Pediatric Hemato-Oncology and Bone Marrow Transplant Department, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel.
Pediatr Blood Cancer. 2010 Dec 1;55(6):1172-9. doi: 10.1002/pbc.22739.
Busulfan (BU), often used in high dose for myeloablation before hematopoietic stem cell transplantation (HSCT), has been implicated in certain HSCT toxicities, including the occurrence of hepatic veno-occlusive disease (HVOD). In addition to weight and age, gene polymorphisms in specific members of the glutathione-transferase (GST) gene family (A1, P1, M1, and T1), involved in BU metabolism, may play a role in the wide inter-patient variability in systemic BU concentrations.
The present study integrated clinical data regarding the occurrence of HVOD, graft versus host disease (GVHD), BU pharmacokinetics and GSTA1, GSTP1, GSTM1, and GSTT1 genotypes of 18 children who received BU in their pre-HSCT conditioning regimen. The children were all treated for congenital hemoglobinopathies and were all of Arab Moslem descent.
The data demonstrate an association between GSTA1 and GSTP1 genotypes and BU-maximal concentration (C(max)) (P = 0.01, P = 0.02, respectively), area under the concentration-time curve (AUC) (P = 0.02, P = 0.01, respectively) and oral BU clearance/kg body weight (P < 0.02, P = 0.08, respectively). GSTM1-null individuals demonstrated lower BU-AUC/Kg compared to GSTM1-positive individuals. In addition, an association between GVHD and GSTM1-null genotype was found.
GSTA1, GSTP1, and GSTM1 genotyping prior to HSCT in children with congenital hemoglobinopathies may allow better prediction of oral BU kinetics and the need for BU dose adjustment, as well as prediction of transplant related toxicity such as GVHD, thereby improving clinical outcome.
白消安（BU）常用于造血干细胞移植（HSCT）前的高剂量骨髓清除，与某些 HSCT 毒性有关，包括肝静脉闭塞性疾病（HVOD）的发生。除了体重和年龄之外，谷胱甘肽转移酶（GST）基因家族特定成员（A1、P1、M1 和 T1）的基因多态性参与 BU 代谢，可能在全身 BU 浓度的患者间广泛变异性中发挥作用。
本研究整合了 18 名接受 HSCT 预处理方案中 BU 的儿童的 HVOD 发生、移植物抗宿主病（GVHD）、BU 药代动力学和 GSTA1、GSTP1、GSTM1 和 GSTT1 基因型的临床数据。这些儿童均因先天性血红蛋白病接受治疗，均为阿拉伯穆斯林后裔。
数据表明，GSTA1 和 GSTP1 基因型与 BU 最大浓度（C(max)）（P = 0.01，P = 0.02）、浓度时间曲线下面积（AUC）（P = 0.02，P = 0.01）和口服 BU 清除率/体重（P < 0.02，P = 0.08）呈相关。GSTM1 缺失个体的 BU-AUC/Kg 低于 GSTM1 阳性个体。此外，还发现 GVHD 与 GSTM1 缺失基因型之间存在关联。
在患有先天性血红蛋白病的儿童中进行 HSCT 前的 GSTA1、GSTP1 和 GSTM1 基因分型可能允许更好地预测口服 BU 动力学和需要调整 BU 剂量，以及预测与移植相关的毒性，如 GVHD，从而改善临床结果。
