Stine Nygaard Nielsen1, Linea Natalie Toksvang1, Kathrine Grell1,2, Jacob Nersting1, Jonas Abrahamsson3, Bendik Lund4, Jukka Kanerva5, Ólafur Gísli Jónsson6, Goda Vaitkeviciene7, Kaie Pruunsild8, Malin Lindqvist Appell9, Lisa Lyngsie Hjalgrim1, Kjeld Schmiegelow10,11. 1. Department of Pediatrics and Adolescent Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 2. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 3. Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 4. Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway. 5. Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. 6. Pediatric Hematology-Oncology, Barnaspitali Hringsins, Landspitali University Hospital, Reykjavik, Iceland. 7. Centre for Paediatric Oncology and Haematology, Vilnius University, Vilnius, Lithuania. 8. Department of Oncology and Haematology, Tallinn Children's Hospital, Tallinn, Estonia. 9. Faculty of Medicine and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden. 10. Department of Pediatrics and Adolescent Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk. 11. Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk.
Abstract
PURPOSE: 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. METHODS: TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 × 109/L. RESULTS: Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). CONCLUSION: TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.
PURPOSE:6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. METHODS:TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 × 109/L. RESULTS: Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). CONCLUSION:TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.
Authors: B A Chabner; C J Allegra; G A Curt; N J Clendeninn; J Baram; S Koizumi; J C Drake; J Jolivet Journal: J Clin Invest Date: 1985-09 Impact factor: 14.808
Authors: M Kato; S Ishimaru; M Seki; K Yoshida; Y Shiraishi; K Chiba; N Kakiuchi; Y Sato; H Ueno; H Tanaka; T Inukai; D Tomizawa; D Hasegawa; T Osumi; Y Arakawa; T Aoki; M Okuya; K Kaizu; K Kato; Y Taneyama; H Goto; T Taki; M Takagi; M Sanada; K Koh; J Takita; S Miyano; S Ogawa; A Ohara; M Tsuchida; A Manabe Journal: Leukemia Date: 2016-10-04 Impact factor: 11.528
Authors: K Schmiegelow; E Forestier; J Kristinsson; S Söderhäll; K Vettenranta; R Weinshilboum; F Wesenberg Journal: Leukemia Date: 2008-11-06 Impact factor: 11.528