Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Pharmacy and Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
Leukemia. 2022 Jul;36(7):1749-1758. doi: 10.1038/s41375-022-01591-4. Epub 2022 Jun 2.
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/m/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.
维持治疗（MT）使用口服甲氨蝶呤（MTX）和 6-巯基嘌呤（6-MP）对于治愈急性淋巴细胞白血病（ALL）至关重要。MTX 和 6-MP 会干扰核苷酸合成和补救途径。主要的细胞毒性机制涉及硫鸟嘌呤核苷酸（TGNs）掺入 DNA 中（即 DNA-TG），这可能通过其他 MTX/6-MP 代谢物抑制从头嘌呤合成来增强。MT 期间的联合用药很常见。虽然预防肺孢子菌感染似乎是安全的，但糖皮质激素/长春新碱脉冲在提高生存率方面的益处以及别嘌醇对 6-MP 药代动力学的适度作用仍不确定。许多遗传多态性会影响 MTX 和硫嘌呤的药理学、疗效和毒性（主要是骨髓抑制和肝毒性）。硫嘌呤 S-甲基转移酶（由 TPMT 编码）减少 TGNs，但增加甲基化的 6-MP 代谢物（MeMPs）；同样，核苷酸二磷酸酶 15（由 NUDT15 编码）也减少了可供 DNA 掺入的 TGNs。这两个基因的失活变体目前用于指导 MT，但不能完全解释硫嘌呤毒性的个体间差异。由于 MTX/6-MP 生物利用度和代谢的个体间差异很大，剂量调整传统上以骨髓抑制程度为指导，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物，较高水平的 DNA-TG 与较低的复发危险相关，导致了硫嘌呤增强 ALL 维持（TEAM）策略的发展——在 6-MP/MTX 主干上加用低剂量（2.5-12.5mg/m/天）6-硫鸟嘌呤——这一策略目前正在 ALLTogether1 随机试验中进行测试（EudraCT：2018-001795-38）。在早期 ALL 复发中发现了硫嘌呤和 MTX 代谢途径以及错配修复基因的突变，为协助制定策略以检测即将发生的复发、促进复发挽救治疗以及甚至改变一线 ALL 治疗以减轻这种复发风险提供了有价值的见解。
