TPMT*3C as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia.

Thawinee Jantararoungtong,Nutthan Nuntharadthanaphong,Pimonpan Jinda,Rattanaporn Sukprasong,Supaporn Wiwattanakul,Napatrupron Koomdee,Suradej Hongeng,Santirhat Prommas,Jiratha Rachanakul,Rawiporn Tiyasirichokchai,Usanarat Anurathapan,Samart Pakakasama,Chonlaphat Sukasem

doi:10.3390/jpm11080783

Thawinee Jantararoungtong, Nutthan Nuntharadthanaphong + Show 11 more

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https://doi.org/10.3390/jpm11080783

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Abstract

The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with acute lymphoblastic leukemia (ALL). The prescribed dosage of 6-MP and its adverse effects were assessed from medical records during the first 8 weeks and 9–24 weeks of maintenance therapy. Children with the TPMT*1/*3C genotype had a higher risk of leukopenia with an odds ratio (OR) of 4.10 (95% confidence interval (CI) of 1.06–15.94; p = 0.033) compared to wild type (TPMT*1/*1) patients. Heterozygous TPMT*3C was significantly associated with severe neutropenia with an increased risk (OR, 4.17; 95% CI, 1.25–13.90); p = 0.014) during the first 8 weeks. No association was found among ITPA 94C > A, ITPA 123G > A, MRP4 912C > A, and MRP4 2269G > A with myelotoxicity and hepatotoxicity. The evidence that TPMT heterozygotes confer risks of 6-MP-induced myelotoxicity also supports the convincing need to genotype this pharmacogenetic marker before the initiation of 6-MP therapy.

Highlights

This study aimed to investigate the frequency of drug metabolizing enzyme variants (TPMT 719A > G (*3C), inosine triphosphate pyrophosphatase (ITPA) 94C > A and ITPA 123G > A) and drug transporter variants (MRP4 912 C > A and multidrug resistance-associated protein 4 (MRP4) 2269G > A) in Thai children with acute lymphoblastic leukemia (ALL) and their association with 6-MP-related adverse events
There is evidence in the literature that males may have worst clinical outcomes than females given equivalent therapy in ALL, such trends were not identified in our study
This study aims to determine the effect of thiopurine-s-methyl transferase (TPMT), ITPA, and MRP4 variation in 6-MPinduced and hepatotoxicity; fifteen patients carried a genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) were exclude from the genetic association analyses