title: Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.
abstract: OBJECTIVE
  Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT.
  
  
  METHODS
  Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy.
  
  
  RESULTS
  The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses).
  
  
  CONCLUSIONS
  For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Levinsen
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosthøj
authors.forename: Ulrikka
authors.initials: U
authors.lastname: Nygaard
authors.forename: Jesper
authors.initials: J
authors.lastname: Heldrup
authors.forename: Arja
authors.initials: A
authors.lastname: Harila-Saari
authors.forename: Olafur G
authors.initials: OG
authors.lastname: Jonsson
authors.forename: Anne Grete
authors.initials: AG
authors.lastname: Bechensteen
authors.forename: Jonas
authors.initials: J
authors.lastname: Abrahamsson
authors.forename: Birgitte
authors.initials: B
authors.lastname: Lausen
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Frandsen
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000453:epidemiology; D060046:Maintenance Chemotherapy / Q000009:adverse effects; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D038042:Myelopoiesis / Q000187:drug effects*; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D012189:Retrospective Studies; D012306:Risk; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D019384:Nucleic Acid Synthesis Inhibitors; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D008727:Methotrexate