Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia

Sponsor

Rigshospitalet, Denmark (Other)

Overall Status

Completed

CT.gov ID

NCT01678508

Collaborator

(none)

1,020

Enrollment

Location

121

Duration (Months)

8.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia

Detailed Description

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.

Study Design

Study Type:

Observational

Actual Enrollment :

1020 participants

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

Study Start Date :

Jan 1, 2002

Actual Primary Completion Date :

Jul 1, 2011

Actual Study Completion Date :

Feb 1, 2012

Outcome Measures

Primary Outcome Measures

Cumulative risk of relapse and risk of second cancer by Kaplan-Meier analysis with Gray's test comparisons at 10 years [Up to 10 years from diagnosis]
The risks will be reported as percentages.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 15 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

included in the NOPHO ALL2000 protocol
entered 6-mercaptopurine/Methotrexate maintenance therapy in first remission
available TPMT phenotype and/or genotype

Exclusion Criteria:

children with Down Syndrome

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rigshospitalet	Copenhagen		Denmark	2100

Sponsors and Collaborators

Rigshospitalet, Denmark

Investigators

Principal Investigator: Kjeld Schmiegelow, M.D., Rigshospitalet, Denmark

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Kjeld Schmiegelow, Professor MD, Rigshospitalet, Denmark

ClinicalTrials.gov Identifier:

NCT01678508

Other Study ID Numbers:

NOPHO ALL2000 TPMT and outcome

First Posted:

Sep 5, 2012

Last Update Posted:

Sep 5, 2012

Last Verified:

Sep 1, 2012

Additional relevant MeSH terms:

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Study Results

No Results Posted as of Sep 5, 2012