell recipients all the more intriguing. The researchers also note that among people without cancer, verbal working memory peaks in young adulthood, around age 30, which may create a window of vulnerability for memory-related cognitive domains in younger patients. Whether the younger patients’ flat memory trajectories reflect biological sensitivity, unmeasured treatment effects, or some other mechanism remains an open question.

The study has clear limitations. The sample was composed largely of male, White, non-Hispanic, married college graduates, which constrains generalizability, and more than a third of patients with baseline data did not provide data at one year, largely because of morbidity or mortality. The sample size also precluded comparisons between patients treated commercially and those treated on clinical trials, an important distinction since outcomes can differ between those settings. Still, the longitudinal design, validated measures, and statistical methods that accommodate missing data give the findings real weight. For patients and clinicians weighing CAR T-cell therapy, the message is cautiously reassuring for older adults: despite their higher risk of acute neurotoxicity, their memory trajectories after axicabtagene ciloleucel were not worse than those of younger patients, and in some respects were better. The authors call for larger studies of cognition in older CAR T-cell recipients, and for closer attention to the cognitive aftereffects experienced by younger patients, whose brains may bear more of the treatment’s hidden cost than anyone anticipated.

Subject of Research: Age-related differences in neurocognitive outcomes after axicabtagene ciloleucel CAR T-cell therapy for large B-cell lymphoma

Article Title: Age as a moderator of neurocognitive performance in patients with large B-cell lymphoma treated with axicabtagene ciloleucel

Article References: Hoogland, A. I., Li, X., Hu, B., Irizarry-Arroyo, N., Welniak, T., Rodriguez, Y., Jain, M. D., Oswald, L. B., Small, B. J., Snider, J. T., Wade, S. W., Chavez, J. C., Khimani, F., Lazaryan, A., Liu, H. D., Nishihori, T., Pinilla-Ibarz, J., Shah, B. D., Pidala, J. A., … Jim, H. S. L. (2026). Age as a moderator of neurocognitive performance in patients with large B-cell lymphoma treated with axicabtagene ciloleucel. Supportive Care in Cancer, 34(10), Article 943. https://doi.org/10.1007/s00520-026-11169-w

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11169-w

Keywords: CAR T-cell therapy, axicabtagene ciloleucel, large B-cell lymphoma, neurocognitive performance, memory, cognitive impairment, aging, neurotoxicity, cytokine release syndrome, immunotherapy, longitudinal study, supportive care