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
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2017
• Subjects: Journal Article; Iceland
• 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

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 ...