Matthias Schwab

Thiopurines in the Treatment of Childhood Acute Lymphoblastic Leukemia and Genetic Variants of the Thiopurine S-Methyltransferase Gene

The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are essential components of treatment protocols for childhood acute lymphoblastic leukemia (ALL). In the past 25 years, considerable insights into thiopurine pharmacology have been gained through continuing research efforts which have led to the development of strategies for improving efficacy and reducing toxicity associated with 6-MP and 6-TG application. One important route of metabolism for thiopurines is methylation by the enzyme thiopurine S-methyltransferase (TPMT). The gene coding for TPMT is subject to phenotypically relevant genetic variation, with heterozygous individuals having intermediate TPMT activity, and homozygous variant individuals having low TPMT activity. In this chapter, we review the role of thiopurines in the treatment of childhood ALL and provide an overview of strategies aimed at optimization of thiopurine application by therapeutic drug monitoring of thiopurine metabolites and geno- or phenotyping of TPMT.