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,
Birgitte Klug Albertsen,
Peder Skov Wehner,
Michael Thude Callesen,
Jukka Kanerva,
Thomas Leth Frandsen,
Bodil Als-Nielsen,
Lisa Lyngsie Hjalgrim,
Kjeld Schmiegelow
Affiliations
Rikke Hebo Larsen
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Cecilie Utke Rank
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen; Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen
Kathrine Grell
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen
Lisbeth Nørgaard Møller
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Ulrik Malthe Overgaard
Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen
Peter Kampmann
Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen
Jacob Nersting
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Matilda Degn
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Stine Nygaard Nielsen
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Helle Holst
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Birgitte Klug Albertsen
Department of Pediatrics and Adolescent Medicine, Aarhus University, Aarhus; Department of Clinical Medicine, Aarhus University, Health, Aarhus
Peder Skov Wehner
Department of Pediatric Hematology and Oncology, H.C. Andersen Children’s Hospital, Odense University Hospital, Odense
Michael Thude Callesen
Department of Pediatric Hematology and Oncology, H.C. Andersen Children’s Hospital, Odense University Hospital, Odense
Jukka Kanerva
HUS, Helsinki University Hospital, University of Helsinki, New Children’s Hospital, Helsinki
Thomas Leth Frandsen
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Bodil Als-Nielsen
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Lisa Lyngsie Hjalgrim
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen
Kjeld Schmiegelow
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen
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.
