This study determined whether phenotype or genotype tests for thiopurine methyltransferase (TPMT) are cost effective interventions for guiding doses of 6-mercaptopurine in children with acute lymphoblastic leukemia (ALL) compared to standard weight-based dosing. A systematic review of the literature was conducted to assess the accuracy of the TPMT technologies, followed by a cost effectiveness analysis which compared genotype, phenotype and weight-based dosing strategies over a three month time horizon. Both TPMT phenotype and genotype technologies were considered accurate though there is no gold standard. Additionally, included studies were of low methodological quality. Neither of the interventions showed a benefit in survival and both were more costly compared to standard weight-based dosing. At this time there is insufficient evidence to recommend the use of phenotype or genotype testing prior to 6-mercaptopurine therapy to guide initial doses in pediatric ALL patients.

This study determined whether phenotype or genotype tests for thiopurine methyltransferase (TPMT) are cost effective interventions for guiding doses of 6-mercaptopurine in children with acute lymphoblastic leukemia (ALL) compared to standard weight-based dosing. A systematic review of the literature was conducted to assess the accuracy of the TPMT technologies, followed by a cost effectiveness analysis which compared genotype, phenotype and weight-based dosing strategies over a three month time horizon. Both TPMT phenotype and genotype technologies were considered accurate though there is no gold standard. Additionally, included studies were of low methodological quality. Neither of the interventions showed a benefit in survival and both were more costly compared to standard weight-based dosing. At this time there is insufficient evidence to recommend the use of phenotype or genotype testing prior to 6-mercaptopurine therapy to guide initial doses in pediatric ALL patients.

Human thiopurine methyltransferase (TPMT) is an enzyme involved in the metabolism of thiopurine drugs, which are widely used in leukemia and inflammatory bowel diseases such as ulcerative colitis and Crohn´s disease. Due to genetic polymorphisms, approximately 30 protein variants are present in the population, some of which have significantly lowered activity. TPMT *5 (Leu49Ser) is one of the protein variants with almost no activity. The mutation is positioned in the hydrophobic core of the protein, close to the active site. Hydrogen exchange rates measured with NMR spectroscopy for N-terminally truncated constructs of TPMT *5 and TPMT *1 (wild type) show that local stability and hydrogen bonding patterns are changed by the mutation Leu49Ser. Most residues exhibit faster exchange rates and a lower local stability in TPMT *5 in comparison with TPMT *1. Changes occur close to the active site but also throughout the entire protein. Calculated overall stability is similar for the two constructs, so the measured changes are due to local stability. Protein dynamics measured with NMR relaxation experiments show that both TPMT *5 and TPMT *1 are monomeric in solution. Millisecond dynamics exist in TPMT *1 but not in TPMT *5, even though a few residues exhibit a faster dynamic. Dynamics on nanosecond to picosecond time scale have changed but no clear trends are observable.