1. DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis
- Author
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Kathrine Grell, Lisa Lyngsie Hjalgrim, Anja Möricke, Jacob Nersting, Jaitri Joshi, Bruce Bostrom, Petter Quist-Paulsen, Kim Dalhoff, Bendik Lund, Kristi Lepik, Anthony V. Moorman, Goda Vaitkevičienė, Kjeld Schmiegelow, Daniel Murdy, Jukka Kanerva, Olafur G. Jonsson, Linea Natalie Toksvang, Bodil Als-Nielsen, Martin Zimmermann, Stine Nygaard Nielsen, Ajay Vora, Matilda Degn, Laimonas Griskevicius, and Jonas Abrahamsson
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Maintenance therapy ,Internal medicine ,medicine ,Humans ,Young adult ,Child ,Thioguanine ,Clinical Trials as Topic ,Proportional hazards model ,business.industry ,Hazard ratio ,DNA, Neoplasm ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Minimal residual disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Biomarker (medicine) ,Female ,Methotrexate ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
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.
- Published
- 2021
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