Michael Cuccione Childhood Cancer Research Program and.
Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Blood. 2022 Jan 13;139(2):287-299. doi: 10.1182/blood.2021013244.
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.
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植（HSCT）后非复发死亡的最常见原因。然而，目前尚无 cGVHD 或晚期急性移植物抗宿主病（aGVHD）的明确生物标志物。本研究对儿科 HSCT 受者 cGVHD 和晚期 aGVHD 的代谢组学模式进行了纵向评估。对 ABLE/PBMTC1202 研究中 222 例可评估儿科患者的血浆代谢物进行了定量分析。我们对 114 日后发生 cGVHD 或晚期 aGVHD 的患者（非 cGVHD 对照组）在第 100 天（D100）进行风险分配分析。第二次分析是在诊断时使用固定和混合多回归分析，将 cGVHD 发病时与时间匹配的非 cGVHD 对照组进行比较。只有当代谢标志物符合所有 3 个选择标准时，才被认为具有生物学相关性：（1）P≤0.05；（2）效应比≥1.3 或≤0.75；（3）接受者操作特征曲线 AUC≥0.60。我们发现，在 cGVHD 发病前（D100）和发病时，血浆α-酮戊二酸水平持续升高，不受 cGVHD 严重程度、青春期状态或先前 aGVHD 的影响。此外，与 cGVHD 相比，晚期 aGVHD 在 D100 时具有独特的代谢组学模式。在肺、新发和进展性 cGVHD 的临床表现中也观察到了其他代谢组学相关模式。α-酮戊二酸在 D100 的风险分配和后来的诊断发病分析中都是与 cGVHD 相关性最强的单一代谢物。这些独特的代谢模式可能导致 cGVHD 的亚分类得到改善。需要进一步验证这些探索性结果。该试验在 www.clinicaltrials.gov 上注册，编号为 NCT02067832。
