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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Early proactive monitoring of DNA-thioguanine in patients with Crohn’s disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers
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
Ting Yang, Xia Zhu, Xue-Ding Wang, Sumyuet Chan, Yan-Ping Guan, Jing Mao, Pan Li, Shao-Xing Guan, Min Huang, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
Ting Yang, Min Huang, Institute of Clinical Pharmacology, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
Kang Chao, Xia Zhu, Xiang Gao, Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
Xia Zhu, Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
Wen Xie, Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States
Author contributions: Yang T, Chao K, and Zhu X contributed equally to this work. Huang M and Gao X contributed to the study conceptualization and supervision and funding acquisition; Chao K and Gao X contributed to the acquisition and curation of data; Mao J and Li P helped to collect and process the blood samples; Guan SX and Xie W monitored the project progress and contributed to the writing and revision of the manuscript; Zhu X, Wang XD, and Guan YP helped to detect the genotypes and revise the manuscript; Yang T and Chan S detected drug concentrations; Yang T administered the project, analyzed the data, and wrote the manuscript; and all authors have read and approved the final manuscript.
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; and Guangdong Basic and Applied Basic Research Foundation, No. 2022A1515012549 and No. 2023A1515012667.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (No. 2021ZSLYEC-151).
Clinical trial registration statement: This trial is registered with the Chinese Clinical Trials Register, No. ChiCTR2100050295.
Informed consent statement: All patients recruited provided a written informed consent form to participate in the trial.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Min Huang, PhD, Professor, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 East Outer Ring Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, Guangdong Province, China.
huangmin@mail.sysu.edu.cn
Received: December 26, 2023
Peer-review started: December 26, 2023
First decision: January 30, 2024
Revised: February 11, 2024
Accepted: March 5, 2024
Article in press: March 5, 2024
Published online: March 28, 2024
Processing time: 93 Days and 5.7 Hours
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 × 109/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.
Core Tip: This study pioneeringly explores if early proactive monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides stable concentration within two months could predict late leucopenia susceptible population under a nudix hydrolase 15 (NUDT15) genotype-guided thiopurines dosing strategy in patients with Crohn’s disease. We first provide evidence indicating that early proactive monitoring of DNATG during the initial stages of thiopurine therapy could be an effective strategy to discern patients susceptible to developing late leukopenia, especially in NUDT15/thiopurine methyltransferase normal metabolizers, with a concentration threshold of 315.72 fmol/μg DNA.
