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 - © 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.
UR - http://www.scopus.com/inward/record.url?scp=85108826835&partnerID=8YFLogxK
U2 - 10.1038/s41375-021-01182-9
DO - 10.1038/s41375-021-01182-9
M3 - Journal article
C2 - 34175901
VL - 36
SP - 33
EP - 41
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 1
ER -