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

PY - 2021

Y1 - 2021

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.

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

ER -