title: Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia.
abstract: BACKGROUND
  Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity.
  
  
  OBJECTIVE
  To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL.
  
  
  METHODS
  TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Münster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses.
  
  
  METHODS
  Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10(-4) were defined as negative.
  
  
  RESULTS
  Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86).
  
  
  CONCLUSIONS
  TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany. Stanulla.Martin@MH-Hannover.de
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Thomas
authors.initials: T
authors.lastname: Flohr
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: André
authors.initials: A
authors.lastname: Schrauder
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D008780:Methyltransferases / Q000235:genetics*; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D011379:Prognosis
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase