Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study
Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study
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DOI：
10.1038/leu.2008.165
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发表时间：
2008-09-01
期刊：
影响因子：
11.4
通讯作者：
Pieters, R.
中科院分区：
文献类型：
--
作者：
Appel, I. M.;Kazemier, K. M.;Pieters, R.
门冬酰胺酶是治疗儿童急性淋巴细胞白血病（ALL）的有效药物。这种有效性被认为是血清和细胞中天冬酰胺耗尽的结果。我们研究了1000 IU/m2聚乙二醇（PEG）-门冬酰胺酶在开始联合化疗前对新诊断ALL儿童的体内临床反应及其药代动力学、药效学和细胞内效应。体内窗口反应与免疫表型和基因型显著相关：与8/17例T-ALL（P = 0.01）和BCRABL阳性ALL（P = 0.04）相比，26/38例普通/前B-ALL病例，尤其是那些具有超二倍体和TELAML 1重排的病例，表现出良好的临床反应。体内临床窗口反应差与体外对L-门冬酰胺酶的耐药性相关（P = 0.02），两者都是长期无事件生存的预后因素（风险比6.4，P = 0.004;风险比3.7，P = 0.01）。在施用一个体内剂量的PEG-天冬酰胺酶后，可以测量白血病细胞中的细胞凋亡参数或细胞内20种氨基酸水平没有变化，这与体外暴露后发现的变化相矛盾。这可以通过从体内循环中快速去除凋亡细胞来解释。在ALL治疗前额外一剂PEG-天冬酰胺酶未导致其他严重毒性。
L-asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is thought to result from depletion of asparagine in serum and cells. We investigated the clinical response in vivo of 1000 IU/m(2) pegylated (PEG)-asparaginase and its pharmacokinetic, pharmacodynamic and intracellular effects in children with newly diagnosed ALL before start of combination chemotherapy. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common/pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (P = 0.01) and BCRABL-positive ALL (P = 0.04). A poor in vivo clinical window response was related to in vitro resistance to L-asparaginase (P = 0.02) and both were prognostic factors for long-term event-free survival (hazard ratio 6.4, P = 0.004; hazard ratio 3.7, P = 0.01). After administration of one in vivo dose of PEG-asparaginase no changes in apoptotic parameters or in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. One additional dose of PEG-asparaginase upfront ALL treatment did not lead to other severe toxicities.