BACKGROUND Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype- tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. METHODS Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to ALL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leu - ko penia and average 6-mercaptopurine dose) and a prob- abilistic model was employed to predict overall 6-mercaptopurine related toxicity. RESULTS We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6- mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (AUC=0.71). CONCLUSIONS This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.

中文翻译：

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TPMT、ITPA、ABCC4 和 ABCB1 基因的变异作为 6-巯基嘌呤诱导的急性淋巴细胞白血病儿童毒性的预测因子。


背景急性淋巴细胞白血病是最常见的儿童恶性肿瘤。抗白血病药物的最佳使用可以减少毒性和不良反应，并提高生存率。硫嘌呤类药物，包括6-巯基嘌呤，主要用作儿童急性淋巴细胞白血病维持治疗阶段的抗白血病药物。对于这些患者，TPMT基因型定制的6-巯基嘌呤治疗已在治疗方案中实施。我们研究了 TPMT、ITPA、ABCC4 和 ABCB1 基因变异作为小儿急性淋巴细胞白血病维持治疗阶段结果和 6-巯基嘌呤诱导毒性的预测因子的作用。方法 68 例急性淋巴细胞白血病儿童纳入本研究。患者已根据 ALL IC-BFM 2002 或 ALL IC-BFM 2009 方案接受治疗。通过替代标志物（治疗结束周数、白细胞减少症发作次数和平均 6-巯基嘌呤剂量）监测毒性和不良事件，并采用概率模型来预测总体 6-巯基嘌呤相关毒性。结果我们证实携带TPMT失活等位基因的急性淋巴细胞白血病患者需要减少6-巯基嘌呤剂量。 ITPA和ABCC4遗传变异未能显示出与维持阶段6-巯基-嘌呤诱导的毒性相关。 ABCB1 变异等位基因的携带者经历了更大的肝毒性。考虑所有分析的遗传变异的概率模型神经网络被评估为最佳预测模型。它能够在 71% 的病例中区分 6-巯基嘌呤耐受性良好和较差的 ALL 患者 (AUC=0.71)。 结论 这项研究有助于设计一组药物遗传学标记，用于预测硫代嘌呤诱导的儿童 ALL 毒性。