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Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic

Meryem Albayrak1, Uljan Konyssova, Zuhre Kaya

  • 1Pediatric Hematology Unit of the Department of Pediatrics, Medical School of Gazi University, Ankara, Turkey. meryemtombak@yahoo.com

Cancer Chemotherapy and Pharmacology
|March 15, 2011
PubMed

Insights

Genetic variations in Thiopurine methyltransferase (TPMT) are common in Turkish children with acute lymphoblastic leukemia (ALL). These TPMT polymorphisms correlate with increased 6-mercaptopurine (6-MP) toxicity, suggesting pre-treatment genetic screening.

Area of Science:

  • Pharmacogenetics
  • Pediatric Oncology
  • Clinical Chemistry

Background:

  • Thiopurine methyltransferase (TPMT) metabolizes 6-mercaptopurine (6-MP), a crucial drug in pediatric acute lymphoblastic leukemia (ALL) treatment.
  • Genetic variations in TPMT can significantly impact 6-MP efficacy and toxicity.
  • Understanding TPMT polymorphism frequency is vital for optimizing ALL treatment in diverse populations.

Purpose of the Study:

  • To determine the prevalence of common TPMT genetic polymorphisms in Turkish children diagnosed with ALL.
  • To investigate the association between these TPMT variants and the tolerance to 6-MP therapy.
  • To evaluate the clinical implications of TPMT genotyping in this pediatric cohort.

Main Methods:

  • Genotyping for TPMT variants (G238C, A719G, G460A) using NanoChip Technology.
  • Retrospective analysis of adverse events within the first six months of 6-MP and methotrexate maintenance therapy.
  • Correlation of identified TPMT genotypes with clinical outcomes, including toxicity and treatment adherence.

Main Results:

  • TPMT polymorphisms were identified in 8.6% of 58 Turkish children with ALL, primarily TPMT*3A and TPMT*3C heterozygotes.
  • Children with TPMT variants exhibited significantly lower leukocyte and neutrophil counts.
  • These patients experienced more frequent grade 2 or higher infections, liver toxicity, and chemotherapy interruptions compared to those with wild-type TPMT.

Conclusions:

  • The frequency of TPMT polymorphisms in Turkish children with ALL aligns with Caucasian populations.
  • TPMT variants are associated with increased 6-MP toxicity, manifesting as hematological, infectious, and hepatic complications.
  • Pre-treatment TPMT genotyping is recommended to personalize 6-MP therapy and mitigate adverse events in pediatric ALL patients.
Abstract

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