title: The circadian schedule for childhood acute lymphoblastic leukemia maintenance therapy does not influence event-free survival in the NOPHO ALL92 protocol.
abstract: BACKGROUND
  The event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning.
  
  
  METHODS
  In the ALL92 MT study we prospectively registered the intake of MTX/6MP. The registration was done when blood samples for erythrocyte MTX/6MP metabolite measurements were collected, and referred to the time of intake in the period since last registration. Nine thousand one hundred ninety-five registrations in total. The administration of MTX/6MP was scored as morning, midday, or evening.
  
  
  RESULTS
  Of 532 patients, 296 took their medication consistently in the evening, 129 in the evening 50.0-99.9% of the time, and 101 in the evening <50% of the time, six did not have any registrations. The circadian schedule did not differ significantly by age, sex, MTX/6MP doses, and average absolute neutrophil counts. The circadian schedule groups did differ on risk groups (P = 0.003) with fewer HR patients in the 50-99.9% group, and there was a negative correlation between percentage of time on evening schedule and average WBC (Spearman's rho -0.15; P = 0.0004). Average WBC was not associated with relapse on ALL92. In a Cox multivariate model the circadian schedule of MTX/6MP was not of prognostic significance for the risk of relapse, and the 10-year cumulative relapse risk was below 20% in all groups.
  
  
  CONCLUSIONS
  An evening schedule may still be recommended based on the previous publications, but in this study morning administration of MTX and 6MP does not seem to impact EFS.
authors.affiliation: Clinic for Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kim K B
authors.initials: KK
authors.lastname: Clemmensen
authors.forename: Regitse H
authors.initials: RH
authors.lastname: Christensen
authors.forename: Diana N
authors.initials: DN
authors.lastname: Shabaneh
authors.forename: Arja
authors.initials: A
authors.lastname: Harila-Saari
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.forename: Olafur G
authors.initials: OG
authors.lastname: Jonsson
authors.forename: Finn
authors.initials: F
authors.lastname: Wesenberg
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosthøj
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D015122:Mercaptopurine; D008727:Methotrexate
keywords: 6-mercaptopurine; Circadian rhythm; acute lymphoblastic leukemia; child; methotrexate