CYP2B6*6 is an independent determinant of inferior response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia
CYP2B6*6 is an independent determinant of inferior response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2013-07-516666
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发表时间：
2013-12-19
期刊：
影响因子：
20.3
通讯作者：
Pettitt, Andrew R.
中科院分区：
文献类型：
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作者：
Johnson, Gillian G.;Lin, Ke;Pettitt, Andrew R.
氟达拉滨联合环磷酰胺（FC）是现代慢性淋巴细胞白血病（CLL）治疗的主要化疗方案。CYP 2B 6是一种多态性细胞色素P450亚型，可将环磷酰胺转化为其活性形式。本研究探讨了CYP 2B 6基因变异对慢性淋巴细胞白血病FC化疗反应的可能影响。来自LRF CLL 4试验的可用DNA样本比较了苯丁酸氮芥、氟达拉滨和FC，通过TaqMan实时聚合酶链反应分析筛选CYP 2B 6 SNP c.516G>T和c.785A>G，这两种SNP定义了最常见的变异等位基因（*6）。在455个成功基因分型的样本中，分别有265个（58.2%）、134个（29.5%）和29个（6.4%）被分类为 *1/*1、*1/*6和 *6/*6。表达至少一个 *6等位基因的患者在FC后获得完全缓解（CR）的可能性显著降低（比值比0.27; P = 0.004），但苯丁酸氮芥或氟达拉滨则没有。个体反应指标的分析证实，这种较差的反应是由于细胞减少受损而不是造血恢复延迟。控制年龄、性别、分期、IGHV突变状态、11 q缺失和TP 53缺失/突变的多变量分析确定CYP 2B 6 *6和TP 53突变/缺失是FC后获得CR的唯一独立决定因素。我们的研究首次证明了宿主药物遗传学可以影响CLL的治疗反应。本试验在www.clinicaltrials.gov注册为国际标准随机对照试验，编号NCT 58585610。
Fludarabine plus cyclophosphamide (FC) is the chemotherapy backbone of modern chronic lymphocytic leukemia (CLL) treatment. CYP2B6 is a polymorphic cytochrome P450 isoform that converts cyclophosphamide to its active form. This study investigated the possible impact of genetic variation in CYP2B6 on response to FC chemotherapy in CLL. Available DNA samples from the LRF CLL4 trial, which compared chlorambucil, fludarabine, and FC, were screened by TaqMan real-time polymerase chain reaction assays for CYP2B6 SNPs c.516G>T and c.785A>G, which define the most common variant allele (*6). Among the 455 samples successfully genotyped, 265 (58.2%), 134 (29.5%), and 29 (6.4%) were classified as *1/*1, *1/*6, and *6/*6, respectively. Patients expressing at least one *6 allele were significantly less likely to achieve a complete response (CR) after FC (odds ratio 0.27; P = .004) but not chlorambucil or fludarabine. Analysis of individual response indicators confirmed that this inferior response resulted from impaired cytoreduction rather than delayed hemopoietic recovery. Multivariate analysis controlling for age, gender, stage, IGHV mutational status, 11q deletion, and TP53 deletion/mutation identified CYP2B6*6 and TP53 mutation/deletion as the only independent determinants of CR attainment after FC. Our study provides the first demonstration that host pharmacogenetics can influence therapeutic response in CLL. This trial is registered as an International Standard Randomised Control Trial, number NCT 58585610 at www.clinicaltrials.gov.