Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Kjeld Schmiegelow, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:
NCT01678508
First received: May 22, 2012
Last updated: September 4, 2012
Last verified: September 2012
  Purpose

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
Acute Lymphoblastic Leukemia

Study Type: Observational
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

Resource links provided by NLM:


Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:
  • 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


Enrollment: 1020
Study Start Date: January 2002
Study Completion Date: February 2012
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   1 Year to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

The study cohort is based on patients enrolled in the NOPHO ALL2000 protocol.

Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01678508

Locations
Denmark
Rigshospitalet
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Rigshospitalet, Denmark
Investigators
Principal Investigator: Kjeld Schmiegelow, M.D. Rigshospitalet, Denmark
  More Information

No publications provided

Responsible Party: Kjeld Schmiegelow, Professor MD, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01678508     History of Changes
Other Study ID Numbers: NOPHO ALL2000 TPMT and outcome
Study First Received: May 22, 2012
Last Updated: September 4, 2012
Health Authority: Denmark: Danish Medicines Agency

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on July 22, 2014