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

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Maintenance therapy containing Methotrexate (MTX) and 6-Mercaptopurine (6MP) is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides (TGN) into DNA (DNA-TG), and higher leucocyte DNA-TG is associated with increased relapse-free survival. As 6-Thioguanine (6TG) provides 6-fold higher cytosol TGN than 6MP, we added low-dose 6TG to MTX/6MP maintenance therapy to explore if this combination results in significantly higher DNA-TG. Target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was n=30 patients, with non-high risk ALL, aged 1-45 years on MTX/6MP maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6TG were added to MTX/6MP maintenance therapy (start 6TG: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). Primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as maximum 6TG dose. TEAM resulted in significantly higher DNA-TG, when compared with both TEAM patients before TEAM inclusion (on average 251 fmol/μg DNA higher (95% CI 160-341; P<0.0001), and with historical patients receiving standard MTX/6MP maintenance therapy (on average 272 fmol/μg DNA higher (95% CI 147-398; P<0.0001). TEAM did not increase myelotoxicity or hepatotoxicity. Conclusively, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG without inducing additional toxicity. It may therefore be an effective strategy to reduce risk of ALL relapse through increased DNA-TG, and this will be tested in a randomized ALLTogether-1 substudy.

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Authors: 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, Birgitte Klug Albertsen, Peder Skov Wehner, Michael Thude Callesen, Jukka Kanerva, Thomas Leth Frandsen, Bodil Als-Nielsen, Lisa Lyngsie Hjalgrim, Kjeld Schmiegelow


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