Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?

Fakhoury, May; Andreu-Gallien, Juliette; Mahr, Alfred; Médard, Yves; Azougagh, Said; Vilmer, E; Jacqz-Aigrain, Évelyne

doi:10.1111/j.1365-2710.2007.00858.x

Cited by 26 publications

(22 citation statements)

References 23 publications

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“…At disease diagnosis TPMT activities are much reduced and are not reflective of on-therapy activities. This reduction has been previously reported [26], along with the resulting TPMT genotypephenotype discordance, in small patient cohorts with low numbers of variant alleles [30,31], and is now confirmed in a large population of children with ALL. The reduction in TPMT activities is well below the ranges recorded for healthy children [15,30] and has been attributed to the Table 5 Thiopurine metabolism in the year 1 and in the end of year 2 assays.…”

Section: Discussionsupporting

confidence: 75%

“…Sequencing revealed only two rare and three novel TPMT alleles. This discordance in the intermediate activity range has previously been reported in small patient cohorts and healthy subjects [19,31,38]. The first large scale TPMT genotype-phenotype concordance study in healthy blood donors (n = 1214) reported a clearly defined trimodal distribution and an overall concordance of >98% yet, after sequencing all discordant samples, reported 13 of 111 (11.7%) individuals with an intermediate activity wild-type in the open-reading frame [19].…”

Section: Discussionsupporting

confidence: 56%

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

Lennard

Cartwright

Wade

et al. 2013

Brit J Clinical Pharma

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AIMSIn 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 ¥ 10 8 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• In healthy children and adults thiopurine methyltransferase (TPMT) activities have a trimodal frequency distribution. In adult populations the concordance between TPMT genotype and phenotype is over 98%. • In childhood acute lymphoblastic leukaemia (ALL) the disease process and subsequent chemotherapy can influence TPMT activity measurements. WHAT THIS STUDY ADDS• In childhood ALL, at disease diagnosis, the extent of the reduction in measured TPMT activity and the resulting TPMT genotype-phenotype discordance, previously reported in small patient cohorts with low numbers of variant alleles, has been confirmed in a large population of children with ALL. TPMT activity should not be used to predict heterozygosity. • During thiopurine chemotherapy, TPMT discordance is 45% in children with intermediate activity. TPMT genotype more accurately predicts mercaptopurine active metabolite accumulation and therefore should be used in preference to phenotyping for dosage recommendations.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 56%

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

Lennard

Cartwright

Wade

et al. 2013

Brit J Clinical Pharma

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“…4,9 Genotyping seems to be an important strategy for the prospective detection of deficiencies in TPMT activity, thus making it possible to provide adequate and individualized doses of 6-MP, minimizing the risks of toxicity 36,37 while maintaining efficacy in the treatment. 32 Differences in survival for patients with the homozygous wild-type and the heterozygous genotype have not been demonstrated, but preliminary data indicate that minimal residual disease positivity on day 78 of treatment is significantly lower in heterozygotes than in patients with homozygous wild-type alleles.…”

Section: Discussionmentioning

confidence: 99%

Thiopurine S-Methyltransferase (TPMT) Gene Polymorphism in Brazilian Children With Acute Lymphoblastic Leukemia: Association With Clinical and Laboratory Data

Silva¹,

Oliveira²,

Viana³

et al. 2008

Therapeutic Drug Monitoring

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The frequency of allele variants of gene TPMT*2, *3A, *3B, and *3C was estimated in a population of 116 Brazilian children with acute lymphoblastic leukemia. The association between genotype and clinical and laboratory data obtained during chemotherapy maintenance phase and the correlation of intraerythrocyte concentration of 6-mercaptopurine metabolites (6-tioguanine nucleotide nucleotides and methylmercaptopurine) were analyzed. A multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used in DNA amplification. Twelve patients presented TPMT gene mutation, all in heterozygous form. The most frequent allele variation was TPMT*3A (3.9%), followed by *3C (0.9%), *2 (0.4%), and *3B (0%). There was no significant association between clinical and laboratory data and the presence of mutation in TPMT gene. Of the 36 patients who were monitored for 6-mercaptopurine metabolite levels, only 1 had the mutation. In this patient, high 6-tioguanine nucleotide and low methylmercaptopurine concentrations were found. Event-free survival (EFS) for the whole group was 73.4%. There was no significant difference in event-free survival in the comparison between the groups with and without mutation (P = 0.06).

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“…It is noteworthy to mention that not all cases of myelosupression are due to a mutation in the gene coding for the TPMT enzyme and therefore, not all cases can be prevented by screening for TPMT with either the enzymatic assay or genotype test [20]. The presence of toxicity in a number of cases and the lack of common types of mutations may result from the existence of other alleles, multigeneic contribution or other nongenetic factors [21]. Measurement of active 6-MP metabolite concentrations was suggested to be a key tool complementary to genotype in predicting toxicity under treatment with thiopurines [3].…”

Section: Discussionmentioning

confidence: 99%

Thiopurine methyltransferase genotyping in Palestinian childhood acute lymphoblastic leukemia patients

Ayesh

Harb²,

Abed

2013

BMC Hematol

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BackgroundThe genetic polymorphism of thiopurine methyltransferase (TPMT) is well characterized in most populations. Four common polymorphic alleles are associated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3B (c.460G>A), TPMT*3A (c.460G>A and c.719A>G) and TPMT*3C (c.719A>G). The aim of the present study was to determine the frequency of TPMT polymorphisms and their association with the occurrence of adverse events, during 6-mercaptopurine therapy in pediatric acute lymphoblastic leukemic (ALL) patients in Gaza Strip.MethodsA total of 56 DNA samples from all pediatric ALL patients admitted to the pediatric hematology departments of Gaza strip hospitals were analyzed. Genomic DNA from peripheral blood leukocytes was isolated and the TPMT*2, TPMT*3B TPMT*3A and TPMT*3C allelic polymorphism was determined by PCR-RFLP and allele specific PCR technique.ResultsNo TPMT*2, *3B or *3C alleles were detected. Only one, out of 56 patients, was found heterozygous for the TPMT*3A allele. Thus, the frequency of TPMT*3A allele was calculated to be 0.89%. Fourteen patients of ALL were suffering from myelotoxicity during 6-MP therapy. From our results, no significant association could be established between clinical and laboratory data and/or the presence of the mutation in TPMT gene.ConclusionTPMT*3A was the only deficiency allele detected in our population with an allelic frequency of 0.89%. Other polymorphic alleles in TPMT gene, or factors other than TPMT polymorphisms may be responsible for the development of myelosuppression in cases that don’t carry the investigated TPMT alleles (*2, *3A, *3B and *3C). Therefore, more studies are recommended to study such factors.

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Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?

Abstract: Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life-threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6-TGN) and methylated metabolites.

Cited by 26 publications

References 23 publications

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

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

Thiopurine S-Methyltransferase (TPMT) Gene Polymorphism in Brazilian Children With Acute Lymphoblastic Leukemia: Association With Clinical and Laboratory Data

Thiopurine methyltransferase genotyping in Palestinian childhood acute lymphoblastic leukemia patients

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