Thiopurine methyltransferase genotype–phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia

摘要

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.MethodsWe 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.ResultsMedian 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.ConclusionsIn 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.