TPMT polymorphisms and minimal residual disease after 6-mercaptopurine post-remission consolidation therapy of childhood acute lymphoblastic leukaemia

Karin Dreisig, Emilie Damgaard Brünner, Hanne V Marquart, Louise Rold Helt, Jacob Nersting, Thomas Leth Frandsen, Olafur Gisli Jonsson, Mervi Taskinen, Goda Vaitkeviciene, Bendik Lund, Jonas Abrahamsson, Kristi Lepik, Kjeld Schmiegelow

4 Citationer (Scopus)

Abstract

Bone marrow minimal residual disease (MRD) is the strongest predictor of relapse in children with acute lymphoblastic leukemia (ALL). 6-mercaptopurine (6MP) in ALL therapy has wide inter-individual variation in disposition and is strongly influenced by polymorphisms in the thiopurine methyltransferase (TPMT) gene. In 952 patients treated according to the NOPHO ALL2008 protocol, we explored the association between thiopurine disposition, TPMT genotypes and MRD levels after consolidation therapy with 6MP, high-dose methotrexate (HD-MTX), asparaginase, and vincristine. The levels of the cytotoxic DNA-incorporated thioguanine were significantly higher on day 70-79 in G460A/A719G TPMT heterozygous (TPMTHZ) compared to TPMT wild type (TPMTWT) patients (mean: 230.7 vs. 149.7 fmol/µg DNA, p = 0.002). In contrast, TPMT genotype did not associate with the end of consolidation MRD levels irrespective of randomization of the patients to fixed dose (25 mg/m2/day) or 6MP escalation (up to 50 or 75 mg/m2/day) during consolidation therapy.

OriginalsprogEngelsk
TidsskriftPediatric Hematology and Oncology
Vol/bind38
Udgave nummer3
Sider (fra-til)227-238
Antal sider12
ISSN0888-0018
DOI
StatusUdgivet - apr. 2021

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