4.7 Article

Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease

Journal

BLOOD
Volume 139, Issue 2, Pages 287-299

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021013244

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Funding

  1. Canadian Institutes of Health Research (CIHR) Team grant
  2. CIHR Foundation grant
  3. Leukemia Lymphoma Canada

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This study longitudinally evaluated the metabolomic patterns of chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (aGVHD) in pediatric hematopoietic stem cell transplant recipients. The results showed that plasma alpha-ketoglutaric acid levels were consistently elevated before and at the onset of cGVHD, and late aGVHD had a unique metabolomic pattern at an early stage compared to cGVHD.
Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day 1 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P <= .05; (2) effect ratio of >= 1.3 or <= 0.75; and (3) receiver operator characteristic AUC >= 0.60. We found a consistent elevation in plasma alpha-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. alpha-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed.

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