Dosage of 6-Mercaptopurine in Relation to Genetic TPMT and ITPA Variants: Toward Individualized Pediatric Acute Lymphoblastic Leukemia Maintenance Treatment

T.W. Kouwenberg*, B.J.C. van den Bosch, J. Bierau, D.M.W.M. te Loo, M.J.H. Coenen, M.M. Hagleitner

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)

Abstract

6-mercaptopurine (6-MP) is the mainstay in pediatric acute lymphoblastic leukemia (ALL) maintenance treatment. Variants in genes coding for thiopurine S-methyl transferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are known to influence 6-MP metabolism. We determined TPMT and ITPA genotype and enzyme activity and the mean 6-MP doses during maintenance treatment in 40 children treated for ALL according to the Dutch Childhood Oncology Group (DCOG)-ALL11 protocol in the Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands. Patients with genetic variants in TPMT (N=3) had significantly lower TPMT enzyme activity (mean 0.46 vs. 0.72 mu mol/mmol hemoglobin/h, P=0.005). Although the difference was not statistically significant, they were treated with lower mean 6-MP doses (28.1 mg/m(2) [SD 25.5 mg/m(2)] vs. 41.3 mg/m(2) [SD 17.2 mg/m(2)], P=0.375). In patients with genetic ITPA variants (N=21), ITPA enzyme activity was significantly lowered (mean 3.67 vs. 6.84 mmol/mmol hemoglobin/h, P<0.0005). The mean 6-MP doses did not differ between patients with and without variants in ITPA (40.0 mg/m(2) [SD 20.3 mg/m(2)] vs. 40.6 mg/m(2) [SD 14.9 mg/m(2)], P=0.663). The TPMT genotype, but not the ITPA genotype, should be considered as part of standard evaluation before starting ALL maintenance treatment.
Original languageEnglish
Pages (from-to)E94-E97
Number of pages4
JournalJournal of Pediatric Hematology Oncology
Volume42
Issue number2
DOIs
Publication statusPublished - 1 Mar 2020

Keywords

  • 6-mercaptopurine
  • acute lymphoblastic leukemia
  • azathioprine
  • children
  • disease
  • itpa
  • pharmacogenetics
  • polymorphisms
  • population
  • susceptibility
  • therapy
  • thiopurine methyltransferase activity
  • tpmt
  • POPULATION
  • TPMT
  • SUSCEPTIBILITY
  • AZATHIOPRINE
  • THIOPURINE METHYLTRANSFERASE ACTIVITY
  • CHILDREN
  • POLYMORPHISMS
  • THERAPY
  • DISEASE
  • PHARMACOGENETICS
  • ITPA

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