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Medical Oncology

, Volume 29, Issue 3, pp 2053–2062 | Cite as

Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia

  • Noha M. EL-Khodary
  • Sahar M. EL-Haggar
  • Manal A. Eid
  • Emad N. Ebeid
Original Paper

Abstract

Methotrexate inhibits the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase (MTHFR). MTHFR has a common functional polymorphism C677T. The present study aimed to investigate the prevalence of MTHFR polymorphisms in Egyptian children with ALL and the relation to MTX-related toxicity, relapse, and MTX pharmacokinetic parameters. Forty patients with ALL were included in the study. They were treated according to ALL-NCI total XIII protocol. MTX-related toxicity and MTX pharmacokinetic parameters were assessed during therapy. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay, and MTX pharmacokinetic parameters were assessed by HPLC. The MTHFR C677T polymeric allele frequencies were 55, 35, and 10% for CC, CT, and TT genotypes, respectively, among the studied patients with ALL. MTX therapy was significantly associated with toxicity signs in TT genotype: elevated transaminases (P < 0.0001), elevated serum alpha 1-microglobulin protein (P < 0.0001), anemia (P < 0.0001), neutropenia (P < 0.0001), thrombocytopenia (P < 0.0001), and elevated CSF-β-glucuronidase activity (P < 0.0001). Patients with TT genotype showed significant increase in MTX t ½ and AUC (P < 0.0001), while MTX elimination rate and total body clearance were significantly decreased (P < 0.0001 and P < 0.05, respectively) compared with CC genotype. The TT genotype was significantly associated with relapse in 2 years in 50% compared with 28.57% in CT and 13.64% in CC alleles. The overall 2-year survival was significantly lower in TT genotype (50%) compared with CC genotype (90.91%; P = 0.01). MTHFR TT genotype is significantly associated with increased toxicity during methotrexate therapy as well as increased relapse rate in pediatric patients with ALL. In future, MTX dose adjustment in ALL treatment protocols should be considered based on patient’s genotype.

Keywords

Methotrexate MTHFR Polymorphism ALL 

Notes

Acknowledgments

All authors gave substantial contributions to the conception and design of the study, analysis and interpretation of the data, drafting and revising the article. We thank the Tanta Cancer Center for help in obtaining samples and the patients and their families for participating.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Noha M. EL-Khodary
    • 1
  • Sahar M. EL-Haggar
    • 1
  • Manal A. Eid
    • 2
  • Emad N. Ebeid
    • 3
  1. 1.Department of Clinical Pharmacy, Faculty of PharmacyTanta UniversityTantaEgypt
  2. 2.Department of Clinical Pathology, Faculty of MedicineTanta UniversityTantaEgypt
  3. 3.Department of Pediatric Oncology and Hematology, National Cancer InstituteCairo UniversityCairoEgypt

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