DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial
BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whet...
Published in: | The Lancet Oncology |
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Online Access: | https://curis.ku.dk/portal/da/publications/dnathioguanine-nucleotide-concentration-and-relapsefree-survival-during-maintenance-therapy-of-childhood-acute-lymphoblastic-leukaemia-nopho-all2008(883f5572-8f13-4f79-9365-e4748a887bf0).html https://doi.org/10.1016/S1470-2045(17)30154-7 |
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ftcopenhagenunip:oai:pure.atira.dk:publications/883f5572-8f13-4f79-9365-e4748a887bf0 2024-05-19T07:42:59+00:00 DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial Nielsen, Stine Nygaard Grell, Kathrine Nersting, Jacob Abrahamsson, Jonas Lund, Bendik Kanerva, Jukka Jónsson, Ólafur Gísli Vaitkeviciene, Goda Pruunsild, Kaie Hjalgrim, Lisa Lyngsie Schmiegelow, Kjeld 2017-04 https://curis.ku.dk/portal/da/publications/dnathioguanine-nucleotide-concentration-and-relapsefree-survival-during-maintenance-therapy-of-childhood-acute-lymphoblastic-leukaemia-nopho-all2008(883f5572-8f13-4f79-9365-e4748a887bf0).html https://doi.org/10.1016/S1470-2045(17)30154-7 eng eng info:eu-repo/semantics/closedAccess Nielsen , S N , Grell , K , Nersting , J , Abrahamsson , J , Lund , B , Kanerva , J , Jónsson , Ó G , Vaitkeviciene , G , Pruunsild , K , Hjalgrim , L L & Schmiegelow , K 2017 , ' DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008) : a prospective substudy of a phase 3 trial ' , The Lancet Oncology , vol. 18 , no. 4 , pp. 515–524 . https://doi.org/10.1016/S1470-2045(17)30154-7 Journal Article article 2017 ftcopenhagenunip https://doi.org/10.1016/S1470-2045(17)30154-7 2024-04-25T00:45:03Z BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. METHODS: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m(2) once per day and methotrexate 20 mg/m(2) once per week, targeted to a leucocyte count of 1·5-3·0 × 10(9) cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. FINDINGS: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated ... Article in Journal/Newspaper Iceland University of Copenhagen: Research The Lancet Oncology 18 4 515 524 |
institution |
Open Polar |
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University of Copenhagen: Research |
op_collection_id |
ftcopenhagenunip |
language |
English |
topic |
Journal Article |
spellingShingle |
Journal Article Nielsen, Stine Nygaard Grell, Kathrine Nersting, Jacob Abrahamsson, Jonas Lund, Bendik Kanerva, Jukka Jónsson, Ólafur Gísli Vaitkeviciene, Goda Pruunsild, Kaie Hjalgrim, Lisa Lyngsie Schmiegelow, Kjeld DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial |
topic_facet |
Journal Article |
description |
BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. METHODS: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m(2) once per day and methotrexate 20 mg/m(2) once per week, targeted to a leucocyte count of 1·5-3·0 × 10(9) cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. FINDINGS: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated ... |
format |
Article in Journal/Newspaper |
author |
Nielsen, Stine Nygaard Grell, Kathrine Nersting, Jacob Abrahamsson, Jonas Lund, Bendik Kanerva, Jukka Jónsson, Ólafur Gísli Vaitkeviciene, Goda Pruunsild, Kaie Hjalgrim, Lisa Lyngsie Schmiegelow, Kjeld |
author_facet |
Nielsen, Stine Nygaard Grell, Kathrine Nersting, Jacob Abrahamsson, Jonas Lund, Bendik Kanerva, Jukka Jónsson, Ólafur Gísli Vaitkeviciene, Goda Pruunsild, Kaie Hjalgrim, Lisa Lyngsie Schmiegelow, Kjeld |
author_sort |
Nielsen, Stine Nygaard |
title |
DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial |
title_short |
DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial |
title_full |
DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial |
title_fullStr |
DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial |
title_full_unstemmed |
DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008):a prospective substudy of a phase 3 trial |
title_sort |
dna-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (nopho all2008):a prospective substudy of a phase 3 trial |
publishDate |
2017 |
url |
https://curis.ku.dk/portal/da/publications/dnathioguanine-nucleotide-concentration-and-relapsefree-survival-during-maintenance-therapy-of-childhood-acute-lymphoblastic-leukaemia-nopho-all2008(883f5572-8f13-4f79-9365-e4748a887bf0).html https://doi.org/10.1016/S1470-2045(17)30154-7 |
genre |
Iceland |
genre_facet |
Iceland |
op_source |
Nielsen , S N , Grell , K , Nersting , J , Abrahamsson , J , Lund , B , Kanerva , J , Jónsson , Ó G , Vaitkeviciene , G , Pruunsild , K , Hjalgrim , L L & Schmiegelow , K 2017 , ' DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008) : a prospective substudy of a phase 3 trial ' , The Lancet Oncology , vol. 18 , no. 4 , pp. 515–524 . https://doi.org/10.1016/S1470-2045(17)30154-7 |
op_rights |
info:eu-repo/semantics/closedAccess |
op_doi |
https://doi.org/10.1016/S1470-2045(17)30154-7 |
container_title |
The Lancet Oncology |
container_volume |
18 |
container_issue |
4 |
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515 |
op_container_end_page |
524 |
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1799482686658576384 |