Long-Term Cognitive Impairment After CAR-T Therapy Versus Autologous Stem Cell Transplantation: A Propensity...

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed outcomes in relapsed or refractory hematologic malignancies, but long-term cognitive outcomes remain poorly understood. We compared the incidence and time course of cognitive impairment and associated neurological complications after CAR-T therapy compared with autologous stem cell transplantation (ASCT). Methods: This retrospective, propensity-matched cohort study utilized the TriNetX US Collaborative Network (January 2014-April 2025). To ensure concurrent comparisons, ASCT recipients were restricted to an index date beginning in August 2017 or later. CAR-T recipients were matched 1:1 to ASCT recipients for demographics, disease, comorbidities, prior and concomitant treatments, and laboratory parameters. The primary endpoint was time to cognitive impairment, as defined by ICD-10 codes. Results: After comparing 3067 CAR-T patients (median follow-up 634 days) with 3067 ASCT patients (median follow-up 713 days), CAR-T recipients had a higher risk of cognitive impairment (HR 1.58; 95% CI 1.39-1.80; p < 0.001). Because the risks were not proportional (Schaenfeld p < 0.001), the difference was also expressed as restricted median survival time (RMST): CAR-T recipients spent approximately 25 and 53 days fewer days without cognitive impairment at 1 and 2 years, respectively (both p < 0.001). The risk was greatest at 30 days (HR 4.22; 95% CI 3.23-5.53), but remained elevated in control analyses at 30 and 90 days that excluded the acute ICANS window (HR 1.30 and 1.25, respectively; both p < 0.05). Neurological dysfunction, particularly encephalopathy (HR 2.04; 95% CI 1.73-2.40), was more common after CAR-T. Conversely, CAR-T was associated with a reduced risk of secondary acute myeloid leukemia (HR 0.46; 95% CI 0.38-0.55; p < 0.001). Conclusions: CAR-T therapy is associated with a higher risk of cognitive impairment that persists beyond the acute phase. As these are observational, code-based data, they should be interpreted as associations rather than evidence of a specific mechanism, and they highlight the need for informed consent discussions, long-term neurocognitive monitoring, and the development of neuroprotective strategies.