Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies

Lennard, Lynne; Lewis, Ian; Michelagnoli, Maria; Lilleyman, J S

doi:10.1002/(sici)1096-911x(199710)29:4<252::aid-mpo3>3.0.co;2-l

Cited by 40 publications

(10 citation statements)

References 13 publications

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“…The remaining 90% of the population carry two wild-type alleles and have full activity. Correspondingly, the tolerable MP dose in the homozygous TPMP deficient patients is 14% of the dose tolerated in patients with the homozygous wild-type genotype, confirming previous reports (Evans et al, 1991;Lennard et al, 1997), and the tolerable dose in the heterozygous group (mean, 64 mg/m 2 per day) is 85% of the dose in the wild-type group (mean, 75 mg/m 2 per day). Therefore, the ratios of toxicity threshold are 0.14 and 0.85, respectively, for homozygous-deficient and heterozygous population compared to the wild-type.…”

Section: Robustness Of Design Performance To Model Misspecificationsupporting

confidence: 87%

Adaptive Bayesian Design for Phase I Dose-Finding Trials Using a Joint Model of Response and Toxicity

Wang

Day

2009

Journal of Biopharmaceutical Statistics

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We present a new adaptive Bayesian method for dose-finding in phase I clinical trials based on both response and toxicity. Although clinical responses are usually rare in phase I cancer trials, molecularly targeted therapy may make clinical responses more likely. In addition, biological responses may be common. Thus responses may be frequent enough to help decide how aggressive a phase I escalation should be. The model assumes that response and toxicity events happen depending on respective dose thresholds for the individual, assuming that the thresholds jointly follow a bivariate log-normal distribution or a mixture. The design utilizes prior information about the population threshold distribution as well as accumulated data. The next dose is assigned to maximize a patient-oriented expected utility integrated over the current posterior distribution. The design is evaluated through simulation with population parameters equaling estimates from early Gleevec trials. This exercise provides evidence for the value of the use of the proposed design for future clinical trials.

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Section: Robustness Of Design Performance To Model Misspecificationsupporting

confidence: 87%

Adaptive Bayesian Design for Phase I Dose-Finding Trials Using a Joint Model of Response and Toxicity

Wang

Day

2009

Journal of Biopharmaceutical Statistics

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“…In white individuals, the most common variants are *3A,*3B, and *3C all involving G460A and/or A719G and accounting for at least 90% of low-activity alleles among white individuals of North European decent 63,76. Approximately 5% to 10% are TPMT heterozygous carrying 1 wild-type and 1 low-activity allele, and 1 in 300 is TPMT deficient and at risk of life-threatening myelosuppression at standard 6MP doses 111,112. Although thiopurine dosing according to the TPMT genotype has been implemented by a few ALL study groups,48,79,113 the benefits of this strategy remain uncertain.…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

Schmiegelow

Nielsen

Frandsen

et al. 2014

Journal of Pediatric Hematology/Oncology

192

169

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“…Life‐threatening bone marrow toxicity, due to excess production of TGN metabolites, occurs in the 0.3% of patients who are TPMT deficient . Less severe myelosuppression can develop in TPMT heterozygotes, approximately 11% of patients, when taking standard doses of mercaptopurine .…”

Section: Introductionmentioning

confidence: 99%

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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Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies

Cited by 40 publications

References 13 publications

Adaptive Bayesian Design for Phase I Dose-Finding Trials Using a Joint Model of Response and Toxicity

Adaptive Bayesian Design for Phase I Dose-Finding Trials Using a Joint Model of Response and Toxicity

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

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

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