Trial Information

Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia - Influence on Cure Rates and Risk of Second Cancer

The thiopurines 6-mercaptopurine (6MP) and 6-thioguanine (6TG) are widely used in the
treatment of childhood acute lymphoblastic leukemia (ALL). They primarily exert their
cytotoxicity through conversion into 6-thioguanine nucleotides (6TGN) that are incorporated
into DNA. Interindividual variations in response to thiopurine therapy are influenced by
genetically determined polymorphisms in the activity of the enzyme thiopurine
methyltransferase (TPMT). TPMT competes with the formation of 6TGN, as it methylates the
thiopurines (especially 6MP) and some of their metabolites. Approximately ten percent of all
individuals are TPMT heterozygous, with one wild type and one low activity allele, and one
in three hundred individuals are TPMT deficient with two low activity alleles. During the
maintenance therapy phase of the treatment of childhood ALL, which may last several years,
6MP is given on a daily basis at a starting dose of 75 mg/m.sq./day, which is subsequently
adjusted to a white blood cell count of 1.5-3.5 x109/L. We have previously demonstrated that
the risk of relapse is reduced by more than 50%, but the risk of second cancer was increased
3-fold among TPMT low activity patients. Accordingly, the Nordic ALL2000 protocol
recommended the dosing of 6MP to be based on the patients TPMT activity. In the present
study of almost 1000 Nordic patients, we will explore whether this strategy of TPMT-based
individualised 6MP dosing have benefitted the patients by reducing their risk of second
cancer while preserving their low risk of relapse.