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

Area of Science:

• Metabolomics
• Hematopoietic Stem Cell Transplantation (HSCT)
• Immunology

Background:

• Chronic graft-versus-host disease (cGVHD) is a major cause of non-relapse mortality following allogeneic HSCT.
• Current diagnostic methods lack specific biomarkers for cGVHD and late acute GVHD (aGVHD).
• Pediatric HSCT recipients require better tools for early detection and management of GVHD.

Purpose of the Study:

• To longitudinally evaluate metabolomic patterns associated with cGVHD and late aGVHD in pediatric HSCT recipients.
• To identify potential metabolomic biomarkers for cGVHD and late aGVHD.
• To explore the correlation of metabolic patterns with clinical manifestations of cGVHD.

Main Methods:

• Quantitative analysis of plasma metabolites in 222 pediatric subjects from the ABLE/PBMTC1202 study.
• Risk-assignment analysis at day +100 (D100) comparing future cGVHD/late aGVHD patients to controls.
• Regression analysis comparing cGVHD at onset to time-matched controls, with biomarker relevance defined by P ≤ .05, effect ratio ≥1.3 or ≤0.75, and AUC ≥0.60.

Main Results:

• Consistent elevation of plasma α-ketoglutaric acid was observed before (D100) and at the onset of cGVHD, independent of severity or patient factors.
• Late aGVHD exhibited a distinct D100 metabolomic profile compared to cGVHD.
• α-ketoglutaric acid emerged as the most significant metabolite associated with cGVHD in both risk-assignment and diagnostic analyses.

Conclusions:

• Distinct metabolomic patterns, particularly elevated α-ketoglutaric acid, are associated with cGVHD in pediatric HSCT recipients.
• These findings suggest potential for improved subclassification of cGVHD based on metabolic profiles.
• Further validation is necessary to translate these exploratory results into clinical practice.