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

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@article{6c04126d6e234366bdfd78efc61af7ea,
title = "Increments in DNA-thioguanine level during thiopurine enhanced maintenance therapy of acute lymphoblastic leukemia",
abstract = "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.",
author = "Larsen, {Rikke Hebo} and {Utke Rank}, Cecilie and Kathrine Grell and {N{\o}rgaard M{\o}ller}, Lisbeth and {Malthe Overgaard}, Ulrik and Peter Kampmann and Jacob Nersting and Matilda Degn and {Nygaard Nielsen}, Stine and Helle Holst and {Klug Albertsen}, Birgitte and {Skov Wehner}, Peder and {Thude Callesen}, Michael and Jukka Kanerva and {Leth Frandsen}, Thomas and Bodil Als-Nielsen and {Lyngsie Hjalgrim}, Lisa and Kjeld Schmiegelow",
year = "2021",
month = may,
day = "27",
doi = "10.3324/haematol.2020.278166",
language = "English",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Fondazione/Ferrata Storti",

}

RIS

TY - JOUR

T1 - Increments in DNA-thioguanine level during thiopurine enhanced maintenance therapy of acute lymphoblastic leukemia

AU - Larsen, Rikke Hebo

AU - Utke Rank, Cecilie

AU - Grell, Kathrine

AU - Nørgaard Møller, Lisbeth

AU - Malthe Overgaard, Ulrik

AU - Kampmann, Peter

AU - Nersting, Jacob

AU - Degn, Matilda

AU - Nygaard Nielsen, Stine

AU - Holst, Helle

AU - Klug Albertsen, Birgitte

AU - Skov Wehner, Peder

AU - Thude Callesen, Michael

AU - Kanerva, Jukka

AU - Leth Frandsen, Thomas

AU - Als-Nielsen, Bodil

AU - Lyngsie Hjalgrim, Lisa

AU - Schmiegelow, Kjeld

PY - 2021/5/27

Y1 - 2021/5/27

N2 - 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.

AB - 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.

U2 - 10.3324/haematol.2020.278166

DO - 10.3324/haematol.2020.278166

M3 - Journal article

C2 - 34047177

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -

ID: 66495373