Rocha V, Porcher R, Fernandes J F, Filion A, Bittencourt H, Silva W, Vilela G, Zanette D L, Ferry C, Larghero J, Devergie A, Ribaud P, Skvortsova Y, Tamouza R, Gluckman E, Socie G, Zago M A
Department of Hematology and Bone Marrow Transplant Unit, University of Paris 7, Hôpital Saint Louis, Paris, France.
Leukemia. 2009 Mar;23(3):545-56. doi: 10.1038/leu.2008.323. Epub 2008 Nov 13.
Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6()4; P=0.0067), HC (recipient CYP2B6()2; P=0.03) and VOD (donor CYP2B6(*)6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.
药物疗效或毒性的个体差异可能受遗传因素影响。我们调查了参与预处理方案及移植物抗宿主病（GvHD）预防用药代谢的药物代谢基因多态性是否与 HLA 相合同胞造血干细胞移植（HSCT）后的结局相关。对 107 例接受 HSCT 的白血病供者及患者进行了药物代谢基因及其多态性研究。候选基因包括：细胞色素 P450 家族（CYP2B6）、谷胱甘肽 -S-转移酶家族（GST）、多药耐药基因、亚甲基四氢叶酸还原酶（MTHFR）和维生素 D 受体（VDR）。研究的终点指标为口腔黏膜炎（OM）、出血性膀胱炎（HC）、毒性反应及肝静脉闭塞病（VOD）、GvHD、移植相关死亡率（TRM）和生存率。以死亡作为竞争事件进行多因素分析，并对临床因素进行校正。在其他临床和遗传因素中，干扰环磷酰胺代谢的 CYP2B6 基因多态性与 OM（受者 CYP2B6()4；P = 0.0067）、HC（受者 CYP2B6()2；P = 0.03）和 VOD（供者 CYP2B6(*)6；P = 0.03）相关。受者 MTHFR 多态性（C677T）与急性 GvHD 相关（P = 0.03），受者 VDR TaqI 与 TRM 和总生存率相关（分别为 P = 0.006 和 P = 0.04）。干扰药物代谢的遗传因素与白血病患者 HLA 相合同胞 HSCT 后的治疗相关毒性反应、GvHD 和生存率相关，应进行前瞻性研究。
