title: Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6-mercaptopurine doses during maintenance therapy: the Polish multicenter analysis.
abstract: BACKGROUND
  6-Mercaptopurine (6-MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6-MP treatment. This multicenter study investigated the association between TPMT genotype, 6-MP dose adjustments, and the incidence of adverse effects in patients.
  
  
  METHODS
  A total of 203 ALL children were genotyped using PCR/allele-specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers.
  
  
  RESULTS
  The TPMT*3A variant allele was found in 16 patients (15 TPMT*1/*3A, 1 TPMT*3A/*3A) and the TPMT*3C (A719G) allele in 1 patient. No TPMT*2 (G238C) or TPMT*3B (G460A) alleles were detected in the study group. TPMT*3A, TPMT*1 (wild-type), and TPMT*3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6-MP dose was reduced more frequently in patients with TPMT*3A and TPMT*3C alleles, compared with wild-type alleles (P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four (P = 0.007) and five (P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6-MP dose reduction (P = 0.028). 6-MP was discontinued more often in patients with TPMT*3A and TPMT*3C alleles (14-fold) as a result of leucopenia, anemia, and/or thrombocytopenia (P = 0.004).
  
  
  CONCLUSIONS
  The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy.
authors.affiliation: Department of Pediatrics, Hematology and Oncology Medical University, Szczecin, Poland. peregud@tstd.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Peregud-Pogorzelski
authors.forename: Edyta
authors.initials: E
authors.lastname: Tetera-Rudnicka
authors.forename: Mateusz
authors.initials: M
authors.lastname: Kurzawski
authors.forename: Andrzej
authors.initials: A
authors.lastname: Brodkiewicz
authors.forename: Natalia
authors.initials: N
authors.lastname: Adrianowska
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
authors.forename: Danuta
authors.initials: D
authors.lastname: Januszkiewicz
authors.forename: Marek
authors.initials: M
authors.lastname: Drozdzik
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics*; D011044:Poland; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase