Individualized use of 6-mercaptopurine in Chinese children with ALL: A multicenter randomized controlled trial

Yue Zhou, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Li Wang, Department of Pediatric Hematology Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China.
Li-Rong Sun, Department of Pediatrics hematology, Affiliated Hospital of Qingdao University, Qingdao, China.
Li Zhang, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Hong-Mei Wang, Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.
Xi-Ting Liu, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Fan Yang, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Ke-Liang Wu, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Yu-Li Liang, Department of Pediatric Hematology Oncology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China.
Bei-Bei Zhao, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Yong Zhuang, Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
Jin-Qiu Fu, Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
Chao Song, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China.
Yun Li, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China.
Ling-Zhen Wang, Department of Pediatrics hematology, Affiliated Hospital of Qingdao University, Qingdao, China.
Hui-Juan Xu, Department of Pediatrics hematology, Affiliated Hospital of Qingdao University, Qingdao, China.
Yan Gu, Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.
John van den Anker, Division of Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA.
Xiu-Li Ju, Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
Xiao-Fan Zhu, Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Wei Zhao, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

Document Type

Journal Article

Publication Date

9-27-2023

Journal

Clinical pharmacology and therapeutics

DOI

10.1002/cpt.3061

Abstract

Continuous 6-mercaptopurine (6-MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose-limiting hematopoietic toxicity. However, evidence-based guidelines for gene-based 6-MP dosing have not been established for Chinese children with acute lymphoblastic leukemia (ALL). This multicenter, randomized, open-label, active-controlled clinical trial randomly assigned Chinese children with low- or intermediate-risk ALL in a 1:1 ratio to receive TPMT-NUDT15 gene-based dosing of 6-MP (N = 44, 10 to 50 mg/m /day) or standard dosing (N = 44, 50 mg/m /day) during maintenance therapy. The primary endpoint was the incidence of 6-MP myelosuppression in both groups. Secondary endpoints included frequencies of 6-MP hepatotoxicity, duration of myelosuppression and leukopenia, event-free survival, and steady-state concentrations of active metabolites (6-thioguaninenucleotides and 6-methylmercaptopurine nucleotides) in erythrocytes. A 2.2-fold decrease in myelosuppression, the primary endpoint, was observed in the gene-based-dose group using approximately 50% of the standard initial 6-MP dose (odds ratio, 0.26, 95% confidence interval, 0.11 to 0.64; p = 0.003). Patients in the gene-based-dose group had a significantly lower risk of developing thiopurine-induced myelosuppression and leukopenia (p = 0.015 and p = 0.022, respectively). No significant differences were observed in the secondary endpoints of the incidence of hepatotoxicity and steady-state concentrations of active metabolites in erythrocytes between the two groups. TPMT- and NUDT15-based dosing of 6-MP will significantly contribute toward further reducing the incidence of leukopenia in Chinese children with ALL. This trial is registered at www.clinicaltrial.gov as #NCT04228393.

Department

Pediatrics

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