Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia
In a population-based study to explore the impact of TPMT-status on the risk of relapse and of second cancer among all patients treated according to the NOPHO ALL2000.
Acute Lymphoblastic Leukemia
|Study Design:||Observational Model: Cohort
Time Perspective: Retrospective
|Official Title:||Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia - Influence on Cure Rates and Risk of Second Cancer|
- Cumulative risk of relapse and risk of second cancer by Kaplan-Meier analysis with Gray's test comparisons at 10 years [ Time Frame: Up to 10 years from diagnosis ] [ Designated as safety issue: No ]The risks will be reported as percentages.
Biospecimen Retention: Samples With DNA
whole blood stored for a subset of patients
|Study Start Date:||January 2002|
|Study Completion Date:||February 2012|
|Primary Completion Date:||July 2011 (Final data collection date for primary outcome measure)|
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.