Abstract

Sporadic incidence of veno-occlusive disease (VOD) continues to occur, despite achievement of recommended busulfan (BU) concentrations after real-time BU dose adjustment. To explore the potential influence of glutathione S-transferase (GST) and cytochrome P450 (CYP) genotypes on plasma BU concentration, subsequent VOD, and transplant outcome, we assessed the polymorphisms of multiple GST and CYP genes. Fifty-five patients were included (median age 38 years; range 21–67). Of these, 49 received dose-adjusted BU/CY therapy. Twenty-six patients received transplants from human leukocyte antigen-identical siblings, 26 from unrelated donors. The GSTA1*A/*A genotype was significantly associated with lower BU first-dose area under curve (AUC1st). We found that patients with higher AUC1st showed a significantly higher serum total bilirubin during the first month after transplantation, but this was not necessarily associated with subsequent development of VOD. We further analyzed a possible association of GST and CYP polymorphisms and VOD development, and found none of the polymorphisms investigated was associated with VOD incidence. Regarding transplant outcomes, GSTM1-positive patients showed lower relapse rates and better overall survival in multivariate analyses. These results suggest that a GSTM1-positive genotype in patients receiving BU/CY conditioning protects against relapse of hematological malignancies after allogeneic hematopoietic stem cell transplantation.

中文翻译：

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剂量调整的环丁砜-环磷酰胺调节受体中谷胱甘肽S-转移酶和细胞色素P450基因多态性的分析

摘要

尽管在实时BU剂量调整后达到了推荐的白消安（BU）浓度，但静脉闭塞性疾病（VOD）的零星发病率仍继续发生。为了探讨谷胱甘肽S-转移酶（GST）和细胞色素P450（CYP）基因型对血浆BU浓度，随后的VOD和移植结果的潜在影响，我们评估了多个GST和CYP基因的多态性。包括55名患者（中位年龄38岁；范围21-67）。其中49例接受了剂量调整的BU / CY治疗。26名患者从与人类白细胞抗原相同的兄弟姐妹那里接受了移植，其中26位来自无关的供体。该GSTA1 * A / * A基因型与曲线下的BU首剂量较低区域（AUC1st）显着相关。我们发现，AUC1st较高的患者在移植后的第一个月内血清总胆红素显着较高，但这未必与随后的VOD发生有关。我们进一步分析了GST和CYP多态性与VOD发生的可能联系，发现所研究的多态性均与VOD发生率无关。关于移植结果，在多变量分析中，GSTM1阳性患者显示出较低的复发率和较好的总体生存率。这些结果表明，GSTM1接受BU / CY调理的患者体内呈阳性的基因型可防止异基因造血干细胞移植后血液系统恶性肿瘤复发。