Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B-cell Lymphoma
Khushali Jhaveri, R. S. Thapa, Dalia Ercan, Aditi Saha, Jerald Noble, Pranit Singh, Johannes F. Fahrmann, Neeraj Saini, Ranran Wu, Jennifer B. Dennison, Samir Hanash, Robert R. Jenq, Karnav Modi, Nicholas Figura, Julio C. Chávez, Bijal Shah, Taiga Nishihori, Aleksandr Lazaryan, Farhad Khimani, Christina A. Bachmeier, Kenneth L. Gage, Asmita Mishra, Fabiana Perna, Marco L. Davila, Jay Y. Spiegel, Kai Rejeski, Marion Subklewe, Frederick L. Locke, Ciara L. Freeman, Nathan H. Parker, Michael D. Jain
Abstract
PURPOSE: Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy is associated with an inflammatory state that may exacerbate sarcopenia. The relationship among CAR T-cell therapy, sarcopenia, and metabolism is poorly understood. EXPERIMENTAL DESIGN: In 83 patients with large B-cell lymphoma, the skeletal muscle index was measured from clinical images obtained at baseline and days 30 and 90 after therapy. Serum metabolomics (n = 57 patients) was performed in the first 4 weeks. RESULTS: Baseline sarcopenia was present in more than half of patients and associated with shorter median overall survival than for non-sarcopenic patients (10.5 vs. 34.3 months; P = 0.006). This reduction was due to increased nonrelapse mortality with all six nonrelapse mortality events occurring in patients with baseline sarcopenia. In the first 30 days after CAR T-cell therapy, one of three patients experienced skeletal muscle loss greater than 10%. Muscle loss was associated with higher tumor burden and neurotoxicity but was not significantly associated with long-term survival. Serum metabolomics revealed an early (weeks 1-2) increase in purine metabolites, followed by a later (weeks 3-4) increase in triglyceride levels. The serum metabolite with the highest fold-increase from baseline was adipic acid, attributed to the inpatient hospital menu of jello and other tart beverages. CONCLUSIONS: Skeletal muscle loss after CAR T-cell therapy is common and is associated with fatty acid catabolism. Patients with baseline sarcopenia have poor tolerance and reduced survival. Future studies of dietary and exercise interventions may improve CAR T-cell therapy outcomes.