Impact of Obesity on Efficacy, Safety, and Expansion Kinetics of Chimeric Antigen Receptor-T (CAR T) Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma (LBCL)

Abstract

Introduction: Obesity causes low-grade inflammation and immune escape, where T-cells lose their ability to infiltrate tumors. However, such T-cell exhaustion, characterized by increased expression of inhibitory checkpoint receptors, has led to better responses to immune checkpoint blockade therapy in patients with higher body mass index (BMI) (Wang Nature Medicine 2019). Previous studies have shown no significant association of obesity with safety or efficacy of Chimeric Antigen Receptor T-cell (CAR T) therapy in hematologic malignancies (Faruqi Blood Advances 2022). However, data on the impact of BMI on outcomes in LBCL and CAR T expansion kinetics is limited. We conducted a single-site study to investigate the effect of obesity on efficacy and safety outcomes, healthcare utilization, and CAR T expansion in patients with relapsed/refractory LBCL treated with Axicabtagene Ciloleucel(axi-cel). Methods: 189 patients with relapsed/refractory LBCL who were consecutively treated with axi-cel from 12/2017 to 5/2022 were included in the study. BMI was calculated on the day of apheresis. Patients were then divided into three BMI categories based on CDC guidelines: underweight/normal (≤24.99kg/m 2), overweight (>25kg/m 2 and ≤29.99kg/m 2), and obese (>30kg/m 2). Response was assessed using the Lugano 2014 criteria, and toxicities via the CTCAE version 5.0 and ASTCT grading. CAR T expansion was measured by real-time flow cytometry with anti-idiotype-FMC63 conjugated to Dylight 650. Areas under the curve (AUCs) were calculated for CAR T expansion in the 28 days following infusion using the linear trapezoidal method on raw values, and results were transformed using a base-10 logarithm. Continuous outcomes were compared using a Kruskal-Wallis test, categorical outcomes using Chi-square tests, and time-to-event outcomes using the Kaplan-Meier estimator and the log-rank test. Statistical significance was determined at p < 0.05. All analyses were conducted in R 4.3.0. Results: Out of 189 patients, 46% (n=87) were in the underweight/normal group, 29% (n=56) in the overweight, and 24% (n=46) were obese. Baseline demographics and clinical characteristics between groups were similar except for gender ( p=0.009). Complete response (CR) and overall response (ORR) including partial response (PR) and CR were compared among these cohorts. Neither complete response nor overall response was found to be significantly different amongst the BMI categories for their best response within 12 months of CAR T infusion ( p=0.9886 and 0.802, respectively). Median progression-free survival (PFS) was 14.6 months (IQR 4.93, 44.81) for the underweight/normal weight cohort, 14.89 months (IQR 5.82, 40.07) for the overweight cohort, and 28.37 months (IQR 3.88, NA) for obese; but was not statistically significant ( p=0.8004) [Figure 1]. Median overall survival (OS) was 44.81 months (IQR 18.18, NA) for the underweight/normal weight cohort and 40.07 months (IQR 23.18, NA) for the overweight category. This was not achieved for the obese category, and no statistical difference was found ( p=0.3478). When cytokine release syndrome (CRS) or immune cell-associated neurologic toxicity syndrome (ICANS) events were compared among these groups, there was no significant difference in either overall incidence or when graded as severe (›3), based on BMI category. Similarly, no significant differences were found in healthcare utilization variables, including length of hospital stay, ICU admissions, tocilizumab, anakinra or steroid use. Differences in day 7 and day 14 CAR T expansion were not statistically significant ( p=0.754 and 0.355, respectively). For AUC calculations, there was no statistically significant difference amongst the BMI categories (CD4: p=0.8284, CD8: p=0.8695, CD4 + CD8: p=0.8820) [Figure 2]. Conclusion: Contrary to the effect of obesity on response to therapies like checkpoint inhibitors we demonstrate that BMI does not significantly impact patients treated with CAR T. Weight has been central to chemotherapy dosing for lymphoma, but despite weight-based dosing for axi-cel, correlative studies on CAR T expansion kinetics did not indicate any significant difference. These findings suggest that obesity may not substantially influence the outcomes or dosing considerations of CAR T therapy, supporting the use of CAR T therapy as an effective treatment option for lymphoma patients, regardless of their BMI.