Trends in muscle and fat metrics and their association with outcomes following CAR T-cell therapy in older adults with non Hodgkin lymphoma.

Abstract

Abstract Chimeric Antigen Receptor (CAR-T) therapy has transformed treatment for non-Hodgkin lymphoma (NHL) and is now standard as early as second line in eligible patients. Its use in older adults (historically considered high-risk for toxicity), has increased the interest in identifying predictors of outcomes given the wide variability of fitness in this population. Body composition parameters are increasingly used in oncology as an objective measure of physiological reserve and frailty. It can be assessed using routine CT scans to evaluate both the quantity and quality of muscle and fat. Skeletal muscle index (SMI), calculated at the L3 level by dividing muscle area by height squared, is used to assess sarcopenia. Skeletal muscle density (SMD) reflects fat infiltration within muscle, with lower Hounsfield Unit (HU) values indicating myosteatosis. Adipose tissue is categorized into subcutaneous (SAT) and visceral (VAT) compartments ( in cm2), and their densities (SATD and VATD) offer additional clinical insight. Higher adipose density (closer to 0 HU) reflects reduced lipid content and is linked to inflammation and fibrosis, while lower density suggests healthier fat. In patients with NHL undergoing autologous stem cell transplant, lower VATD has been associated with better survival (Aleixo et al., 2019). In this single-center retrospective cohort of older adults with NHL treated with CAR T-cell therapy, we hypothesize that body composition parameters may serve as markers of frailty associated with worse survival and clinical outcomes. Methods We conducted a single-center retrospective cohort study of consecutive patients aged ≥65 years who received CAR T-cell therapy for NHL between 2019 and 2025. CT scans within 45 days before and 90 days after infusion were analyzed to estimate body composition parameters, including SMI, SAT, VAT, and their densities. Baseline characteristics were summarized descriptively. Pre- and post-infusion body composition metrics were then compared between age groups (65–75 vs. >75 years) using Wilcoxon rank-sum tests for cross-sectional differences. Overall Survival (OS) was defined from infusion to death or last follow-up and analyzed using Kaplan-Meier curves and Cox models. Logistic regression was used to evaluate associations between clinical and body composition variables with infections within 180 days. Univariate analyses were followed by a multivariable model. Results A total of 153 patients were included; 135 had baseline CT scans, 124 had 90-day scans, and 106 had both available for delta calculations. The median age was 71 years (IQR 68–75). Most patients (84%) had diffuse large B-cell lymphoma, including 9% with double-hit disease; 7% had follicular lymphoma, 9% had mantle cell lymphoma, and 1% had chronic lymphocytic leukemia. Overall, 62% had received more than two prior lines of therapy, and CHOP-based regimens were the most common first-line treatment (65%). Tisagenlecleucel was the most frequently used CAR T-cell product (62%). Patients over 75 years had significantly lower skeletal muscle mass both at baseline (SMI 36.6 vs. 40.33, p=0.02) and at 90 days post-infusion (SMI 35.8 vs. 40.9, p=0.029) compared to patients aged 65–75. However, the change in SMI over time did not differ significantly between age groups (p=0.391). No significant differences were observed between age groups in other body composition parameters. After adjusting for age, CAR T-cell product, ECOG performance status, BMI, and number of prior therapies, higher post-therapy VATD (HR 1.04, 95% CI 1.02–1.05, p < 0.001) and SATD (HR 1.03, 95% CI 1.01–1.04, p = 0.001) remained independently associated with shorter overall survival. Furthermore, each unit increase in VATD or SATD from baseline to 90 days post-CAR-T further portended worse outcome (VATD: HR 1.05, 95% CI 1.02–1.1, p = 0.001; SATD: HR 1.04, 95% CI 1.02–1.07, p = 0.001). Similarly, higher post-therapy SATD (Odds Ratio (OR) 1.04, 95% CI 1.01–1.07, p = 0.003) and increases in SATD at 90 days post-CAR-T (OR 1.04, 95% CI 1.01–1.09, p = 0.01) were associated with increased risk of infection within 180 days. Conclusion Our findings suggest that higher adipose tissue density is associated with worse survival and increased infection rates in older adults with NHL treated with CAR T-cell therapy. These results support further investigation of adiposity markers as objective, imaging-based indicators of frailty.