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dc.contributor.authorNielsen, Stine Nygaard
dc.contributor.authorToksvang, Linea Natalie
dc.contributor.authorGrell, Kathrine
dc.contributor.authorNersting, Jacob
dc.contributor.authorAbrahamsson, Jonas
dc.contributor.authorLund, Bendik
dc.contributor.authorKanerva, Jukka
dc.contributor.authorJónsson, Ólafur Gísli
dc.contributor.authorVaitkeviciene, Goda
dc.contributor.authorPruunsild, Kaie
dc.contributor.authorAppell, Malin Lindqvist
dc.contributor.authorHjalgrim, Lisa Lyngsie
dc.contributor.authorSchmiegelow, Kjeld
dc.date.accessioned2021-08-23T12:51:28Z
dc.date.available2021-08-23T12:51:28Z
dc.date.issued2021-04-29
dc.date.submitted2021-08
dc.identifier.citationNielsen SN, Toksvang LN, Grell K, Nersting J, Abrahamsson J, Lund B, Kanerva J, Jónsson ÓG, Vaitkeviciene G, Pruunsild K, Appell ML, Hjalgrim LL, Schmiegelow K. No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study. Cancer Chemother Pharmacol. 2021 Aug;88(2):271-279. doi: 10.1007/s00280-021-04281-7.en_US
dc.identifier.pmid33928426
dc.identifier.doi10.1007/s00280-021-04281-7
dc.identifier.urihttp://hdl.handle.net/2336/621849
dc.descriptionTo access publisher's full text version of this article click on the hyperlink belowen_US
dc.description.abstractPurpose: 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. Methods: TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 × 109/L. Results: Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). Conclusion: TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008. Keywords: 6-mercaptopurine; Childhood acute lymphoblastic leukemia; Maintenance therapy; Relapse; Thiopurine methyltransferase.en_US
dc.description.sponsorshipDanish Cancer Society Childhood Cancer Foundation (Denmark) Childhood Cancer Foundation (Sweden) Nordic Cancer Union Otto Christensen Foundation University Hospital Rigshospitale Novo Nordisk Foundationen_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.relation.urlhttps://link.springer.com/article/10.1007%2Fs00280-021-04281-7en_US
dc.subject6-mercaptopurineen_US
dc.subjectChildhood acute lymphoblastic leukemiaen_US
dc.subjectMaintenance therapyen_US
dc.subjectRelapseen_US
dc.subjectThiopurine methyltransferaseen_US
dc.subjectBráðahvítblæðien_US
dc.subjectLyfjagjöfen_US
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphomaen_US
dc.subject.meshMaintenance Chemotherapyen_US
dc.titleNo association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.en_US
dc.typeArticleen_US
dc.identifier.eissn1432-0843
dc.contributor.department1Department of Pediatrics and Adolescent Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 2Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 3Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 4Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway. 5Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. 6Pediatric Hematology-Oncology, Barnaspitali Hringsins, Landspitali University Hospital, Reykjavik, Iceland. 7Centre for Paediatric Oncology and Haematology, Vilnius University, Vilnius, Lithuania. 8Department of Oncology and Haematology, Tallinn Children's Hospital, Tallinn, Estonia. 9Faculty of Medicine and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden. 10Department of Pediatrics and Adolescent Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk. 11Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk.en_US
dc.identifier.journalCancer chemotherapy and pharmacologyen_US
dc.rights.accessNational Consortium - Landsaðganguren_US
dc.departmentcodePED12
dc.source.journaltitleCancer chemotherapy and pharmacology
dc.source.volume88
dc.source.issue2
dc.source.beginpage271
dc.source.endpage279
dc.source.countryGermany


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