According to research published in Blood, plasma alpha-ketoglutaric acid appears to be consistently elevated both before and at the onset of chronic graft vs host disease (cGVHD) in children and adolescents. The study also found distinctive metabolomics profiles among patients with cGVHD, late acute GVHD (aGVHD), and different clinical presentations of cGVHD.

To identify potential metabolic biomarkers for cGVHD or late aGVHD, the researchers longitudinally evaluated metabolomic patterns of cGVHD and late aGVHD in pediatric patients who underwent hematopoietic stem cell transplant (HSCT).

Plasma samples of 222 evaluable pediatric patients from the Applied Biomarkers of Late Effects of Childhood Cancer/Pediatric Blood and Marrow Transplant Consortium 1202 protocol (ABLE/PBMTC 1202; Identifier: NCT02067832), a prospective study for the discovery of biomarkers for pediatric cGVHD, were used for quantitative analysis of plasma metabolites.

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The team performed a risk-assignment analysis of plasma metabolites at day +100 (D100) of patients who later developed either cGVHD (n = 27) or late aGVHD after day 114 (n = 45) against control participants who did not develop cGVHD (n = 110). They also conducted a regression analysis at diagnosis to compare plasma metabolites of patients with cGVHD at onset to time-matched control participants without cGVHD. They considered a metabolomic biomarker biologically relevant if it satisfied 3 selection criteria, a P ≤.05, an effect ratio of ≥1.3 or ≤.75, and a receiver operator characteristic area under the curve (AUC) ≥.60. They also performed subgroup analyses of different types of cGVHD.

The researchers discovered that plasma α-ketoglutaric acid was consistently elevated before D100 and at the onset of cGVHD, independent of cGVHD severity, pubertal status, or previous aGVHD. They also found that late aGVHD had a unique metabolomic pattern at D100 compared with that of cGVHD and that clinical presentations of pulmonary, de novo, and progressive cGVHD had other metabolomic patterns. In the D100 risk-assignment and later diagnostic onset analysis, the team found that alpha-ketoglutaric acid was the most significant metabolite associated with cGVHD.

“This study represents the largest prospective, well-characterized pediatric cohort with cGVHD and late aGVHD to date and is larger than any other adult study,” the researchers wrote. “These distinctive metabolic patterns may lead to improved subclassification of cGVHD.”

The primary limitation of the study was small sample sizes within each cGVHD subgroup, warranting validation studies in additional cohorts.


Subburaj D, Ng B, Kariminia A, et al. Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease. Blood. 2022;139(2):287-299. doi:10.1182/blood.2021013244