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ACUTE LYMPHOBLASTIC LEUKEMIA

DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis

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.

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Fig. 1: Distribution of DNA-TG samples, median and interquartile range (IQR) in 464 patients with ten or more samples who finished treatment and remained in first remission.
Fig. 2: Forest plot, IPD meta-analysis of the full data and sub-analyses by minimal residual disease status. Hazard ratio for relapse per 100 fmol/μg increase in wmDNA-TG.

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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.

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Contributions

LNT compiled and analyzed data and drafted the manuscript. KG analyzed the data and revised the manuscript. JN developed the DNA-TG analysis. JN and MDV supervised DNA-TG analyses. SNN originally compiled and analyzed data from the NOPHO2008 pediatric cohort. JA, BL, JK, OJ, KL, GV, LG, PQ, LHH, and BAN coordinated blood sample and data collection for NOPHO ALL2008. LHH and BAN revised the manuscript. AV, AM and DM coordinated blood sample and data collection for UK ALL2003 and revised the manuscript. MZ and AM coordinated bone marrow sample and data collection for BFM ALL2000 and revised the manuscript. BB and JJ coordinated blood sample and data collection for the Minneapolis cohort. KPD supervised the study and revised the manuscript. KS initiated, coordinated, supervised the study, revised the manuscript, and was Nordic/Baltic principal investigator for NOPHO ALL2008, and Danish principal investigator for NOPHO 2000 and NOPHO 1992 maintenance therapy studies. All authors approved the final manuscript.

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Correspondence to Kjeld Schmiegelow.

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Presented in part elsewhere: The association of DNA-TG and risk of relapse in the NOPHO ALL2008 pediatric cohort has previously been published (Nielsen SN et al. Lancet Oncol 18:515–524, 2017).

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Toksvang, L.N., Grell, K., Nersting, J. et al. DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis. Leukemia 36, 33–41 (2022). https://doi.org/10.1038/s41375-021-01182-9

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