伊马替尼谷浓度与中国慢性髓性白血病患者疗效的相关性。

Correlation between imatinib trough concentration and efficacy in Chinese chronic myelocytic leukemia patients.

机构信息

Department of Haematology, Guangzhou Red Cross Hospital, China.

出版信息

Acta Haematol. 2012;127(4):221-7. doi: 10.1159/000336244. Epub 2012 Mar 30.

DOI:10.1159/000336244

PMID:22473087

Abstract

BACKGROUND

Trough imatinib plasma concentration, intracellular drug levels and expression of drug transporters can be indicative of clinical responses in chronic myelocytic leukemia (CML) patients receiving imatinib. We aimed to determine plasma imatinib concentration, intracellular imatinib concentration, human organic cation transporter 1 (hOCT1) and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in bone marrow cells of CML patients in order to evaluate the potential usefulness of these measures as markers of imatinib efficacy and understand their clinical relationships.

METHODS

Eighty-four CML patients receiving imatinib treatment were included in this study. Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry. Real-time quantitative PCR with a TaqMan probe was used to assess hOCT1 and ABCB1 mRNA expression in bone marrow cells. All patients were divided into the major molecular response (MMR), complete cytogenetic response (CCyR), partial cytogenetic response (PCyR) or drug-resistant groups according to their response.

RESULTS

The plasma imatinib trough concentration was significantly higher in the MMR group than in the PCyR (p = 0.002) or drug-resistant groups (p = 0.011). The plasma imatinib trough concentration was also significantly higher in the CCyR group than in the PCyR group (p = 0.027). There were no significant differences between the CCyR and MMR groups with regard to the plasma imatinib trough concentration (p = 0.136). The intracellular imatinib concentration in bone marrow cells was significantly higher in the CCyR group compared to the drug-resistant or PCyR groups (p = 0.013). The hOCT1 mRNA expression in bone marrow cells was significantly higher in the CCyR group than in the drug-resistant or PCyR groups (p = 0.036). The ABCB1 mRNA expression in bone marrow cells was significantly higher in the drug-resistant group than in the CCyR or PCyR groups (p = 0.013). Plasma imatinib trough concentration was positively correlated with α(1)-acid glycoprotein (r = 0.443, p < 0.001) or dose (r = 0.422, p < 0.001).

CONCLUSIONS

Clinical responses in CML patients are correlated with both the plasma trough concentrations and intracellular levels of imatinib.

摘要

背景

通过伊马替尼的血药浓度、细胞内药物浓度和药物转运体的表达，可以预测接受伊马替尼治疗的慢性髓细胞白血病（CML）患者的临床反应。本研究旨在检测 CML 患者骨髓细胞中伊马替尼的血药浓度、细胞内伊马替尼浓度、人有机阳离子转运体 1（hOCT1）和三磷酸腺苷结合盒亚家族 B 成员 1（ABCB1）mRNA 的表达，以评估这些指标作为伊马替尼疗效标志物的潜在作用，并了解其临床相关性。

方法

本研究纳入了 84 例接受伊马替尼治疗的 CML 患者。采用高效液相色谱-串联质谱法测定伊马替尼的血药浓度。采用 TaqMan 探针实时定量 PCR 检测骨髓细胞中 hOCT1 和 ABCB1mRNA 的表达。所有患者根据其反应分为主要分子反应（MMR）、完全细胞遗传学反应（CCyR）、部分细胞遗传学反应（PCyR）或耐药组。

结果

MMR 组的伊马替尼血药浓度明显高于 PCyR 组（p=0.002）和耐药组（p=0.011）。CCyR 组的伊马替尼血药浓度也明显高于 PCyR 组（p=0.027）。CCyR 组与 MMR 组的伊马替尼血药浓度无显著差异（p=0.136）。骨髓细胞内伊马替尼浓度在 CCyR 组明显高于耐药组或 PCyR 组（p=0.013）。骨髓细胞中 hOCT1mRNA 的表达在 CCyR 组明显高于耐药组或 PCyR 组（p=0.036）。骨髓细胞中 ABCB1mRNA 的表达在耐药组明显高于 CCyR 组或 PCyR 组（p=0.013）。伊马替尼血药浓度与α（1）-酸性糖蛋白（r=0.443，p＜0.001）或剂量（r=0.422，p＜0.001）呈正相关。