A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours
A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours
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DOI：
10.1016/j.ejca.2009.05.008
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发表时间：
2009-09-01
影响因子：
8.4
通讯作者：
Bouffet, Eric
中科院分区：
文献类型：
--
作者：
Baruchel, Sylvain;Sharp, Julia R.;Bouffet, Eric
目的：评估伊马替尼的安全性，疗效和药代动力学在儿童复发或难治性中枢神经系统（CNS）肿瘤表达KIT和/或PDGFRA.Methods：19例患者年龄2-18岁，复发或难治性中枢神经系统肿瘤表达的靶受体KIT和/或PDGFRA（免疫组化）是合格的。受试者口服伊马替尼，剂量为440 mg/m2/天，并监测毒性和肿瘤反应。在一个同意的患者子集中获得用于药代动力学的系列血液和脑脊液样本。冷冻肿瘤样本进行了回顾性分析KIT和PDGFRA基因扩增的患者的一个子集，其中的样本available.Results：常见的毒性淋巴细胞减少，白细胞减少，血清转氨酶升高和呕吐。未观察到瘤内出血。尽管伊马替尼治疗无客观缓解，但4例患者病情长期稳定（SD）（38-104周）。我们的研究结果表明KIT表达与伊马替尼治疗SD的维持之间可能存在关系; KIT免疫阳性仅见于58%（11/19）的研究参与者，但在38周时100%的SD患者中。所有患者肿瘤均显示PDGFRA表达。药代动力学数据显示患者间变异性较高，但与先前报道的值一致。结论：伊马替尼440 mg/m2/d治疗儿童复发性CNS肿瘤相对安全，但无客观反应。在既往进展患者（表达KIT）中证实SD表明伊马替尼具有细胞抑制活性。(C)2009爱思唯尔有限公司版权所有。
Purpose: To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA.Methods: Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available.Results: Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values.Conclusions: Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib. (C) 2009 Elsevier Ltd. All rights reserved.