title: The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine.
  
  
  METHODS
  Consecutive children were randomized to receive thioguanine or mercaptopurine during maintenance chemotherapy. Toxicity data were collected by an adverse event-reporting system with follow-up questionnaires. Red blood cell thiopurine methyltransferase (TPMT) activity and thioguanine nucleotide concentrations were measured by standard techniques.
  
  
  RESULTS
  Of the children, 748 were randomized to thioguanine and 744 were randomized to mercaptopurine. There was no difference in the event-free survival rate between the 2 groups (80% and 81%, respectively, at 5 years). Thioguanine was associated with veno-occlusive disease (VOD) of the liver in 95 children, and persistent splenomegaly as a result of portal hypertension developed in 43 children. TPMT activity was significantly lower in the children in whom VOD developed, with a median of 13.4 U (range, 5.8-23 U) compared with 15.2 U (range, 5.3-27) in a control group of 161 leukemia patients in whom VOD did not develop (median difference, 1.8 U; 95% confidence interval, 0.9-2.7 U; P = .0001). TPMT activity in children with persistent splenomegaly was also lower than that in control subjects (median difference, 1.6 U; 95% confidence interval, 0.3-2.8 U; P = .012). There was no difference in red blood cell thioguanine nucleotide concentrations.
  
  
  CONCLUSIONS
  Thioguanine was associated with liver damage in 11% of children randomized to thioguanine without an improvement in event-free survival rate. The association of lower TPMT activity with thioguanine-related liver damage could provide a means of identifying at-risk patients.
authors.affiliation: Academic Unit of Clinical Pharmacology, University of Sheffield, Sheffield, United Kingdom. L.Lennard@sheffield.ac.uk
authors.forename: Lynne
authors.initials: L
authors.lastname: Lennard
authors.forename: Sue
authors.initials: S
authors.lastname: Richards
authors.forename: Cher S
authors.initials: CS
authors.lastname: Cartwright
authors.forename: Chris
authors.initials: C
authors.lastname: Mitchell
authors.forename: John S
authors.initials: JS
authors.lastname: Lilleyman
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000150:complications; D006801:Humans; D006975:Hypertension, Portal / Q000150:complications / Q000209:etiology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects; D008780:Methyltransferases / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics*; D013163:Splenomegaly / Q000209:etiology; D013866:Thioguanine / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine