Early proactive monitoring of DNA-thioguanine in patients with Crohn’s disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers  

作　　者：Ting Yang Kang Chao Xia Zhu Xue-Ding Wang Sumyuet Chan Yan-Ping Guan Jing Mao Pan Li Shao-Xing Guan Wen Xie Xiang Gao Min Huang 

机构地区：[1]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,Guangdong Province,China [2]Institute of Clinical Pharmacology,Sun Yat-sen University,Guangzhou 510006,Guangdong Province,China [3]Department of Gastroenterology,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510655,Guangdong Province,China [4]Department of Pharmacy,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,Guangdong Province,China [5]Center for Pharmacogenetics and Department of Pharmaceutical Sciences,University of Pittsburgh,Pittsburgh,PA 15261,United States

出　　处：《World Journal of Gastroenterology》2024年第12期1751-1763,共13页世界胃肠病学杂志（英文版）

基　　金：Supported by the National Natural Science Foundation of China,No.82020108031,No.81973398,and No.82104290;Guangdong Provincial Key Laboratory of Construction Foundation,No.2020B1212060034;Guangdong Basic and Applied Basic Research Foundation,No.2022A1515012549 and No.2023A1515012667.

摘　　要：BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.

关 键 词：Thiopurine-induced late leucopenia DNA-thioguanine 6-thioguanine nucleotide Proactive therapeutic drug monitoring Crohn’s disease 

分 类 号：R735.9[医药卫生—肿瘤]