Kato M, Manabe A (2018) Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr Int 60:4–12

Article  PubMed  Google Scholar 

Relling MV, Hancock ML, Boyett JM et al (1999) Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93:2817–2823. https://doi.org/10.1182/blood.v93.9.2817.409k04_2817_2823

Article  CAS  PubMed  Google Scholar 

Toksvang LN, Lee SHR, Yang JJ, Schmiegelow K (2022) Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations. Leukemia. https://doi.org/10.1038/s41375-022-01591-4

Article  PubMed  PubMed Central  Google Scholar 

Nielsen SN, Grell K, Nersting J et al (2017) DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial. Lancet Oncol 18:515–524. https://doi.org/10.1016/S1470-2045(17)30154-7

Article  CAS  PubMed  Google Scholar 

Innocenti F, Danesi R, Favre C et al (2000) Variable correlation between 6-mercaptopurine metabolites in erythrocytes and hematologic toxicity: implications for drug monitoring in children with acute lymphoblastic leukemia. Ther Drug Monit 22:375–382. https://doi.org/10.1097/00007691-200008000-00002

Article  CAS  PubMed  Google Scholar 

Relling MV, Hancock ML, Rivera GK et al (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008. https://doi.org/10.1093/jnci/91.23.2001

Article  CAS  PubMed  Google Scholar 

Lennard L, Cartwright CS, Wade R et al (2013) Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia. Br J Clin Pharmacol 76:125–136. https://doi.org/10.1111/bcp.12066

Article  CAS  PubMed  Google Scholar 

Tanaka Y, Kato M, Hasegawa D et al (2015) Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol 171:109–115. https://doi.org/10.1111/bjh.13518

Article  CAS  PubMed  Google Scholar 

Moriyama T, Nishii R, Perez-Andreu V et al (2016) NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 48:367–373. https://doi.org/10.1038/ng.3508

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moriyama T, Nishii R, Lin TN et al (2017) The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics 27:236–239. https://doi.org/10.1097/FPC.0000000000000282

Article  CAS  PubMed  PubMed Central  Google Scholar 

Relling MV, Schwab M, Whirl-Carrillo M et al (2019) Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT 15 genotypes: 2018 update. Clin Pharmacol Ther 105:1095–1105. https://doi.org/10.1002/cpt.1304

Article  CAS  PubMed  Google Scholar 

Kirchherr H, Shipkova M, Von AN (2013) Improved method for therapeutic drug monitoring of 6-thioguanine nucleotides and 6-methylmercaptopurine in whole-blood by lc/msms using isotope-labeled internal standards. Ther Drug Monit 35:313–321. https://doi.org/10.1097/FTD.0b013e318283ed5d

Article  CAS  PubMed  Google Scholar 

Coulthard SA, Berry P, McGarrity S et al (2016) Liquid chromatography–mass spectrometry for measuring deoxythioguanosine in DNA from thiopurine-treated patients. J Chromatogr B Anal Technol Biomed Life Sci 1028:175–180. https://doi.org/10.1016/j.jchromb.2016.06.017

Article  CAS  Google Scholar 

Yang JJ, Landier W, Yang W et al (2015) Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 33:1235–1242. https://doi.org/10.1200/JCO.2014.59.4671

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsujimoto S, Osumi T, Uchiyama M et al (2018) Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms. Leukemia 32:2710–2714. https://doi.org/10.1038/s41375-018-0190-1

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lennard L, Rees C, Lilleyman J, Maddocks J (1983) Childhood leukaemia: a relationship between intracellular 6- mercaptopurine metabolites and neutropenia. Br J Clin Pharmacol 16:359–363. https://doi.org/10.1111/j.1365-2125.1983.tb02178.x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hedeland RL, Hvidt K, Nersting J et al (2010) DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Cancer Chemother Pharmacol 66:485–491. https://doi.org/10.1007/s00280-009-1184-5

Article  CAS  PubMed  Google Scholar 

Tanaka Y, Yeoh AEJ, Moriyama T et al (2021) An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia. Haematologica 106:2026–2029. https://doi.org/10.3324/haematol.2020.266320

Article  PubMed  PubMed Central  Google Scholar 

Nygaard U, Toft N, Schmiegelow K (2004) Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther 75:274–281. https://doi.org/10.1016/j.clpt.2003.12.001

Article  CAS  PubMed  Google Scholar 

Nielsen SN, Grell K, Nersting J et al (2016) Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 78:983–994. https://doi.org/10.1007/s00280-016-3151-2

Article  CAS  PubMed  Google Scholar 

Yi ES, Choi YB, Choi R et al (2018) NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels in children with acute lymphoblastic leukemia. Cancer Res Treat 50:872–882. https://doi.org/10.4143/crt.2017.283

Article  CAS  PubMed  Google Scholar 

Ebbesen MS, Nersting J, Jacobsen JH et al (2013) Incorporation of 6-thioguanine nucleotides into DNA during maintenance therapy of childhood acute lymphoblastic leukemia-the influence of thiopurine methyltransferase genotypes. J Clin Pharmacol 53:670–674. https://doi.org/10.1002/jcph.81

Article  CAS  PubMed  Google Scholar 

Ebbesen MS, Nygaard U, Rosthøj S et al (2017) Hepatotoxicity during Maintenance Therapy and Prognosis in Children with Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol 39:161–166. https://doi.org/10.1097/MPH.0000000000000733

Article  CAS  PubMed  Google Scholar 

Schmiegelow K, Schrøder H, Pulczynska MK, Hejl M (1989) Maintenance chemotherapy for childhood acute lymphoblastic leukemia: relation of bone-marrow and hepatotoxicity to the concentration of methotrexate in erythrocytes. Cancer Chemother Pharmacol 25:65–69. https://doi.org/10.1007/BF00694341

Article  CAS  PubMed  Google Scholar 

Rostami-Hodjegan A, Lennard L, Lilleyman J (1995) The accumulation of mercaptopurine metabolites in age fractionated red blood cells. Br J Clin Pharmacol 40:217–222. https://doi.org/10.1111/j.1365-2125.1995.tb05776.x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nishii R, Moriyama T, Janke LJ et al (2018) Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy. Blood 131:2466–2474. https://doi.org/10.1182/blood-2017-11-815506

Article  CAS  PubMed  PubMed Central  Google Scholar