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.

• Published in: The Lancet Oncology
• Main Authors: 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
• Other Authors: 1 Rigshosp, Univ Hosp, Dept Pediat & Adolescent Med, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Show the Organization-Enhanced name(s) 2 Univ Copenhagen, Dept Publ Hlth, Sect Biostat, Copenhagen, Denmark Show the Organization-Enhanced name(s) 3 Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark Show the Organization-Enhanced name(s) 4 Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden Show the Organization-Enhanced name(s) 5 St Olavs Hosp, Dept Pediat, Trondheim, Norway Show the Organization-Enhanced name(s) 6 Norwegian Univ Sci & Technol, Fac Med, Dept Lab Med Childrens & Womens Hlth, Trondheim, Norway Show the Organization-Enhanced name(s) 7 Univ Helsinki, Cent Hosp, Childrens Hosp, Helsinki, Finland Show the Organization-Enhanced name(s) 8 Univ Helsinki, Helsinki, Finland Show the Organization-Enhanced name(s) 9 Landspitali Univ Hosp, Barnaspitali Hringsins, Pediat Hematol Oncol, Reykjavik, Iceland 10 Univ Childrens Hosp, Ctr Paediat Oncol & Haematol, Vilnius, Lithuania 11 Tallinn Childrens Hosp, Dept Haematol & Oncol, Tallinn, Estonia
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier Science Publishers 2017
• Subjects: Bráðahvítblæði; Hvítblæði; Börn; PED12; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Norway; Iceland
• Online Access: http://hdl.handle.net/2336/620155; https://doi.org/10.1016/S1470-2045(17)30154-7

To access publisher's full text version of this article click on the hyperlink below 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. 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. 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 ...