Impact of Sarcopenia and Subsequent Muscle Loss on Post-CAR T-Cell Outcomes in Relapsed/Refractory Large B-Cell Lymphoma
Authors: Jhaveri Khushali , Thapa Ram , Noble Jerald , Ercan Dalia , Singh Pranit , Fahrmann Johannes , Saini Neeraj Y. , Wu Ranran , Dennison Jennifer , Hanash Samir , Jenq Robert R. , Modi Karnav , Figura Nicholas , Chavez Julio C , Shah Bijal D. , Nishihori Taiga , Lazaryan Aleksandr , Khimani Farhad , Bachmeier Christina A , Gage Kenneth , Mishra Asmita , Perna Fabiana , Davila Marco , Rejeski Kai , Subklewe Marion , Locke Frederick L. , Freeman Ciara Louise L. , Parker Nathan , Jain Michael D. 
Published: December 2023

Background:
Sarcopenia is a hallmark of cachexia commonly found in cancer patients that is caused by immune and metabolic mediators of catabolism. Chimeric antigen receptor (CAR) T-cell therapy is used to treat cancer and is characterized by the release of inflammatory cytokines and other potentially catabolic mediators. Previously, we showed that baseline sarcopenia and other immuno-nutritional scores were associated with poor outcomes after CD19-directed CAR T-cell therapies in patients with R/R LBCL (Rejeski et al. Cancer Immunol. Res. 2023). Here we examined the relationship between body composition and serum metabolite levels over time after CAR T-cell infusion.
Methods: This is a single-center retrospective study of N=83 patients with R/R LBCL who received CAR T-cell therapy. The median clinical follow-up was 18.4 months. Muscle and adipose tissue distribution were calculated from clinical pre-lymphodepletion, day (d) 30, and day (d) 90 CT imaging using Slice-O-Matic software (v5.0, Tomovision). Baseline sarcopenia status was determined using established criteria (SMI 52.4 cm2/m2 for Males and 38.5 cm2/m2 for Females) . Immuno-nutritional scores included: GPS Score: CRP ≤ 10 mg/L = 0; CRP &gt; 10 mg/L and albumin &gt; 3.5 g/dL = 1; CRP &gt; 10 mg/L and albumin &lt; 3.5 g/dL = 2. PNI Score: Albumin (g/L) + 5 × total lymphocyte count (10^9/L). Muscle loss at d30 or d90 after CAR T-cell therapy was defined by a decrease of &gt; 10% in their skeletal muscle index (SMI) from baseline. Patients who had relapsed, died or had missing scans were censored during the analysis. Univariate and multivariable Cox regression models using LASSO regularization assessed the association between various factors and survival outcomes. Serum metabolites were profiled at baseline and at regular time points up to 4 weeks after CAR T cell therapy (n=55) as previously described (Fahrmann et al. Cell Rep. Medicine 2022).
Results:
Patients with baseline sarcopenia (n=44) had worse progression-free (PFS) and overall survival (OS) after CD19 CAR T cell therapy for R/R LBCL compared to non-sarcopenic patients (n=39) (OS: HR=2.5, 95% CI: 1.3-4.9, P=0.008; PFS: HR=1.8, 95% CI: 1.0-3.2, P=0.037). In multivariable Cox fits (MVA) for OS, male gender (HR=3.3, 95% CI: 1.3-8.8, P=0.014), and GPS score of 2 (HR=3.8, 95% CI: 1.4-10.6, P=0.011) were associated with worse OS. On MVA for PFS, a lower PNI score was mildly associated with worse outcomes (HR=0.9, 95% CI: 0.8-1.0, P=0.039).
Muscle loss occurred between baseline and d30 and d90 after CAR T-cell therapy in 34% and 32% of patients, respectively. Muscle loss correlated with concurrent adipose tissue loss and overall weight loss. Patients who had baseline sarcopenia had more pronounced muscle loss at d30 and d90 compared to patients who were non-sarcopenic at baseline. Associations with d30 muscle loss included ICANS grade 2 or higher (P=0.046) and baseline LDH (P=0.033). Further, patients with ICANS grade 2 or higher had a significantly higher d30 median muscle loss compared to patients with grade 0-1 ICANS (9.1% versus 6.4%; p=0.049). However, whether landmarked at d30 or d90, muscle loss after CAR T-cell therapy did not significantly associate with the risk of subsequent progression or death.
Individual serum metabolites that significantly decreased between pre-infusion and after CAR T-cell infusion included those potentially associated with gut microbiome alterations (indole-3-acetate and xanthosine). Pathway analysis revealed changes in purine and pyrimidine metabolism over time after CAR T-cell therapy. Subgroup analyses comparing metabolites over time in sarcopenia versus non-sarcopenia, as well as based on muscle loss are in progress.
Conclusions: Sarcopenia is highly prevalent (53%) in R/R DLBCL patients presenting for CAR-T and approximately 1/3 of patients lose muscle mass during the course of therapy, with the greatest risk noted in those with baseline sarcopenia. High immuno-nutritional scores are associated with inferior outcomes. Muscle loss was associated with a higher disease burden and higher-grade toxicities. Further study is needed to understand the association between antibiotics use and clinical factors for microbiome-related metabolites that change over time after CAR T-cell infusion. Interventional approaches to improve functional and nutritional reserve to optimize outcomes are warranted.