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

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.

Automated summary

This study investigated the association between genetic polymorphisms of drug-metabolizing enzymes and drug transporters with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with ALL. The results showed that children with TPMT*1/*3C genotype were at higher risk of leukopenia, while heterozygous TPMT*3C was significantly associated with severe neutropenia. No association was found between ITPA and MRP4 gene polymorphisms with myelotoxicity and hepatotoxicity. The findings emphasize the importance of genotyping the TPMT gene before initiating 6-MP therapy to assess the risk of myelotoxicity.