Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis
Shan Du,
Xuefei Huang,
Xia He,
Mian Mao,
Min Chen,
Rong Zhang,
Huikai Shao,
Ziyan Lv,
Xinxia Liu,
Junlan Chuan
Affiliations
Shan Du
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Xuefei Huang
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Xia He
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Mian Mao
Department of Pharmacy, Sichuan Cancer Hospital, Chengdu
Min Chen
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Rong Zhang
Department of Pediatrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu
Huikai Shao
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Ziyan Lv
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Xinxia Liu
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
Junlan Chuan
Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu
6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.
