Increments in DNA-thioguanine level during thiopurine enhanced maintenance therapy of acute lymphoblastic leukemia
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Increments in DNA-thioguanine level during thiopurine enhanced maintenance therapy of acute lymphoblastic leukemia. / Larsen, Rikke Hebo; Utke Rank, Cecilie; Grell, Kathrine; Nørgaard Møller, Lisbeth; Malthe Overgaard, Ulrik; Kampmann, Peter; Nersting, Jacob; Degn, Matilda; Nygaard Nielsen, Stine; Holst, Helle; Klug Albertsen, Birgitte; Skov Wehner, Peder; Thude Callesen, Michael; Kanerva, Jukka; Leth Frandsen, Thomas; Als-Nielsen, Bodil; Lyngsie Hjalgrim, Lisa; Schmiegelow, Kjeld.
I: Haematologica, Bind 106, Nr. 11, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2021
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
VL - 106
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 11
ER -
ID: 272017894