Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma.
Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma.
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DOI：
10.1016/j.bbmt.2015.02.001
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发表时间：
2015-05
期刊：
影响因子：
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通讯作者：
Lamba JK
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作者：
Bachanova V;Shanley R;Malik F;Chauhan L;Lamba V;Weisdorf DJ;Burns LJ;Lamba JK
环磷酰胺（Cy）是一种前药，其细胞毒性依赖于肝细胞色素P450（CYP）酶的生物活化作用。我们评估了CYP酶的单核苷酸多态性（SNPs）对淋巴瘤自体造血细胞移植（HCT）疗效的影响。对2004 - 2012年间93例霍奇金淋巴瘤（n = 52）和非霍奇金淋巴瘤（n = 41）患者的22个基因的SNPs进行了分析，这些患者接受了高剂量Cy治疗后进行自体HCT。预处理方案包括Cy（120mg/kg）联合卡莫司汀/依托泊苷（n = 61）或Cy（6000mg/m²）联合全身照射（n = 32）。移植前正电子发射断层扫描显示未完全缓解是与复发风险增加相关的唯一临床因素（风险比2.1）。在基因组分析中，我们在CYP2B6基因第9外显子（C>T）中鉴定出一个单核苷酸多态性rs3211371（等位基因命名为2B6*5），它显著影响患者的预后。在对疾病状态和预处理方案进行调整后，CYP2B6*1/*5基因型的患者2年复发率更高（风险比3.3；95%置信区间1.6 - 6.5；p = 0.041），总生存率降低（风险比13.5；95%置信区间3.5 - 51.9；p = 0.008），与野生型等位基因患者相比。具有两种功能降低的CYP2B6变异基因型*5和*6的患者，2年无进展生存率仅为11%（95%置信区间1 - 39%），而第9外显子中具有野生型CYP2B6*1等位基因的患者为67%（95%置信区间55 - 77%）。我们的研究结果表明，CYP2B6的SNPs影响高剂量Cy的疗效，并显著降低了具有CYP2B6*5变异的淋巴瘤患者自体HCT的成功率。
Cyclophosphamide (Cy) is a prodrug that depends on bioactivation by hepatic cytochrome P450 (CYP) enzymes for its cytotoxicity. We evaluated the influence of single nucleotide polymorphisms (SNPs) of CYP enzymes on the efficacy of autologous hematopoietic cell transplantation (HCT) for lymphoma. SNPs of 22 genes were analyzed in 93 patients with Hodgkin (n=52) and non-Hodgkin lymphoma (n=41) treated with high-dose Cy followed by autologous HCT between 2004–2012. Preparative regimens contained Cy (120mg/kg) combined with carmustine/etoposide (n=61) or Cy (6000mg/m2) with total body irradiation (n=32). Lack of complete remission as measured by pre-transplant positron emission tomography was the sole clinical factor associated with increased risk of relapse (HR 2.1). In genomic analysis, we identified a single SNP rs3211371 in exon 9 (C >T) of the CYP2B6 gene (allele designation 2B6*5) that significantly impacted patient outcomes. After adjusting for disease status and conditioning regimen, patients with CYP2B6*1/*5 genotype had a higher 2-year relapse rate (HR 3.3; 95%CI 1.6–6.5; p=0.041) and decreased overall survival (HR 13.5; 95%CI 3.5–51.9; p=0.008) than patients with wild-type allele. Patients with two hypo-functional CYP2B6 variant genotypes, *5 and *6, experienced 2-year PFS of only 11% (95%CI 1–39%) compared to 67% (95% CI 55–77%) for patients with the wild-type CYP2B6*1 allele in exon 9. Our results suggest that CYP2B6 SNPs influence the efficacy of high-dose Cy and significantly reduce the success of autologous HCT for lymphoma patients with the CYP2B6*5 variant.