Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease
Divya Subburaj, Bernard Ng, Amina Kariminia, Sayeh Abdossamadi, Madeline Lauener, Eneida R. Nemecek, Jacob Rozmus, Sandhya Kharbanda, Carrie L. Kitko, Victor Lewis, Tal Schechter-Finklestein, David A. Jacobsohn, Andrew C. Harris, Michael A. Pulsipher, Henrique Bittencourt, Sung Won Choi, Emi Caywood, Kimberly A. Kasow, Monica Bhatia, Benjamin Oshrine, Donald W. Coulter, Joseph H. Chewning, Michael Joyce, Anna Pawłowska, Gail Megason, Ánita Lawitschka, Elena Ostroumov, Ramon I. Klein Geltink, Geoff D.E. Cuvelier, Kirk R. Schultz
Abstract
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 + 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 α-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. α-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. This trial was registered at www.clinicaltrials.gov as #NCT02067832.