Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B cell Lymphoma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Khushali Jhaveri, Ram Thapa, Dalia Ercan, Aditi Saha, Jerald Noble, Pranit Singh, Johannes Fahrmann, Neeraj Saini, Ranran Wu, Jennifer B Dennison, Sam Hanash, Robert R Jenq, Karnav Modi, Nicholas Figura, Julio Chavez, Bijal Shah, Taiga Nishihori, Aleksandr Lazaryan, Farhad Khimani, Christina Bachmeier, Kenneth Gage, Asmita Mishra, Fabiana Perna, Marco L Davila, Jay Spiegel, Kai Rejeski, Marion Subklewe, Frederick L Locke, Ciara Freeman, Nathan Parker, Michael D Jain

TLDR

  • CAR T-cell therapy is associated with muscle loss and poor survival in patients with large B-cell lymphoma, particularly those with baseline sarcopenia.

Abstract

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 between CAR T-cell therapy, sarcopenia, and metabolism is poorly understood. In 83 large B-cell lymphoma patients, the skeletal muscle index (SMI) was measured from clinical images obtained at baseline and days 30 and 90 post-therapy. Serum metabolomics (n=57 patients) was performed in the first 4 weeks. Baseline sarcopenia was present in over half of patients and associated with shorter median overall survival (OS) than for non-sarcopenic patients (10.5 versus 34.3 months; P=0.006). This reduction was due to increased non-relapse mortality (NRM) with all six NRM events occurring in patients with baseline sarcopenia. In the first 30 days after CAR T-cell therapy, 1/3 of 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. 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.

Overview

  • The study investigates the relationship between CAR T-cell therapy, sarcopenia, and metabolism in large B-cell lymphoma patients.
  • The study aims to identify the frequency and predictors of sarcopenia, as well as the impact of sarcopenia on survival and metabolism during CAR T-cell therapy.
  • The study also explores the potential benefits of dietary and exercise interventions in improving CAR T-cell therapy outcomes in patients with sarcopenia.

Comparative Analysis & Findings

  • The study found that baseline sarcopenia was present in over half of patients and associated with shorter median overall survival (OS) and increased non-relapse mortality (NRM).
  • The study also found that skeletal muscle loss after CAR T-cell therapy is common, occurring in 1/3 of patients in the first 30 days, and is associated with higher tumor burden and neurotoxicity.
  • Serum metabolomics revealed an early increase in purine metabolites, followed by a later increase in triglyceride levels, with adipic acid exhibiting the highest fold-increase from baseline, attributed to the hospital menu.

Implications and Future Directions

  • The study highlights the importance of identifying and addressing sarcopenia in patients undergoing CAR T-cell therapy to improve outcomes.
  • Future studies should investigate the effects of dietary and exercise interventions on sarcopenia and survival during CAR T-cell therapy.
  • Dysregulation of muscle metabolism may be a key determinant of sarcopenia and poor survival in patients undergoing CAR T-cell therapy, and targeting this pathway may improve outcomes.
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