Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Pharmacogenomics J. 2012 Oct;12(5):379-85. doi: 10.1038/tpj.2011.25. Epub 2011 Jul 12.
Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⁻² had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⁻² (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL.
近年来，儿童急性淋巴细胞白血病（ALL）的治疗进展显著提高了治疗效果。在巩固治疗期间，高剂量甲氨蝶呤（MTX）是最常用的方案，但最佳剂量仍有待确定。我们在 ALL/SHOP-2005 方案中纳入的 141 例儿童 ALL 患者中研究了 MTHFR 基因型在巩固期增加 MTX 剂量的有用性。我们还研究了 MTX 代谢相关基因多态性的药物遗传学作用对治疗相关毒性和生存的影响。具有有利 MTHFR 基因型（正常酶活性）的患者接受 5g/m² MTX 剂量治疗的事件风险明显低于具有不利 MTHFR 基因型（降低的酶活性）的患者接受经典 3g/m² MTX 剂量治疗的事件风险（P=0.012）。我们的结果表明，分析 MTHFR 基因型是优化儿童 ALL 患者 MTX 治疗的有用工具。
