Lubis Isfahan Shah, Anggadiredja Kusnandar, Artarini Aluicia Anita, Sari Nur Melani, Suryawan Nur, Zazuli Zulfan
Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia.
Department of Pharmaceutics, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia.
Med Sci (Basel). 2025 Aug 5;13(3):112. doi: 10.3390/medsci13030112.
The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase () was initially the primary focus, the discovery of () appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines.
急性淋巴细胞白血病（ALL）是最常见的儿童恶性肿瘤，在维持治疗阶段，其治疗严重依赖硫嘌呤类药物，如6-巯基嘌呤（6-MP）。然而，个体间显著的反应差异和骨髓抑制的高风险常常影响治疗效果。药物遗传学为个性化治疗提供了关键策略。虽然硫嘌呤甲基转移酶（）最初是主要研究焦点，但（）的发现似乎是硫嘌呤不耐受更全面的决定因素。本综述旨在总结并批判性地评估在阐明硫嘌呤治疗中药物遗传学的生物学机制和临床意义方面所取得的进展。基础研究表明，在活性硫嘌呤的解毒过程中发挥着至关重要的作用，常见的基因变异（例如，p.Arg139Cys）会显著干扰其活性，导致有毒代谢产物的积累。观察性研究一致表明，基因变异与严重的骨髓抑制相关，尤其是在亚洲人群中。最近的随机对照试验（RCT）证实，根据基因型指导给药可有效降低硫嘌呤诱导的毒性，且不影响治疗效果。尽管取得了这些进展，但挑战依然存在，包括罕见变异的特征描述不完整、亚洲不同人群的数据有限，以及与代谢物监测进行标准化整合的需求。总之，在ALL治疗中，药物遗传学对于提高患者安全性和优化硫嘌呤剂量至关重要。为了广泛且公平地实施硫嘌呤个体化治疗，未来的研究应聚焦于增加不同人群的基因数据、改进剂量调整算法以及统一治疗指南。
