急性淋巴细胞白血病患儿维持治疗期肌酐三磷酸焦磷酸酶活性与6-巯基嘌呤毒性的关系

Activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy in children with acute lymphoblastic leukemia

目的预测肌酐三磷酸焦磷酸酶(ITPA)活性与6-巯基嘌呤(6-MP)维持治疗儿童急性淋巴细胞白血病(ALL)不良反应发生。方法选取于2002年3月至2012年9月就诊,采用6-MP和甲氨蝶呤维持治疗的54例ALL患儿作为研究对象。回顾性分析患儿ITPA浓度与治疗期间白细胞减少和肝毒性等不良反应发生,检测患儿ITPA以及6-巯嘌呤基转移酶等位基因突变体(TPMT)的基因型。结果 54例患儿的ITPA活性在2.2-343μmol/(h.gHb)之间。18例为ITPA 94C>A突变杂合子,2例为纯合子。6-MP不良反应发生率为70.4%,其中白细胞减少发生率为35.8%,肝毒性发生率为58.2%。有肝毒性患儿的ITPA活性低于无肝毒性患儿,差异有统计学意义(P=0.01)。20例ITPA活性<126μmol/(h.gHb)患儿中有10例(50.0%)因肝毒性而不得不降低6-MP治疗浓度者,而34例ITPA活性≥126μmol/(h.gHb)患儿中无一降低治疗浓度,差异有统计学意义(P=0.01);ITPA活性<126μmol/(h.gHb)患儿的6-MP治疗浓度低于ITPA活性≥126μmol/(h.gHb)的患儿,差异有统计学意义(P=0.01)。结论 ALL患儿维持治疗期ITPA活性与6-MP不良反应发生有关。

Objectives To explore the relationship between inosine triphosphate pyrophosphatase （ITPA） and toxicity of 6-mercaptopurine （6-MP） during maintenance therapy in children with acute lymphoblastic leukemia （ALL）. Methods A total of 54 in-patients with ALL applied maintenance therapy with 6-MP and methotrexate from Mar. 2002 to Sep. 2012 were selected. The activity of ITPA and the relationship of adverse reaction and leucopenia during maintenance therapy were ana- lyzed retrospectively. Genotyping of ITPA and thiopurine S-methyltransferase （TPMT） were performed. Results The ITPA activity level were 2.2-343 μmol/（h.gHb）. Eighteen patients were ITPA 94C〉A heterozygous, 2 patients were 1TPA 94C〉A homozygote. The adverse reactions of 6-MP was 70.4%, leukopenia was 35.8%, hepatotoxicity was 58.2%. The ITPA activity was significantly lower in patients presented with hepatotoxicity than patients with no hepatotoxicity （P=0.01）. Ten of the 20 patients with ITPA 〈 126 μmol/（h.gHb） patients had to reduce the 6-MP therapeutic concentrations, no patients had to reduce the 6-MP therapeutic concentration in 34 patients with ITPA ≥ 126 μmol/（h.gHb）, it was significantly different （P=0.01）. The 6-MP therapeutic concentration was significantly lower in patients with ITPA 〈 126 μmol/（h.gHb） than patients with ITPA ≥ 126 μmol/（h.gHb） （P=0.01）. Conclusion The ITPA activity is related to the toxicity of 6-MP during the maintenance therapy in children with ALL.