title: Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.
abstract: Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.
authors.affiliation: Faculty of Medicine, Institute of Gynecology, Obstetrics, and Pediatrics, University of Copenhagen, Copenhagen, Denmark. kschmiegelow@rh.dk
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Modhwahi
authors.forename: Mette Klarskov
authors.initials: MK
authors.lastname: Andersen
authors.forename: Mikael
authors.initials: M
authors.lastname: Behrendtz
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.forename: Jon
authors.initials: J
authors.lastname: Kristinsson
authors.forename: Jacob
authors.initials: J
authors.lastname: Nersting
authors.forename: Randi
authors.initials: R
authors.lastname: Nygaard
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Svendsen
authors.forename: Kim
authors.initials: K
authors.lastname: Vettenranta
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007621:Karyotyping; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008780:Methyltransferases / Q000378:metabolism; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011379:Prognosis; D012074:Remission Induction; D012307:Risk Factors; D033581:Stem Cell Transplantation; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D008727:Methotrexate