Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children, representing nearly one-third of all pediatric cancers. Although current treatment protocols can cure approximately 80% of pediatric ALL patients, a number of children will relapse, with a relapse rate shown to vary within a group of patients with similar risk even though their leukemia blast carry the same characteristics. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. Pharmacogenetics investigates genetic variations that affect pharmacokinetics and pharmacodynamics of drugs by changing the structure of proteins involved in drug metabolism and cellular transport, and their influence on drug response phenotypes. The methotrexate (MTX) and 6-mercaptopurine (6-MP) are an essential part of the multi-drug regimens used for successful treatment of childhood ALL. Although MTX and thiopurines have been in use for over sixty years, there is significant uncertainty associated with their use, which is mainly caused by inter-individual differences in the bioavailability and metabolism of these extensively metabolized drugs. Study I: We compared the relapse free survival (RFS) in Vietnamese (n=141) and Caucasian (n=94) children with ALL living in Vietnam and Belgium, respectively, and treated by the same FRALLE 2000 protocol. RFS was significantly worse in Vietnamese children (hazards ratio=4.48; 95% confidence interval [CI], 2.16-9.3; P<0.01). The 5-year RFS was 83.8% (95% CI, 76.3%-92.0%) and 47.8% (95% CI, 35.6%-64.2%) for Caucasian and Vietnamese children, respectively. In Vietnamese group, relapses occurred in bone marrow (BM) and cerebrospinal fluid (CSF) at a much earlier stage. Several factors may contribute to the poor RFS in Vietnamese children, which include the time interval before the first intrathecal therapy and differences in the management of drugrelated toxicity. ...