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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6077-6084. Prepublished online as a Blood First Edition Paper on February 17, 2009; DOI 10.1182/blood-2008-11-187880. This Article Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2008-11-187880v1 113/24/6077    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Schmiegelow, K. Articles by Weinshilboum, R. Search for Related Content PubMed PubMed Citation Articles by Schmiegelow, K. Articles by Weinshilboum, R. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 5, 2008 Accepted January 22, 2009 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 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, and Richard Weinshilboum Faculty of Medicine, Institute of Gynecology, Obstetrics and Pediatrics, University of Copenhagen, Copenhagen, Denmark Department of Pediatrics, University Hospital Rigshospitalet, Copenhagen, Denmark The Cytogenetic Laboratory, University Hospital Rigshospitalet, Copenhagen, Denmark Department of Pediatrics, University Hospital Linkoping, Linkoping, Sweden Department of Pediatrics, University Hospital Umea, Umea, Sweden Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark Department of Pediatrics, University Hospital Astrid Lindgrens Barnsjukus, Stockholm, Sweden Department of Pediatrics, University Hospital Reykjavik, Reykjavik, Iceland Department of Pediatrics, University Hospital Trondheim, Trondheim, Norway Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark Department of Pediatrics, University Hospital Helsinki, Helsinki, Finland Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, United States * Corresponding author; email: kschmiegelow{at}rh.dk. We explored the impact of 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy of childhood acute lymphoblastic leukemia (ALL) on the risk of second malignant neoplasms (SMN) among 1614 patients treated with the NOPHO ALL-92 protocol. Twenty patients developed an SMN 0.8-11.6 years (median: 3.4 years) from the diagnosis of ALL (risk at 12 years: 1.6%). Sixteen of the twenty SMNs were acute myeloid leukemias or myelodysplastic syndromes, and 9 of these had either monosomy 7 (n=7) or 7q deletions (n=2). In Cox multivariate analysis longer duration of oral MTX/6MP maintenance therapy (p=0.02; being longest for standard risk patients) and presence of high-hyperdiploidy (p=0.07) were related to increased risk of SMN. 524 patients were assessed for erythrocyte activity of thiopurine methyltransferase (TPMT), which methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of patients who had TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in those that did not develop an SMN (Median: 12.1 vs 18.1 IU/ml; p=0.02). Among 427 TPMT wild type patients for whom the 6MP dose was registered, those who developed SMN received higher 6MP doses than the remaining (69.7 vs 60.4 mg/m2, p=0.03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMN in childhood ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Maintenance loses its innocence Michael A. Pulsipher Blood 2009 113: 6041-6042. [Full Text] [PDF] On the malignant potential of thiopurine therapy Nanne K. H. de Boer, Dirk P. van Asseldonk, and Adriaan A. van Bodegraven Blood 2009 113: 6258. [Full Text] [PDF] Response: Could mutations in the hypoxanthine-guanine phosphoribosyl transferase gene induced by thiopurine therapy promote the development of second malignant neoplasms? Kjeld Schmiegelow, Ibrahim Al-Modhawi, Mette Klarskov Andersen, Mikael Berendtz, Erik Forestier, Henrik Hasle, Mats Heyman, Jon Kristinsson, Jacob Nersting, Randi Nygaard, Anne Louise Svendsen, Kim Vettenranta, and Richard Weinshilboum, the Nordic Society for Paediatric Haematology and Oncology Blood 2009 113: 6258-6259. [Full Text] [PDF] This article has been cited by other articles: C.-H. Pui Toward a Total Cure for Acute Lymphoblastic Leukemia J. Clin. Oncol., November 1, 2009; 27(31): 5121 - 5123. [Full Text] [PDF] M. A. Pulsipher Maintenance loses its innocence Blood, June 11, 2009; 113(24): 6041 - 6042. [Full Text] [PDF] N. K. H. de Boer, D. P. van Asseldonk, and A. A. van Bodegraven On the malignant potential of thiopurine therapy Blood, June 11, 2009; 113(24): 6258 - 6258. [Full Text] [PDF] K. Schmiegelow, I. Al-Modhawi, M. K. Andersen, M. Berendtz, E. Forestier, H. Hasle, M. Heyman, J. Kristinsson, J. Nersting, R. Nygaard, et al. Response: Could mutations in the hypoxanthine-guanine phosphoribosyl transferase gene induced by thiopurine therapy promote the development of second malignant neoplasms? Blood, June 11, 2009; 113(24): 6258 - 6259. [Full Text] [PDF]

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