Abstract：
BACKGROUND: Diminished bioavailability of imatinib in leukemic cells contributes to poor clinical response. We examined the impact of genetic polymorphisms of imatinib on the pharmacokinetics and clinical response in 190 patients with chronic myeloid leukaemia (CML).
METHODS: Single nucleotide polymorphisms were genotyped using pyrophosphate sequencing. Plasma trough levels of imatinib were measured using liquid chromatography-tandem mass spectrometry.
RESULTS: Patients carrying the TT genotype for ABCB1 (rs1045642, rs2032582, and rs1128503), GG genotype for CYP3A5-rs776746 and AA genotype for ABCG2-rs2231142 polymorphisms showed higher concentration of imatinib. Patients with T allele for ABCB1 (rs1045642, rs2032582, and rs1128503), A allele for ABCG2-rs2231142, and G allele for CYP3A5-rs776746 polymorphisms showed better cytogenetic response and molecular response. In multivariate analysis, carriers of the CYP3A5-rs776746 G allele exhibited higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR). Similarly, patients with the T allele of ABCB1-rs1045642 and rs1128503 demonstrated significantly increased CCyR rates. Patients with the A allele of ABCG2-rs2231142 were associated with higher MMR rates. The AA genotype for CYP3A5-rs776746, and the CC genotype for ABCB1-rs104562, and rs1128503 polymorphisms were associated with a higher risk of imatinib failure. Patients with the G allele for CYP3A5-rs776746 exhibited a higher incidence of anemia, and T allele for ABCB1-rs2032582 demonstrated an increased incidence of diarrhea.
CONCLUSIONS: Genotyping of ABCB1, ABCG2, and CYP3A5 genes may be considered in the management of patients with CML to tailor therapy and optimize clinical outcomes.
METHODS: Single nucleotide polymorphisms were genotyped using pyrophosphate sequencing. Plasma trough levels of imatinib were measured using liquid chromatography-tandem mass spectrometry.
RESULTS: Patients carrying the TT genotype for ABCB1 (rs1045642, rs2032582, and rs1128503), GG genotype for CYP3A5-rs776746 and AA genotype for ABCG2-rs2231142 polymorphisms showed higher concentration of imatinib. Patients with T allele for ABCB1 (rs1045642, rs2032582, and rs1128503), A allele for ABCG2-rs2231142, and G allele for CYP3A5-rs776746 polymorphisms showed better cytogenetic response and molecular response. In multivariate analysis, carriers of the CYP3A5-rs776746 G allele exhibited higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR). Similarly, patients with the T allele of ABCB1-rs1045642 and rs1128503 demonstrated significantly increased CCyR rates. Patients with the A allele of ABCG2-rs2231142 were associated with higher MMR rates. The AA genotype for CYP3A5-rs776746, and the CC genotype for ABCB1-rs104562, and rs1128503 polymorphisms were associated with a higher risk of imatinib failure. Patients with the G allele for CYP3A5-rs776746 exhibited a higher incidence of anemia, and T allele for ABCB1-rs2032582 demonstrated an increased incidence of diarrhea.
CONCLUSIONS: Genotyping of ABCB1, ABCG2, and CYP3A5 genes may be considered in the management of patients with CML to tailor therapy and optimize clinical outcomes.
摘要：
背景：伊马替尼在白血病细胞中的生物利用度降低导致临床反应不良。我们研究了伊马替尼的遗传多态性对190例慢性髓性白血病（CML）患者的药代动力学和临床反应的影响。
方法：使用焦磷酸测序对单核苷酸多态性进行基因分型。使用液相色谱-串联质谱法测量伊马替尼的血浆谷水平。
结果：携带ABCB1TT基因型的患者（rs1045642、rs2032582和rs1128503），CYP3A5-rs776746的GG基因型和ABCG2-rs2231142多态性的AA基因型显示伊马替尼浓度较高。ABCB1的T等位基因患者（rs1045642，rs2032582和rs1128503），ABCG2-rs2231142的等位基因和CYP3A5-rs776746多态性的G等位基因显示出更好的细胞遗传学反应和分子反应。在多变量分析中，CYP3A5-rs776746G等位基因的携带者表现出更高的完全细胞遗传学反应（CCyR）和主要分子反应（MMR）。同样，ABCB1-rs1045642和rs1128503的T等位基因患者的CCyR率显著升高.ABCG2-rs2231142等位基因A的患者与较高的MMR率相关。CYP3A5-rs776746的AA基因型和ABCB1-rs104562的CC基因型以及rs1128503多态性与伊马替尼失败的较高风险相关。CYP3A5-rs776746的G等位基因患者表现出更高的贫血发生率，ABCB1-rs2032582的T等位基因显示腹泻发生率增加。
结论：ABCB1，ABCG2和CYP3A5基因的基因分型可以在CML患者的治疗中考虑，以调整治疗和优化临床结果。
方法：使用焦磷酸测序对单核苷酸多态性进行基因分型。使用液相色谱-串联质谱法测量伊马替尼的血浆谷水平。
结果：携带ABCB1TT基因型的患者（rs1045642、rs2032582和rs1128503），CYP3A5-rs776746的GG基因型和ABCG2-rs2231142多态性的AA基因型显示伊马替尼浓度较高。ABCB1的T等位基因患者（rs1045642，rs2032582和rs1128503），ABCG2-rs2231142的等位基因和CYP3A5-rs776746多态性的G等位基因显示出更好的细胞遗传学反应和分子反应。在多变量分析中，CYP3A5-rs776746G等位基因的携带者表现出更高的完全细胞遗传学反应（CCyR）和主要分子反应（MMR）。同样，ABCB1-rs1045642和rs1128503的T等位基因患者的CCyR率显著升高.ABCG2-rs2231142等位基因A的患者与较高的MMR率相关。CYP3A5-rs776746的AA基因型和ABCB1-rs104562的CC基因型以及rs1128503多态性与伊马替尼失败的较高风险相关。CYP3A5-rs776746的G等位基因患者表现出更高的贫血发生率，ABCB1-rs2032582的T等位基因显示腹泻发生率增加。
结论：ABCB1，ABCG2和CYP3A5基因的基因分型可以在CML患者的治疗中考虑，以调整治疗和优化临床结果。
