title: Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia.
abstract: Etoposide, an effective agent for acute lymphoblastic leukemia (ALL), can cause secondary acute myeloid leukemia (AML) in a subset of patients. Our objectives were to determine whether patients who develop secondary AML displayed altered etoposide pharmacokinetics or other pharmacologic characteristics compared to identically treated patients who did not develop AML. Children with newly diagnosed ALL were treated according to a protocol which included etoposide 300 mg/m2 given three times over 8 days during remission induction and once every 2-4 weeks during 120 weeks of continuation therapy. Characteristic 11q23 rearrangements were documented in seven of the eight patients with AML. Etoposide clearance, time that etoposide concentrations exceeded 10 microM, etoposide or etoposide catechol area-under-the-plasma-concentration vs time curve (AUC), serum albumin, and average methotrexate concentration did not differ significantly between the two groups; thiopurine methyltransferase (TPMT) activity tended to be lower in the eight children who did vs the 23 matched control children who did not develop AML (P=0.16). Further regression analyses likewise indicated that lower TPMT activity tended to be associated with shorter onset of secondary AML (P=0.11); it also tended to be lower among the eight index cases compared to the entire unmatched cohort of 105 identically treated children with ALL (P=0.10). We observed no statistically significant differences in etoposide disposition and antimetabolite pharmacology between patients who did and did not develop secondary AML.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, and The University of Tennessee, Memphis 38105, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
authors.forename: Y
authors.initials: Y
authors.lastname: Yanishevski
authors.forename: J
authors.initials: J
authors.lastname: Nemec
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: J M
authors.initials: JM
authors.lastname: Boyett
authors.forename: F G
authors.initials: FG
authors.lastname: Behm
authors.forename: C H
authors.initials: CH
authors.lastname: Pui
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000201:enzymology; D005047:Etoposide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008780:Methyltransferases / Q000097:blood; D008954:Models, Biological; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012044:Regression Analysis; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D012709:Serum Albumin; D005047:Etoposide; D008780:Methyltransferases; C022745:thiopurine methyltransferase