Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy—the addition of low-dose (2.5–12.5 mg/m²/day) 6-thioguanine to the 6-MP/MTX backbone—that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.

口服甲氨蝶呤 (MTX) 和 6-巯基嘌呤 (6-MP) 的维持疗法 (MT) 对于治愈急性淋巴细胞白血病 (ALL) 至关重要。MTX 和 6-MP 干扰核苷酸合成和补救途径。主要的细胞毒性机制涉及将硫鸟嘌呤核苷酸 (TGN) 掺入 DNA（作为 DNA-TG），这可能会因其他 MTX/6-MP 代谢物抑制嘌呤从头合成而增强。MT 期间的联合用药很常见。尽管预防耶氏肺孢子虫似乎是安全的，但糖皮质激素/长春新碱脉冲在提高生存率和别嘌醇对中度 6-MP 药代动力学方面的益处仍不确定。许多基因多态性影响 MTX 和硫嘌呤的药理学、功效和毒性（主要是骨髓抑制和肝毒性）。TPMT ) 减少 TGN 但增加甲基化 6-MP 代谢物 (MeMP)；类似地，nudix 水解酶 15（由NUDT15编码) 也减少了可用于 DNA 掺入的 TGN。这两个基因中的功能丧失变异目前用于指导 MT，但不能完全解释硫嘌呤毒性的患者间变异性。由于 MTX/6-MP 生物利用度和代谢的个体间差异很大，剂量调整传统上由骨髓抑制程度指导，但这并不能准确反映治疗强度。DNA-TG 是 MTX/6-MP 联合化疗的常见下游代谢产物，较高水平的 DNA-TG 与较低的复发风险相关，导致硫嘌呤增强 ALL 维持 (TEAM) 策略的发展——添加低剂量 (2.5–12.5 mg/m ²/天) 6-硫鸟嘌呤到 6-MP/MTX 骨干——目前正在随机 ALLTogether1 试验中进行测试 (EudraCT: 2018-001795-38)。硫嘌呤和 MTX 代谢途径中的突变以及错配修复基因中的突变已在早期 ALL 复发中被鉴定出来，提供了有价值的见解，以协助制定检测即将发生的复发的策略，促进复发挽救治疗，甚至带来改变一线 ALL 治疗以减轻这种复发风险。