Pediatric Oncology research laboratory, The University Hospital Rigshospitalet, Copenhagen, Denmark.
The Tissue Typing Laboratory, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Pediatr Hematol Oncol. 2021 Apr;38(3):227-238. doi: 10.1080/08880018.2020.1842570. Epub 2020 Nov 18.
Bone marrow minimal residual disease (MRD) is the strongest predictor of relapse in children with acute lymphoblastic leukemia (ALL). 6-mercaptopurine (6MP) in ALL therapy has wide inter-individual variation in disposition and is strongly influenced by polymorphisms in the thiopurine methyltransferase () gene. In 952 patients treated according to the NOPHO ALL2008 protocol, we explored the association between thiopurine disposition, genotypes and MRD levels after consolidation therapy with 6MP, high-dose methotrexate (HD-MTX), asparaginase, and vincristine. The levels of the cytotoxic DNA-incorporated thioguanine were significantly higher on day 70-79 in G460A/A719G heterozygous () compared to wild type () patients (mean: 230.7 vs. 149.7 fmol/µg DNA, p = 0.002). In contrast, genotype did not associate with the end of consolidation MRD levels irrespective of randomization of the patients to fixed dose (25 mg/m/day) or 6MP escalation (up to 50 or 75 mg/m/day) during consolidation therapy.
骨髓微小残留病（MRD）是儿童急性淋巴细胞白血病（ALL）复发的最强预测因子。6-巯基嘌呤（6MP）在 ALL 治疗中存在广泛的个体间变异性，并且强烈受到硫嘌呤甲基转移酶（TPMT）基因多态性的影响。在按照 NOPHO ALL2008 方案治疗的 952 名患者中，我们探讨了硫嘌呤处置、TPMT 基因型与巩固治疗后 MRD 水平之间的关系，巩固治疗包括 6MP、高剂量甲氨蝶呤（HD-MTX）、门冬酰胺酶和长春新碱。与野生型（）患者相比，G460A/A719G 杂合子（）患者在第 70-79 天的细胞毒性 DNA 结合硫鸟嘌呤水平明显更高（平均值：230.7 与 149.7 fmol/µg DNA，p=0.002）。相比之下，TPMT 基因型与巩固治疗结束时的 MRD 水平无关，无论患者在巩固治疗期间随机接受固定剂量（25 mg/m/天）或 6MP 递增（至 50 或 75 mg/m/天）。
