Individualized Use of 6‐Mercaptopurine in Chinese Children with ALL: A Multicenter Randomized Controlled Trial

Author:

Zhou Yue1,Wang Li2,Sun Li‐Rong3,Zhang Li4,Wang Hong‐Mei5,Liu Xi‐Ting16,Yang Fan1,Wu Ke‐Liang1,Liang Yu‐Li2,Zhao Bei‐Bei4,Zhuang Yong7,Fu Jin‐Qiu7,Song Chao8,Li Yun8,Wang Ling‐Zhen3,Xu Hui‐Juan3,Gu Yan5,van den Anker John91011,Ju Xiu‐Li7,Zhu Xiao‐Fan4,Zhao Wei112ORCID

Affiliation:

1. 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

2. Department of Pediatric Hematology Oncology Children's Hospital of Hebei Province affiliated to Hebei Medical University Shijiazhuang China

3. Department of Pediatrics Hematology Affiliated Hospital of Qingdao University Qingdao China

4. 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

5. Department of Pediatrics The First Affiliated Hospital of Shandong, First Medical University & Shandong Provincial Qianfoshan Hospital Jinan China

6. Department of Pharmacy China‐Japan Friendship Hospital Beijing China

7. Department of Pediatrics Qilu Hospital of Shandong University Jinan China

8. The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd. Nanjing China

9. Division of Clinical Pharmacology Children's National Medical Center Washington DC USA

10. Departments of Pediatrics, Pharmacology & Physiology School of Medicine and Health Sciences, George Washington University Washington DC USA

11. Department of Paediatric Pharmacology and Pharmacometrics University Children's Hospital Basel Basel Switzerland

12. NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug Qilu Hospital of Shandong University, Shandong University Jinan China

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 TPMTNUDT15 gene–based dosing of 6‐MP (N = 44, 10 to 50 mg/m2/day) or standard dosing (N = 44, 50 mg/m2/day) during maintenance therapy. The primary end point was the incidence of 6‐MP myelosuppression in both groups. Secondary end points 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 end point, was observed in the gene‐based–dose group using ~ 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 end points 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.

Funder

Natural Science Foundation of Shandong Province

Postdoctoral Innovation Project of Shandong Province

Publisher

Wiley

Subject

Pharmacology (medical),Pharmacology

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