Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy
Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy
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DOI：
10.3324/haematol.2012.066480
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发表时间：
2013-02-01
期刊：
影响因子：
10.1
通讯作者：
Martinelli, Giovanni
中科院分区：
文献类型：
--
作者：
Angelini, Sabrina;Soverini, Simona;Martinelli, Giovanni
伊马替尼是目前治疗慢性粒细胞白血病的首选药物，疗效显著。然而，只有一部分患者达到主要的分子反应-因此，需要找到结果的生物学预测因子，以选择最佳的治疗策略，现在更有效的抑制剂是可用的。我们研究了一组20个多态性的7个基因，可能与伊马替尼的药物遗传学，在一个子集的189例新诊断的慢性髓性白血病患者入组的TOPS试验。分析包括转运蛋白hOCT 1、MDR 1、ABCG 2、OCTN 1和OATP 1A 2以及代谢基因CYP 3A 4和CYP 3A 5的多态性。在总体人群中，OCTN 1 C等位基因（rs 1050152）、hOCT 1基因多态性的简单组合和伊马替尼摄取相关基因的另一种组合与主要分子学缓解显著相关。伊马替尼摄取的多态性组合也与完全分子反应显著相关。仅限于高加索人的分析强调了MDR 1 CC（rs60023214）基因型与完全分子反应的显着相关性。我们证明了药物遗传学方法的有用性，根据他们的可能性，实现重大或完全的分子反应伊马替尼的慢性粒细胞白血病患者进行分层。这代表了一个有吸引力的治疗优化机会，值得在临床试验中进行测试。
Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response - hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. We investigated a panel of 20 polymorphisms in seven genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 patients with newly diagnosed chronic myeloid leukemia enrolled in the TOPS trial. The analysis included polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and another combination in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. We demonstrate the usefulness of a pharmacogenetic approach for stratifying patients with chronic myeloid leukemia according to their likelihood of achieving a major or complete molecular response to imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.