title: Systemic Exposure to Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic Leukemia: A Children's Oncology Group Study.
abstract: OBJECTIVE
  Variability in prescribed doses of 6-mercaptopurine (6MP) and lack of adherence to a 6MP treatment regimen could result in intra-individual variability in systemic exposure to 6MP (measured as erythrocyte thioguanine nucleotide [TGN] levels) in children with acute lymphoblastic leukemia (ALL). The effect on relapse risk of this variability is unknown.
  
  
  OBJECTIVE
  To determine the effect of high intra-individual variability of 6MP systemic exposure on relapse risk in children with ALL.
  
  
  METHODS
  We used a prospective longitudinal design (Children's Oncology Group study [COG-AALL03N1]) to monitor 6MP and disease relapse in 742 children with ALL in ambulatory care settings of 94 participating institutions from May 30, 2005, to September 9, 2011. All participants met the following eligibility criteria: (1) diagnosis of ALL at 21 years or younger; (2) first continuous remission in progress at the time of study entry; (3) receiving self-, parent-, or caregiver-administered oral 6MP during maintenance therapy; and (4) completion of at least 6 months of maintenance therapy at the time of study enrollment. The median patient age at diagnosis was 5 years; 68% were boys; and 43% had National Cancer Institute-based high-risk disease.
  
  
  METHODS
  Daily 6MP regimen adherence was measured over 68 716 person-days using an electronic system that recorded the date and time of each 6MP bottle opening; adherence rate was defined as the ratio of days that a 6MP bottle was opened to days thata 6MP bottle was prescribed. Average monthly 6MP dose intensity was measured over 120 439 person-days by dividing the number of 6MP doses actually prescribed by the number of planned protocol doses (75 mg/m2/d). Monthly erythrocyte TGN levels (pmol/8 × 108 erythrocytes) were measured over 6 consecutive months per patient (n = 3944 measurements). Using intra-individual coefficients of variation (CV%), patients were classified as having stable (CV% <85th percentile) vs varying (CV% ≥85th percentile) indices. Median follow-up time was 6.7 years from the time of diagnosis.
  
  
  RESULTS
  Adjusting for clinical prognosticators, we found that patients with 6MP nonadherence (mean adherence rate <95%) were at a 2.7-fold increased risk of relapse (95% CI, 1.3-5.6; P = .01) compared with patients with a mean adherence rate of 95% or greater. Among adherers, high intra-individual variability in TGN levels contributed to increased relapse risk (hazard ratio, 4.4; 95% CI, 1.2-15.7; P = .02). Furthermore, adherers with varying TGN levels had varying 6MP dose intensity (odds ratio [OR], 4.5; 95% CI, 1.5-13.4; P = .01) and 6MP drug interruptions (OR, 10.2; 95% CI, 2.2-48.3; P = .003).
  
  
  CONCLUSIONS
  These findings emphasize the need to maximize 6MP regimen adherence and maintain steady thiopurine exposure to minimize relapse in children with ALL.
authors.affiliation: City of Hope, Duarte, California2University of Alabama, Birmingham.
authors.forename: Smita
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: City of Hope, Duarte, California2University of Alabama, Birmingham.
authors.forename: Wendy
authors.initials: W
authors.lastname: Landier
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Hageman
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Heeyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Can-Lan
authors.initials: CL
authors.lastname: Sun
authors.affiliation: St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kornegay
authors.affiliation: St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Children's National Medical Center, The George Washington School of Medicine, Washington, DC.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Angiolillo
authors.affiliation: Children's Hospitals and Clinics of Minnesota, Minneapolis.
authors.forename: Bruce
authors.initials: B
authors.lastname: Bostrom
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Casillas
authors.affiliation: Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
authors.forename: Glen
authors.initials: G
authors.lastname: Lew
authors.affiliation: University of Colorado School of Medicine, Aurora.
authors.forename: Kelly W
authors.initials: KW
authors.lastname: Maloney
authors.affiliation: Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California,Los Angeles.
authors.forename: Leo
authors.initials: L
authors.lastname: Mascarenhas
authors.affiliation: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: A Kim
authors.initials: AK
authors.lastname: Ritchey
authors.affiliation: Keck School of Medicine, University of Southern California,Los Angeles.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Termuhlen
authors.affiliation: New York University Cancer Institute, New York, New York.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: City of Hope, Duarte, California.
authors.forename: F Lennie
authors.initials: FL
authors.lastname: Wong
authors.affiliation: St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D055118:Medication Adherence; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D015999:Multivariate Analysis; D016017:Odds Ratio; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D011446:Prospective Studies; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine