TY - JOUR
T1 - DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia
T2 - an IPD meta-analysis
AU - Toksvang, Linea N.
AU - Grell, Kathrine
AU - Nersting, Jacob
AU - Degn, Matilda
AU - Nielsen, Stine N.
AU - Abrahamsson, Jonas
AU - Lund, Bendik
AU - Kanerva, Jukka
AU - Jónsson, Ólafur G.
AU - Lepik, Kristi
AU - Vaitkevičienė, Goda
AU - Griškevičius, Laimonas
AU - Quist-Paulsen, Petter
AU - Vora, Ajay
AU - Moorman, Anthony V.
AU - Murdy, Daniel
AU - Zimmermann, Martin
AU - Möricke, Anja
AU - Bostrom, Bruce
AU - Joshi, Jaitri
AU - Hjalgrim, Lisa L.
AU - Dalhoff, Kim P.
AU - Als-Nielsen, Bodil
AU - Schmiegelow, Kjeld
N1 - Funding Information:
Acknowledgements This work was supported by The Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, Copenhagen University Hospital Rigshospitalet, and Novo Nordic Foundation. The United Kingdom Medical Research Council funded the UK ALL2003 study. Bloodwise Childhood Leukemia Cell Bank supplied blood samples from the UK.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/1
Y1 - 2022/1
N2 - Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78–0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82–1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68–0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.
AB - Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78–0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82–1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68–0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.
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U2 - 10.1038/s41375-021-01182-9
DO - 10.1038/s41375-021-01182-9
M3 - Article
C2 - 34175901
AN - SCOPUS:85108826835
SN - 0887-6924
VL - 36
SP - 33
EP - 41
JO - Leukemia
JF - Leukemia
IS - 1
ER -