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DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis.
- Source :
-
Leukemia [Leukemia] 2022 Jan; Vol. 36 (1), pp. 33-41. Date of Electronic Publication: 2021 Jun 26. - Publication Year :
- 2022
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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 ( <subscript>wm</subscript> DNA-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 <subscript>wm</subscript> DNA-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 <subscript>wm</subscript> DNA-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.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Adult
Child
Cohort Studies
Female
Humans
Male
Neoplasm Recurrence, Local metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
Prognosis
Young Adult
Clinical Trials as Topic statistics & numerical data
DNA, Neoplasm metabolism
Neoplasm Recurrence, Local pathology
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Thioguanine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 36
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 34175901
- Full Text :
- https://doi.org/10.1038/s41375-021-01182-9