Maillard Maud, Nguyen Jenny Q, Yang Wenjian, Hoshitsuki Keito, Relling Mary V, Caudle Kelly E, Crews Kristine R, Jeha Sima, Inaba Hiroto, Pui Ching-Hon, Bhatia Smita, Karol Seth E, Antillon-Klussmann Federico G, Haidar Cyrine E, Bhojwani Deepa, Yang Jun J
Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Personalized Care Program, Children's Hospital Los Angeles, Los Angeles, California, USA.
Clin Pharmacol Ther. 2025 Mar;117(3):724-731. doi: 10.1002/cpt.3501. Epub 2024 Dec 17.
Nudix hydrolase 15 (NUDT15) deficiency is strongly associated with thiopurine-induced myelosuppression. Currently, testing for NUDT15 deficiency is based on the genotyping of the most frequent and clinically characterized no-function variants, that is, *2, *3 and *9. The Hispanic/Latino-predominant variant NUDT15 *4 (p.R139H) is classified as "uncertain function" by the Clinical Pharmacogenetics Implementation Consortium, because of insufficient data to ascertain its clinical actionability. In this study, we evaluated the association of NUDT15 *4 with mercaptopurine (6-MP) tolerance in a retrospective cohort of 1,399 patients with acute lymphoblastic leukemia (ALL) of diverse ancestries. All patients were wildtype for thiopurine methyltransferase gene. Patients were treated with 6-MP in the context of ALL frontline clinical trials. The tolerated dose of 6-MP was used to assess drug toxicity during the maintenance phase of ALL therapy. Patients with NUDT15 *1/*4 (n = 16, all of whom self-identified as Hispanic/Latino) tolerated a significantly lower dose of 6-MP than did those with NUDT15 *1/*1: median [interquartile range] of 39.0 [21.2-52.8] mg/m, vs. 62.2 [47.9-71.6] mg/m, P value < 0.001. No patient homozygous for *4 was detected. In a separate retrospective validation study, six patients were identified as having NUDT15 *1/*4 by routine clinical pharmacogenetics testing and tolerated a 6-MP median dose of 38.7 mg/m (IQR, 33.7-54.0), confirming the need for dose reduction attributed to the NUDT15 *4 variant. These results point to the need to include NUDT15 *4 in pharmacogenetics-guided thiopurine dosing algorithms.
Nudix水解酶15（NUDT15）缺乏与硫嘌呤诱导的骨髓抑制密切相关。目前，NUDT15缺乏的检测基于最常见且具有临床特征的无功能变异体的基因分型，即*2、3和9。西班牙裔/拉丁裔为主的变异体NUDT15 *4（p.R139H）被临床药物基因组学实施联盟归类为“功能不确定”，因为确定其临床可操作性的数据不足。在本研究中，我们在一个由1399名不同血统的急性淋巴细胞白血病（ALL）患者组成的回顾性队列中评估了NUDT15 *4与巯嘌呤（6-MP）耐受性的关联。所有患者的硫嘌呤甲基转移酶基因均为野生型。患者在ALL一线临床试验中接受6-MP治疗。6-MP的耐受剂量用于评估ALL治疗维持阶段的药物毒性。携带NUDT15 *1/*4的患者（n = 16，均自我认定为西班牙裔/拉丁裔）耐受的6-MP剂量明显低于携带NUDT15 *1/1的患者：中位数[四分位间距]为39.0 [21.2 - 52.8] mg/m²，而后者为62.2 [47.9 - 71.6] mg/m²，P值<0.001。未检测到4纯合的患者。在另一项回顾性验证研究中，通过常规临床药物基因组学检测确定6名患者携带NUDT15 *1/*4，其6-MP中位剂量为38.7 mg/m²（IQR，33.7 - 54.0），证实了因NUDT15 *4变异体而需要降低剂量。这些结果表明需要将NUDT15 *4纳入药物基因组学指导的硫嘌呤给药算法中。
