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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.

Journal article
Authors Kjeld Schmiegelow
Ibrahim Al-Modhwahi
Mette Klarskov Andersen
Mikael Behrendtz
Erik Forestier
Henrik Hasle
Mats Heyman
Jon Kristinsson
Jacob Nersting
Randi Nygaard
Anne Louise Svendsen
Kim Vettenranta
Richard Weinshilboum
Berit Kriström
Lotta Mellander
Published in Blood
Volume 113
Issue 24
Pages 6077-84
ISSN 1528-0020
Publication year 2009
Published at Institute of Clinical Sciences, Department of Pediatrics
Pages 6077-84
Language en
Keywords 6-Mercaptopurine, administration & dosage, adverse effects, Administration, Oral, Adolescent, Antineoplastic Combined Chemotherapy Protocols, adverse effects, Child, Child, Preschool, Combined Modality Therapy, Cranial Irradiation, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Infant, Karyotyping, Male, Methotrexate, administration & dosage, adverse effects, Methyltransferases, metabolism, Neoplasms, Second Primary, chemically induced, diagnosis, metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma, drug therapy, pathology, radiotherapy, Prognosis, Remission Induction, Risk Factors, Stem Cell Transplantation, Survival Rate, Treatment Outcome
Subject categories Pediatrics


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.

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