Evidence map›Paper›PMID 34047177›Full record

ArticleHaematologica2021

Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia.

Rikke Hebo Larsen, Cecilie Utke Rank, Kathrine Grell, Lisbeth Nørgaard Møller, Ulrik Malthe Overgaard, Peter Kampmann, Jacob Nersting, Matilda Degn, Stine Nygaard Nielsen, Helle Holst and 8 more

Abstract read
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Article in Haematologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed, 2 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

21 citing papers in PubMed, 2 syntheses or guidelines pooled it.

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  9. Novel Therapeutic Approaches in Pediatric Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2025
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors.

Rikke Hebo LarsenDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Cecilie Utke RankDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen; Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen.
Kathrine GrellDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen.
Lisbeth Nørgaard MøllerDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Ulrik Malthe OvergaardDepartment of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen.
Peter KampmannDepartment of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen.
Jacob NerstingDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Matilda DegnDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Stine Nygaard NielsenDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Helle HolstDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Birgitte Klug AlbertsenDepartment of Pediatrics and Adolescent Medicine, Aarhus University, Aarhus; Department of Clinical Medicine, Aarhus University, Health, Aarhus.
Peder Skov WehnerDepartment of Pediatric Hematology and Oncology, H.C. Andersen Children's Hospital, Odense University Hospital, Odense.
Michael Thude CallesenDepartment of Pediatric Hematology and Oncology, H.C. Andersen Children's Hospital, Odense University Hospital, Odense.
Jukka KanervaHUS, Helsinki University Hospital, University of Helsinki, New Children's Hospital, Helsinki.
Thomas Leth FrandsenDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Bodil Als-NielsenDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Lisa Lyngsie HjalgrimDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen.
Kjeld SchmiegelowDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Maintenance therapy containing methotrexate and 6-mercapto - purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6- fold higher cytosolic levels of thioguanine nucleotides than does 6- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P<0.0001]), and with historical patients receiving standard methotrexate/6-mercapto - purine maintenance therapy (on average 272 fmol/mg DNA higher [95% confidence interval: 147-398; P<0.0001]). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.

Indexed as

Precursor Cell Lymphoblastic Leukemia-LymphomaThioguanineAdolescentAdultAntineoplastic Combined Chemotherapy ProtocolsChildChild, PreschoolDNAHumansInfantMercaptopurineMiddle AgedYoung AdultDNAMercaptopurineThioguanine

Identifiers

PMID34047177
PMCPMC8561300

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.