title: Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?
abstract: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines.
  
  
  
  To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 109/l.
  
  
  
  After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 109/l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109/l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, rs= 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model.
  
  
  
  This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark. kschmiegelow@rh.dk.|Faculty of Medicine, Institute of Clinical Medicine, University of Copenhagen, Denmark. kschmiegelow@rh.dk.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nersting
authors.affiliation: Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Stine Nygaard
authors.initials: SN
authors.lastname: Nielsen
authors.affiliation: Astrid Lindgrens Barnsjukhus, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.affiliation: Department of Pediatric Oncology, The University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Finn
authors.initials: F
authors.lastname: Wesenberg
authors.affiliation: Department of Pediatric Oncology, The National Hospital, Reykjavik, Iceland.
authors.forename: Jon
authors.initials: J
authors.lastname: Kristinsson
authors.affiliation: Department of Pediatric Oncology, The University Hospital, Helsinki, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Vettenranta
authors.affiliation: Department of Pediatric Oncology, Århus University Hospital, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Schrøeder
authors.affiliation: Department of Pharmacology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
authors.affiliation: Section of Biostatistics, Department of Public Health, The University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katrine Lykke
authors.initials: KL
authors.lastname: Jensen
authors.affiliation: Section of Biostatistics, Department of Public Health, The University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kathrine
authors.initials: K
authors.lastname: Grell
authors.affiliation: Section of Biostatistics, Department of Public Health, The University of Copenhagen, Copenhagen, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosthoej
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D009504:Neutrophils; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D016016:Proportional Hazards Models
chemical_list: D015122:Mercaptopurine; D008727:Methotrexate
keywords: ALL; ALL relapse; chemotherapy; molecular diagnosis and therapy; pharmacokinetics; pharmacology; white blood cell count