TPMT polymorphisms and minimal residual disease after 6-mercaptopurine post-remission consolidation therapy of childhood acute lymphoblastic leukaemia. (20th April 2021)

• Record Type: Journal Article
• Authors: Dreisig, Karin; Brünner, Emilie Damgaard; Marquart, Hanne V.; Helt, Louise Rold; Nersting, Jacob; Frandsen, Thomas Leth; Jonsson, Olafur Gisli; Taskinen, Mervi; Vaitkeviciene, Goda; Lund, Bendik; Abrahamsson, Jonas; Lepik, Kristi; Schmiegelow, Kjeld
• Is Part Of: Pediatric hematology and oncology. Volume 38:Number 3(2021)
• Page Start: 227
• Page End: 238
• Publication Date: 2021-04-20
• Subjects: Childhood acute lymphoblastic leukemia -- 6-mercaptopurine -- minimal residual disease -- thiopurine methyltransferase; Pediatric hematology -- Periodicals; Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Hematologic Diseases -- Child; Hematologic Diseases -- Infant; Neoplasms -- Child; 618.9215
• DOI: 10.1080/08880018.2020.1842570
• Languages: English
• ISSNs: 0888-0018

Abstract

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 ( TPMT HZ ) compared to TPMT wild type ( TPMT WT ) 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/m 2 /day) or 6MP escalation (up to 50 or 75 mg/m 2 /day) during consolidation therapy.