title: Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.
abstract: Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P=0.03). In Cox multivariate regression analysis, sex (male worse; P=0.06), age (higher age worse, P=0.02), and TPMT activity (wild type worse; P=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (P=0.82), possibly because of an excess of secondary cancers among these 75 patients (P=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.
authors.affiliation: The Institute of Gynecology, Obstetrics, and Pediatrics, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. kschmiegelow@rh.dk
authors.forename: K
authors.initials: K
authors.lastname: Schmiegelow
authors.forename: E
authors.initials: E
authors.lastname: Forestier
authors.forename: J
authors.initials: J
authors.lastname: Kristinsson
authors.forename: S
authors.initials: S
authors.lastname: Söderhäll
authors.forename: K
authors.initials: K
authors.lastname: Vettenranta
authors.forename: R
authors.initials: R
authors.lastname: Weinshilboum
authors.forename: F
authors.initials: F
authors.lastname: Wesenberg
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001711:Biotransformation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004249:DNA Damage; D005260:Female; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008745:Methylation; D008780:Methyltransferases / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D016609:Neoplasms, Second Primary / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D011110:Polymorphism, Genetic; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D012008:Recurrence; D012306:Risk; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D013866:Thioguanine / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine