Pharmacogenetic Study of Methotrexate and 6-Mercaptopurine Related Genes in Korean Pediatric Patients with Acute Lymphoblastic Leukemia.

The cure rate of pediatric acute lymphoblastic leukemia (ALL) has dramatically improved after the introduction of maintenance therapy. But many Korean patients could not tolerate the planned dose of methotrexate (MTX) and 6-mercaptopurine (MP) from Western protocols. Recently, tailored therapy based on individual pharmacogenetic background is introduced to improve the survival with the reduction of complication. To establish the basis for the tailored therapy, genes associated with MTX and MP metabolism were analyzed in Korean children with ALL. The dose percent to the planned dose of MTX (20 mg/m²) and MP (50 mg/m²) at final maintenance cycle were analyzed with the 7 polymorphism site (MTHFR 677 C>T, MTHFR 1298 A>C, RFC 80 G>A, TYMS enhancer repeat, TPMT 238 G>C, TPMT 460 G>A, TPMT 719 A>G) in 96 ALL patient using TotalPlex PCR method (except TYMS). The median dose percent of MTX and MP of all patients were 57.5% and 49%, respectively. Only 31/96 and 22/96 patients tolerated more than 75% of planned MTX and MP doses, respectively. Variant TPMT was found in 6 patients (one *1/*3B and five *1/*3C). The mean dose percent of MP in patients with variant TPMT (33.2%) was lower than that of others (53.5%), significantly (P=0.04). MTHFR 677, MTHFR 1298, RFC 80, and TYMS enhancer repeat were not associated with the dose percent of MTX. But the dose percent of MTX was correlated with the dose percent of MP significantly (R²=0.64, P=0.00). The 5 year event free survival of all patients was 93.7%. Although 16/96 patients received less than 25% of full MP dose, there was no event in these patients. Dose reduction of MP is recommended for the patients with 3 major variant types of TPMT but many others with wild type could not tolerate the planned dose of MP. Study of novel polymorphism is necessary for the basis of tailored therapy in Korean pediatric ALL patients.