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Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT01678508
Recruitment Status : Completed
First Posted : September 5, 2012
Last Update Posted : September 5, 2012
Sponsor:
Information provided by (Responsible Party):
Kjeld Schmiegelow, Rigshospitalet, Denmark

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
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 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 : January 2002
Actual Primary Completion Date : July 2011
Actual Study Completion Date : February 2012





Primary Outcome Measures :
  1. 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 ]
    The risks will be reported as percentages.


Biospecimen Retention:   Samples With DNA
whole blood stored for a subset of patients


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Ages Eligible for Study:   1 Year to 15 Years   (Child)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01678508


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

Responsible Party: Kjeld Schmiegelow, Professor MD, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01678508     History of Changes
Other Study ID Numbers: NOPHO ALL2000 TPMT and outcome
First Posted: September 5, 2012    Key Record Dates
Last Update Posted: September 5, 2012
Last Verified: September 2012

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