Department of Clinical Science, University of Bergen, 5020, Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway.
Department of Clinical Science, University of Bergen, 5020, Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway.
Transplant Cell Ther. 2023 Jun;29(6):375.e1-375.e14. doi: 10.1016/j.jtct.2023.03.020. Epub 2023 Mar 24.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used in the treatment of high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, the treatment has high risk of severe transplantation-related mortality (TRM). In this study, we examined pretransplantation serum samples derived from 92 consecutive allotransplant recipients with AML or MDS. Using nontargeted metabolomics, we identified 1274 metabolites including 968 of known identity (named biochemicals). We further investigated metabolites that differed significantly when comparing patients with and without early extensive fluid retention, pretransplantation inflammation (both being associated with increased risk of acute graft-versus-host disease [GVHD]/nonrelapse mortality) and development of systemic steroid-requiring acute GVHD (aGVHD). All three factors are associated with TRM and were also associated with significantly altered amino acid metabolism, although there was only a minor overlap between these three factors with regard to significantly altered individual metabolites. Furthermore, steroid-requiring aGVHD was especially associated with altered taurine/hypotaurine, tryptophan, biotin, and phenylacetate metabolism together with altered malate-aspartate shuttle and urea cycle regulation. In contrast, pretransplantation inflammation was associated with a weaker modulation of many different metabolic pathways, whereas extensive fluid retention was associated with a weaker modulation of taurine/hypotaurine metabolism. An unsupervised hierarchical cluster analysis based on the 13 most significantly identified metabolites associated with aGVHD identified a patient subset with high metabolite levels and increased frequencies of MDS/MDS-AML, steroid-requiring aGVHD and early TRM. On the other hand, a clustering analysis based on metabolites that were significantly altered for aGVHD, inflammation, and fluid retention comparison groups identified a patient subset with a highly significant association with TRM. Our study suggests that the systemic pretransplantation metabolic profiles can be used to identify patient subsets with an increased frequency of TRM.
异基因造血干细胞移植（allo-HSCT）用于治疗高危急性髓系白血病（AML）和骨髓增生异常综合征（MDS）；然而，该治疗方法存在严重的移植相关死亡率（TRM）风险。在这项研究中，我们检查了 92 例连续接受 AML 或 MDS allo-HSCT 的患者的移植前血清样本。使用非靶向代谢组学，我们鉴定了包括 968 种已知身份的代谢物（命名为生化标志物）在内的 1274 种代谢物。我们进一步研究了在比较患者有无早期广泛液体潴留、移植前炎症（两者均与急性移植物抗宿主病[GVHD]/非复发死亡率增加相关）以及发展为全身性类固醇依赖性急性 GVHD（aGVHD）时差异显著的代谢物。所有这三个因素都与 TRM 相关，并且与氨基酸代谢的显著改变相关，尽管这三个因素在显著改变的个体代谢物方面只有很小的重叠。此外，类固醇依赖性 aGVHD 尤其与牛磺酸/次牛磺酸、色氨酸、生物素和苯乙酸代谢的改变以及苹果酸天冬氨酸穿梭和尿素循环调节的改变相关。相反，移植前炎症与许多不同代谢途径的弱调节相关，而广泛的液体潴留与牛磺酸/次牛磺酸代谢的弱调节相关。基于与 aGVHD 相关的 13 种最显著鉴定代谢物的无监督层次聚类分析，确定了具有高代谢物水平和 MDS/MDS-AML、类固醇依赖性 aGVHD 和早期 TRM 频率增加的患者亚组。另一方面，基于与 aGVHD、炎症和液体潴留比较组显著改变的代谢物的聚类分析，确定了与 TRM 具有高度显著关联的患者亚组。我们的研究表明，移植前的系统代谢谱可用于识别具有较高 TRM 频率的患者亚组。
