Thiopurine S-Methyltransferase (TPMT) Polymorphisms in Children With Acute Lymphoblastic Leukemia, and the Need for Reduction or Cessation of 6-Mercaptopurine Doses During Maintenance Therapy: The Polish Multicenter Analysis
Thiopurine S-Methyltransferase (TPMT) Polymorphisms in Children With Acute Lymphoblastic Leukemia, and the Need for Reduction or Cessation of 6-Mercaptopurine Doses During Maintenance Therapy: The Polish Multicenter Analysis
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DOI：
10.1002/pbc.23013
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发表时间：
2011-10-01
影响因子：
3.2
通讯作者：
Drozdzik, Marek
中科院分区：
文献类型：
--
作者：
Peregud-Pogorzelski, Jaroslaw;Tetera-Rudnicka, Edyta;Drozdzik, Marek
背景：6-巯基嘌呤（6-MP）用于儿童急性淋巴细胞白血病（ALL）的治疗。TPMT基因突变可能影响6-MP治疗的有效性和安全性。这项多中心研究调查了TPMT基因型、6-MP剂量调整和患者不良反应发生率之间的关系。过程。采用PCR/等位基因特异性扩增和PCR/RFLP对203例ALL患儿进行基因分型。对照组由394名健康志愿者组成。结果。16例患者发现TPMT* 3A变异等位基因（TPMT* 1/* 3A 15例，TPMT* 3A/* 3A 1例），1例患者发现TPMT* 3C （A719G）等位基因。研究组未检测到TPMT* 2 （G238C）、TPMT* 38 （G460A）等位基因。TPMT* 3A、TPMT* 1（野生型）和TPMT* 3C等位基因的检出频率分别为3.94%、95.81%和0.25%。ALL组和对照组的基因型和等位基因分布相似。携带TPMT* 3A和TPMT* 3C等位基因的患者与携带野生型等位基因的患者相比，6-MP剂量减少的频率更高（P = 0.042）。白细胞减少合并呼吸道感染、白细胞减少、贫血和/或血小板减少的发生率分别为4倍（P = 0.007）和5倍（P = 0.03）。各组在6-MP剂量减少率方面存在差异（P = 0.028）。携带TPMT* 3A和TPMT* 3C等位基因的患者（14倍）由于白细胞减少、贫血和/或血小板减少而更常停药（P = 0.004）。结论。结果表明，TPMT基因型影响ALL治疗的安全性和有效性，因此基因型信息可能有助于优化6-MP治疗。儿科血癌2011；57:578-582。(C) 2011 Wiley-Liss, Inc。
Background. 6-Mercaptopurine (6-MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6-MP treatment. This multicenter study investigated the association between TPMT genotype, 6-MP dose adjustments, and the incidence of adverse effects in patients. Procedure. A total of 203 ALL children were genotyped using PCR/allele-specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers. Results. The TPMT* 3A variant allele was found in 16 patients (15 TPMT* 1/* 3A, 1 TPMT* 3A/* 3A) and the TPMT* 3C (A719G) allele in 1 patient. No TPMT* 2 (G238C) or TPMT* 38 (G460A) alleles were detected in the study group. TPMT* 3A, TPMT* 1 (wild-type), and TPMT* 3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6-MP dose was reduced more frequently in patients with TPMT* 3A and TPMT* 3C alleles, compared with wild-type alleles (P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four (P = 0.007) and five (P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6-MP dose reduction (P = 0.028). 6-MP was discontinued more often in patients with TPMT* 3A and TPMT* 3C alleles (14-fold) as a result of leucopenia, anemia, and/or thrombocytopenia (P = 0.004). Conclusions. The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy. Pediatr Blood Cancer 2011;57:578-582. (C) 2011 Wiley-Liss, Inc.