The Influence of Thiopurine Methyltransferase Activity on Toxicity After High-dose Methotrexate in Childhood Acute Lymphoblastic Leukemia

June 21, 2013 updated by: Kjeld Schmiegelow, Rigshospitalet, Denmark

The Influence of Thiopurine Methyltransferase Activity on Bone Marrow- and Hepato-toxicity After High-dose Methotrexate in Childhood Acute Lymphoblastic Leukemia

The purpose of this study is to explore the impact of thiopurine methyltransferase (TPMT) activity on the risk of HDM-related bone marrow- and hepatotoxicity and treatment interruptions during maintenance therapy for children with ALL.

Hypothesis of the study: Patients with TPMT activity compatible with TPMT low activity polymorphisms have an increased risk of toxicity following high-dose methotrexate (HDM) compared to children with normal TPMT activity.

Study Overview

Status

Completed

Conditions

Detailed Description

High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood ALL. Several studies have indicated that MTX and 6MP act synergistically. It has previously been reported that the risk of significant bone-marrow suppression is increased if oral 6MP is coadministered with HDM during maintenance therapy and that reductions of the dose of concurrently given oral 6MP can reduce the risk of significant myelotoxicity following HDM. MTX may increase the bioavailability of 6MP through inhibition of xanthine oxidase, which catabolizes 6MP. In addition, MTX may through inhibition of de novo purine synthesis enhance the availability of 6-thioguanine nucleotides (6TGN) that primarily exert the cytotoxic effect of 6MP.

The enzyme TPMT competes with the formation of 6TGN, as it methylates 6MP and thus create relatively non-toxic metabolites. TPMT heterozygous patients with one wild type and one low-activity allele have a higher risk of myelosuppression and treatment interruption compared to patients with TPMT wild type. Furthermore, TPMT heterozygous patients have a reduced risk of relapse and a higher risk of secondary malignancy compared to patients with TPMT wild type.

Little has been published on the influence of both TPMT activity and 6MP dosage on myelo- and hepatotoxicity following HDM.

Study Type

Observational

Enrollment (Actual)

411

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Kjeld Schmiegelow

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 15 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

The study cohort was based on patients enrolled in the NOPHO ALL92 protocol, where 97% of all eligible patients were included.

Participation in this study was on the basis of TPMT status that was randomly missing.

Description

Inclusion Criteria:

  • included in the NOPHO ALL92 protocol
  • available TPMT phenotype
  • treated at least once with HD-MTX 5.0 g/m2 (+- 10%) during maintenance therapy
  • at least one available measurement on blood counts or alanine aminotransferase levels 28 days after HD-MTX

Exclusion Criteria:

  • HR ALL
  • children with Down Syndrome
  • Events during maintenance therapy
  • TPMT deficiency

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Toxicity of treatment, degree of myelo- and hepatotoxicity
Time Frame: 7-28 days after high-dose methotrexate
7-28 days after high-dose methotrexate

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rigshospitalet, Denmark

Collaborators

Nordic Society for Pediatric Hematology and Oncology

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2011

Primary Completion (Actual)

February 1, 2012

Study Completion (Actual)

February 1, 2012

Study Registration Dates

First Submitted

June 21, 2013

First Submitted That Met QC Criteria

June 21, 2013

First Posted (Estimate)

June 26, 2013

Study Record Updates

Last Update Posted (Estimate)

June 26, 2013

Last Update Submitted That Met QC Criteria

June 21, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NOPHO ALL92 study HDM TPMT

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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