Authorship statement: Lynne Lennard contributed to the design of the study, conducted laboratory analyses, was involved in data collection, data analysis, data interpretation and wrote the manuscript. Cher Cartwright conducted laboratory analyses, was involved in data collection, data analysis, data interpretation and edited the manuscript. Rachel Wade and Sue Richards contributed to the design of the study, were involved in data collection and edited the manuscript. Ajay Vora was a trial co-ordinator, contributed to the design of the study and edited the manuscript. All authors approved the final version of the manuscript.
Thiopurine methyltransferase genotype–phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia
Article first published online: 20 JUN 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 76, Issue 1, pages 125–136, July 2013
How to Cite
Lennard, L., Cartwright, C. S., Wade, R., Richards, S. M. and Vora, A. (2013), Thiopurine methyltransferase genotype–phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia. British Journal of Clinical Pharmacology, 76: 125–136. doi: 10.1111/bcp.12066
- Issue published online: 20 JUN 2013
- Article first published online: 20 JUN 2013
- Accepted manuscript online: 18 DEC 2012 05:41AM EST
- Manuscript Accepted: 9 DEC 2012
- Manuscript Received: 3 SEP 2012
- Leukaemia and Lymphoma Research, London, UK
- childhood leukaemia;
- genotype–phenotype discordance;
- thioguanine nucleotides;
- thiopurine methyltransferase
In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype–genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation.
We measured TPMT (activity, as units ml−1 packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8 × 108 RBCs) during chemotherapy (n = 1131) in children randomized to thioguanine or mercaptopurine on the United Kingdom trial ALL97.
Median TPMT activity at diagnosis (8.5 units) was significantly lower than during chemotherapy (13.8 units, median difference 5.1 units, 95% confidence interval (CI) 4.8, 5.4, P < 0.0001). At diagnosis genotype–phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754 pmol) than wild-type (360 pmol) patients (median difference 406 pmol, 95% CI 332, 478, P < 0.0001), whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10 650 pmol) than heterozygous patients (3868 pmol) (P < 0.0001). In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366 pmol) and MeMPN (median 8590 pmol) concentrations were similar to those in wild-type, high activity patients.
In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy.