title: Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer.
abstract: BACKGROUND
  Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.
  
  
  METHODS
  We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype.
  
  
  RESULTS
  The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMT(LA) who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03).
  
  
  CONCLUSIONS
  This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT).
authors.affiliation: Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Levinsen
authors.forename: Elisabeth Ørskov
authors.initials: EØ
authors.lastname: Rotevatn
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosthøj
authors.forename: Jacob
authors.initials: J
authors.lastname: Nersting
authors.forename: Jonas
authors.initials: J
authors.lastname: Abrahamsson
authors.forename: Malin Lindqvist
authors.initials: ML
authors.lastname: Appell
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
authors.forename: Anne-Grete
authors.initials: AG
authors.lastname: Bechensteen
authors.forename: Arja
authors.initials: A
authors.lastname: Harila-Saari
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.forename: Olafur Gisli
authors.initials: OG
authors.lastname: Jonsson
authors.forename: Jakob Bernhard Cohn
authors.initials: JB
authors.lastname: Maxild
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Stefan
authors.initials: S
authors.lastname: Söderhäll
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D008780:Methyltransferases / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D016609:Neoplasms, Second Primary / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D011379:Prognosis; D012307:Risk Factors
chemical_list: D004273:DNA, Neoplasm; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D008727:Methotrexate
keywords: ALL; late effects of cancer treatment; outcomes research; therapy