Pharmacogenetic Outcomes of Pediatric Acute Lymphoblastic Leukemia in Korea

Abstract

Treatment result of pediatric acute lymphoblastic leukemia (ALL) has been markedly improved, but treatment related toxicities and relapse are still remaining problems. Genetic polymorphism is an important factor in the effectiveness and toxicity of anti-leukemic drugs and pharmacogenetics are beginning to emerge as useful research filed to solve those problems. In our experience in the treatment of ALL, many Korean patients could not tolerate full dosages of Western protocols. To make basis for individualized therapy with pharmacogenetics, we analyzed major genes implicated in the treatment of ALL. Fourteen genes of total 103 patients with ALL were analyzed with TotalPlex gene amplification methods (Mol Cell Probes. 2008. 22: 193). Among the drug related genes (percentage of mutant type) including CYP3A4*1B (0%), CYP3A5*3 (0%), GSTP1 (22.3%), GSTM1 (20.4%), GSTT1 (16.5%), MDR1 exon 21 (76.3%), MDR1 exon 26 (61.2%), MTHFR (64.1%), MTHFR 1298 (29.1%), NR3C1 1088 (0%), RFC 80 (79.6%), TPMT combined genotype (7%), VDR intron 8 (10.7%), VDR FokI (67%), incidence of mutant was higher in GSTM1 deletion, lower in MTHFR 1298, TYMS enhancer repeat, and VDR intron 8 comparing with the data of Western whites (Rocha J.C. et al. Blood 2005). As we had modified the dose of anti-leukemic agents depending on the toxicity during the treatment, we analyzed the relationship between the dose percent of actually administered dose and the distribution of each mutant to find out polymorphisms affecting toxicities of chemotherapeutic drugs. The mean dose percent of mercaptopurine was lower in patients with variant TPMT then those with wild type (33.2% vs. 53.5%, P=0.04), but there was no polymorphism that influenced the dose percent of methotrexate, daunorubicin, doxorubicin, and L-asparaginase. There was no significant difference in the incidence of genotypes between risk groups and individual mutant did not affect long term survival and relapse in Korean patients with ALL. In conclusion, we found some difference in the incidence of mutant genotypes related to the pharmacogenetics of ALL between Korean and Western whites, but there was no individual genetic polymorphism that affect on the treatment outcome. We expect more extensive researches about pharmacogenetics of Korean to establish the basis for individualized therapy with the consideration of ethnical difference.