Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, Minnesota.
Biol Blood Marrow Transplant. 2018 Nov;24(11):2190-2196. doi: 10.1016/j.bbmt.2018.06.036. Epub 2018 Jul 7.
Post-transplant biomarkers of acute graft-versus-host disease (aGVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) have been extensively studied. However, pretransplant biomarkers may provide a greater window of opportunity to intervene. We measured serum biomarkers of various aspects of gut barrier physiology before HCT (median, day -7) and 7 and 28 days post-HCT in 95 consecutive allo-HCT recipients enrolled in an open-label biorepository protocol. Biomarkers included citrulline for total functional enterocyte mass, Reg3a for antibacterial activity of the gut, and intestinal fatty acid binding protein (I-FABP) for enterocyte turnover. Compared to 16 healthy control subjects, we demonstrated that patients came to transplant with abnormal levels of all 3 biomarkers (P < .05), reflecting residual damage from prior chemotherapy. All 3 biomarkers initially declined from pre-HCT to day +7 (more pronounced after myeloablative than reduced-intensive conditioning) followed by a recovery phase and return toward pre-HCT values by day +28. A lower pre-HCT citrulline was independently associated with a higher risk of aGVHD grades II to IV (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69; P = .02), and this association was not specific to gut GVHD. The strongest correlate of NRM was a higher level of Reg3a at day +7 (P < .001). I-FABP did not predict transplant outcomes. In conclusion, pre-HCT serum citrulline levels identify patients at high risk for developing aGVHD. Our results suggest that pre-HCT interventions to augment the gut barrier may decrease the risk of aGVHD.
移植后急性移植物抗宿主病（aGVHD）和非复发死亡率（NRM）的生物标志物已在异基因造血细胞移植（allo-HCT）后得到广泛研究。然而，移植前的生物标志物可能提供了更大的干预机会。我们在 95 例连续接受开放标签生物样本库方案的 allo-HCT 受者中，测量了移植前（中位数，-7 天）和移植后第 7 天和第 28 天与肠道屏障生理学各个方面相关的血清生物标志物。生物标志物包括瓜氨酸用于总功能性肠细胞质量，Reg3a 用于肠道的抗菌活性，以及肠脂肪酸结合蛋白（I-FABP）用于肠细胞更新。与 16 例健康对照相比，我们证明患者在移植前就存在所有 3 种生物标志物水平异常（P <.05），反映了先前化疗造成的残留损伤。所有 3 种生物标志物最初都从移植前下降到第 +7 天（在清髓性与非清髓性预处理后下降更为明显），随后进入恢复阶段，到第 +28 天恢复到移植前水平。较低的移植前瓜氨酸水平与较高的 II 至 IV 级 aGVHD 风险独立相关（风险比，1.32；95%置信区间，1.03 至 1.69；P =.02），并且这种关联并不特定于肠道 GVHD。与 NRM 最强相关的是第 +7 天 Reg3a 水平较高（P <.001）。I-FABP 不能预测移植结果。总之，移植前血清瓜氨酸水平可识别发生 aGVHD 风险较高的患者。我们的结果表明，移植前增强肠道屏障的干预措施可能会降低 aGVHD 的风险。
