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

2.50
Hdl Handle:
http://hdl.handle.net/2336/87891
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
Authors:
Schmiegelow, Kjeld; Al-Modhwahi, Ibrahim; Andersen, Mette Klarskov; Behrendtz, Mikael; Forestier, Erik; Hasle, Henrik; Heyman, Mats; Kristinsson, Jon; Nersting, Jacob; Nygaard, Randi; Svendsen, Anne Louise; Vettenranta, Kim; Weinshilboum, Richard
Citation:
Blood. 2009, 113(24):6077-84
Issue Date:
11-Jun-2009
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.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://dx.doi.org/10.1182/blood-2008-11-187880

Full metadata record

DC FieldValue Language
dc.contributor.authorSchmiegelow, Kjelden
dc.contributor.authorAl-Modhwahi, Ibrahimen
dc.contributor.authorAndersen, Mette Klarskoven
dc.contributor.authorBehrendtz, Mikaelen
dc.contributor.authorForestier, Eriken
dc.contributor.authorHasle, Henriken
dc.contributor.authorHeyman, Matsen
dc.contributor.authorKristinsson, Jonen
dc.contributor.authorNersting, Jacoben
dc.contributor.authorNygaard, Randien
dc.contributor.authorSvendsen, Anne Louiseen
dc.contributor.authorVettenranta, Kimen
dc.contributor.authorWeinshilboum, Richarden
dc.date.accessioned2009-12-14T14:46:12Z-
dc.date.available2009-12-14T14:46:12Z-
dc.date.issued2009-06-11-
dc.date.submitted2009-12-14-
dc.identifier.citationBlood. 2009, 113(24):6077-84en
dc.identifier.issn1528-0020-
dc.identifier.pmid19224761-
dc.identifier.doi10.1182/blood-2008-11-187880-
dc.identifier.urihttp://hdl.handle.net/2336/87891-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractAmong 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.en
dc.language.isoenen
dc.publisher1528-0020en
dc.relation.urlhttp://dx.doi.org/10.1182/blood-2008-11-187880en
dc.subject.mesh6-Mercaptopurineen
dc.subject.meshAdministration, Oralen
dc.subject.meshAdolescenten
dc.subject.meshAntineoplastic Combined Chemotherapy Protocolsen
dc.subject.meshChilden
dc.subject.meshChild, Preschoolen
dc.subject.meshCombined Modality Therapyen
dc.subject.meshCranial Irradiationen
dc.subject.meshFemaleen
dc.subject.meshFollow-Up Studiesen
dc.subject.meshHumansen
dc.subject.meshImmunoenzyme Techniquesen
dc.subject.meshInfanten
dc.subject.meshKaryotypingen
dc.subject.meshMaleen
dc.subject.meshMethotrexateen
dc.subject.meshMethyltransferasesen
dc.subject.meshNeoplasms, Second Primaryen
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphomaen
dc.subject.meshPrognosisen
dc.subject.meshRemission Inductionen
dc.subject.meshRisk Factorsen
dc.subject.meshStem Cell Transplantationen
dc.subject.meshSurvival Rateen
dc.subject.meshTreatment Outcomeen
dc.titleMethotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 studyen
dc.typeArticleen
dc.contributor.departmentFaculty of Medicine, Institute of Gynecology, Obstetrics, and Pediatrics, University of Copenhagen, Copenhagen, Denmark. kschmiegelow@rh.dken
dc.identifier.journalBlooden

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