MDR1和CYP3A5基因多态性对伊马替尼治疗慢性骨髓性白血病预后的影响

Effect of MDR1 and CYP3A5 gene polymorphisms on outcomes of patients receiving imatinib treatment for chronic myeloid leukemia

目的研究MDR1和CYP3A5基因多态性对伊马替尼治疗慢性骨髓性白血病(CML)预后的影响。方法选择100例采用伊马替尼治疗的慢性骨髓性白血病患者作为研究对象,其中50例细胞遗传学复发患者作为研究组,另外50例无复发患者作为对照组,随访45个月。分析MDR1基因中的C1236T、C3435T、G2677T/A和CYP3A5基因中的A6986G位点的单核苷酸多态性与细胞遗传学复发风险之间的关系。结果 MDR1-C1236T与MDR1-C3435T多态性位点中CC基因型细胞遗传学复发的风险均明显比CT+TT基因型患者高(P<0.05)。MDR1-C3435T和MDR1-C1236T多态性位点的TT基因型患者的无复发生存时间中位数显著高于CC基因型和CT基因型,差异均有统计学意义(P<0.05)。研究组患者中血液毒性和中性白细胞减少症的发生率明显比对照组患者高,差异有统计学意义(P<0.05)。MDR1-C3435T基因型和伊马替尼谷浓度是细胞遗传学复发的独立预测因子。结论 MDR1基因的C1236T和C3435T位点多态性和伊马替尼谷浓度水平显著影响CML细胞遗传学复发的风险。MDR1-C3435T基因型可用于预测CML患者细胞遗传学复发风险的潜在生物标志物。

Objective To study the effect of MDR1 and CYP3 A5 gene polymorphisms on the outcomes of imatinib treatment in patients with chronic myeloid leukemia（CML）. Methods A total of 100 patients with CML treated with imatinib were enrolled in this study, including 50 patients with cytogenetic relapse（study group） and 50 without cytogenetic relapse（control group）during the follow-up for 45 months. For all the patients, single nucleotide polymorphisms（SNPs） of C1236 T, C3435 T, and G2677 T/A loci in the MDR1 gene and A6986 G locus in CYP3 A5 gene were genotyped and the trough levels of imatinib was measured using LC-MS/MS. The relationship between SNPs of the loci and the risk of cytogenetic relapse were analyzed.Results The risk of cytogenetic recurrence was significantly higher in patients with CC genotypes of MDR1-C1236 T and MDR1-C3435 T than in those with CT ＋ TT genotypes（P〈0.05）. The median survival time of the patients with TT genotypes of MDR1-C3435 T and MDR1-C1236 T was significantly higher than that of patients with CC genotypes and CT genotypes（P〈0.05）. The incidences of hematologic toxicity and neutropenia were significantly higher in patients with cytogenetic relapse than in those without cytogenetic relapse（P〈0.05）. MDR1-C3435 T genotype and imatinib concentration were independent predictors of cytogenetic relapse of CML. Conclusion The risk of cytogenetic relapse of CML was significantly affected by SNPs of C1236 T and C3435 T loci of MDR1 gene and blood imatinib concentration. MDR1-C3435 T genotype can be used as a potential biomarker for predicting cytogenetic relapse in CML patients.