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

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Brief Title

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

Official Title

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

Brief Summary

      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.
    

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


Primary Outcome

Toxicity of treatment, degree of myelo- and hepatotoxicity


Condition

Acute Lymphoblastic Leukemia



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

411

Start Date

July 2011

Completion Date

February 2012

Primary Completion Date

February 2012

Eligibility Criteria

        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
      

Gender

All

Ages

1 Year - 15 Years

Accepts Healthy Volunteers

No

Contacts

Kjeld Schmiegelow, M.D., , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT01886651

Organization ID

NOPHO ALL92 study HDM TPMT


Responsible Party

Principal Investigator

Study Sponsor

Rigshospitalet, Denmark

Collaborators

 Nordic Society for Pediatric Hematology and Oncology

Study Sponsor

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


Verification Date

June 2013