Background Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. Methods MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by Clinical Pharmacogenetics Implementation Consortium (CPIC) were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt +/-/Nudt15 +/-). Results Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range [IQR], 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P< .001). Similarly, Tpmt +/-/Nudt15 +/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wildtype or single heterozygous mice, that was effectively mitigated by a genotype-guided dose titration of MP. Conclusion We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

中文翻译：

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TPMT 和 NUDT15 对多种族人群急性淋巴细胞白血病儿童硫嘌呤毒性的累加效应

背景硫嘌呤如巯嘌呤（MP）广泛用于治疗急性淋巴细胞白血病（ALL）。硫嘌呤-S-甲基转移酶 (TPMT) 和 Nudix 水解酶 15 (NUDT15) 可使硫嘌呤失活，无功能变异体与药物诱导的骨髓抑制相关。对于 TPMT 和 NUDT15 中度或完全丧失活性的患者，强烈建议调整 MP 剂量。然而，对于两种酶具有中等活性的患者建议的剂量减少程度目前尚不清楚。方法 收集新加坡、危地马拉、印度和北美 1768 名 ALL 患者维持期间的 MP 剂量。对患者进行 TPMT 和 NUDT15 基因分型，并使用临床药物遗传学实施联盟 (CPIC) 定义的可操作变异将患者分类为 TPMT 和 NUDT15 正常代谢者 (TPMT/NUDT15 NM)、TPMT 或 NUDT15 中间代谢者 (TPMT IM 或 NUDT15 IM) ，或TPMT和NUDT15复合中间代谢剂（TPMT/NUDT15 IM/IM）。与此同时，我们使用 Tpmt/Nudt15 组合杂合小鼠模型 (Tpmt +/-/Nudt15 +/-) 评估了 MP 毒性、代谢和剂量调整。结果 队列中 22 名患者 (1.2%) 为 TPMT/NUDT15 IM/IM，其中大多数自我报告为西班牙裔 (68.2%, 15/22)。TPMT/NUDT15 IM/IM 患者耐受的中位每日 MP 剂量为 25.7 mg/m2（四分位数范围 [IQR]，19.0-31.1 mg/m2），显着低于 TPMT IM 和 NUDT15 IM 剂量（P<.001）。同样，Tpmt +/-/Nudt15 +/- 小鼠表现出过度的造血毒性，并且比野生型或单一杂合小鼠积累了更多的代谢物 (DNA-TG)，通过基因型引导的 MP 剂量滴定可以有效缓解这种毒性。结论 我们建议更大幅度地减少剂量，以个体化 MP 治疗并减轻 TPMT/NUDT15 IM/IM 患者的毒性。