Pilot Study of Longitudinal Geriatric Assessment and Neurocognitive Evaluation in CAR T-Cell Therapy for Older Patients with Relapsed Refractory, Large B-Cell Lymphoma

Introduction: Chimeric antigen receptor T-cell (CAR T) therapy is increasingly utilized for older patients with relapsed refractory, large b-cell lymphoma (LBCL) with promising efficacy. However, the feasibility of conducting serial geriatric assessments with appropriate management has not been examined in this vulnerable population of patients. Moreover, the short-term and long-term impact of CAR T-cell therapy on the older patient's overall physical and neurocognitive functioning remains unknown.

Methods: In this prospective pilot study (NCT04300998), we enrolled older patients with LBCL receiving commercial CAR T and conducted serial geriatric assessments (GA), formal neurocognitive testing in domains sensitive to cancer therapy side effects including attention, memory, and executive functions, and quality-of-life surveys prior to and following CAR T treatment at 3, 6, and 12 months among patients who remained in remission. CAR T manufacturing, treatment, and follow-ups followed national and institutional guidelines. Cytokine release syndrome (CRS) and Immune effector cell-associated neurologic syndromes (ICANS) were graded according to the ASTCT criteria. Standard statistical analysis was performed for CAR T treatment outcomes. GA impairment in each domain (binary outcome) was tabulated as percentages. For neurocognitive testing, means across timepoints were estimated for each test score using a linear mixed model predicting the score by timepoint. A random intercept was included to account for multiple assessments per patient.

Results: Between April 2020 to March 2022, 18 patients were enrolled. The median age was 69.8 years (range 63.7 to 85.0) and 8 of 18 patients, 44%, were female. Eight patients received Axicabtagene ciloleucel while 6 and 4 patients received Tisagenlecleucel and Lisocabtagene maraleucel, respectively. Fourteen out of 18 patients, 78% (95% confidence interval [CI] 52 - 94), completed all required GA visits (baseline and all follow-up timepoints while in remission), meeting the prespecified feasibility endpoint of 75%. Geriatric vulnerabilities detected by GA were highly prevalent at the baseline including functional impairment by instrumental activities of daily living (44%), mobility impairment (24%), multimorbidity (61%), polypharmacy (44%), poor psychosocial support (39%), and depression (28%). Moreover, on a panel of 7 neurocognitive tests, 52.9% of patients had at least one and 29.4% had 2 or more impairments at baseline.

With a median follow-up of 24 months (95% 23 - not reached), the 2-year overall and progression-free survival was 70% (95% CI 51 - 96) and 42% (95% CI 24 - 74), respectively. Ten patients had relapsed/progressed and among them 5 had died. Thirteen patients, 72%, experienced CRS with the majority grade 1-2 and only 2 patients (11%) had grade 3 CRS. Four patients, 22%, experienced ICANS (three grade 1 and one grade 2). The most common high-grade toxicities within 100 days of CAR T treatment were infections (n=4); cardiac complications (n=2); and thrombotic complications (n=2). There was no treatment-related death.

Finally, longitudinal GA post-CAR T revealed the stability of geriatric impairment overtime among patients remaining in remission (Figure 1 left). Moreover, detailed neurocognitive testing revealed global stability of cognitive performance with improvements in 3 cognitive tests overtime, HVLT, ZBTA, and ZBF (Figure 1 right HVLT test). These findings support the notion among patients who achieve remission.

Conclusions: In this prospective pilot study, we showed that longitudinal GA was feasible to perform in older, vulnerable lymphoma patients receiving CAR T therapy. Despite advanced age and high prevalence of baseline geriatric and cognitive deficits, CAR T treatment was well tolerated without excessive or unexpected toxicities. Stable GA deficits and improvement in some areas of cognitive performance were observed descriptively among patients in ongoing remission, supporting that CAR T treatment in older patients is safe without detrimental, long-term cognitive and functional impacts. Although the small sample size and incomplete data limited study interpretation and generalization, GA and geriatric management may provide valuable, actionable information to optimize older lymphoma patients for CAR T-cell therapy.