TPMT genotyping

The association between low TPMT activity and excessive hematological toxicity has been recognized [31, 35, 37]. Molecular analysis of the TPMT genotype is able to identify patients at risk for acute toxicity from thiopurines. A recent study involving 180 children identified that the TPMT genotype plays an important role in a patients tolerance to 6-MP therapy [51]. Two of the patients, who were TPMT-de-... 

Patients deficient in thiopurine S-methyltransferase (TPMT) are at greater risk of bone marrow suppression from azathioprine and mercaptopurine. Determination of TPMT or TPMT genotype is recommended to guide dosage. 

Tests for the TPMT genotype and phenotype are commercially available. Attention should be paid for those patients who test negative for TPMT status. Patients with poor or intermediate TPMT activity may tolerate only 1/10 to 1/2 of the average 6-MP dose. A pharmacoeconomic model has been developed to analyze the potential cost of screening to prevent azathioprine toxicity. In this model, it was assumed that TPMT deficiency is present in 0.3% of the population, that intermediate activity is present in 11%, and that both groups have an increased risk of developing myelosuppression. Under these circumstances, the model predicted that the costs per Caucasian patient for the first 6 mo of therapy with screening are lower... 

Stanulla, M., Schaeffeler, E., Hohr, T., et al. (2005) Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia JAMA. 293, 1485-1489. 

Thus, both TPMT genotyping and measnrement of TPMT activity in RBCs may be usefnl in predicting and preventing AZA toxicity. Clearly, large, prospective studies are needed to validate the observations from the smaller stndies described (see Table 14.2). Of note, TPMT genotyping is available to clinicians currently to... 

With relevance to the administration of thiopurines in the early course of childhood ALL, the BFM Study Group reported on the association of TPMT genotype and minimal residual disease (MRD) in 810 children with childhood ALL enrolled into their trial ALL-BFM 2000 (206). In this trial, DNA-based MRD analysis after induction and after consolidation treatment was used for risk-adapted treatment stratification. A 4-week cycle of 6-MP was applied in-between these two MRD measurements. In patients homozygous for the TPMT 1 allele or those heterozygous for a variant TPMT allele, MRD levels on treatment day 33 were equally distributed between the groups. However, when MRD levels were assessed on treatment day 78, after administration of consolidation... 

In contrast, successful TPMT genotyping of 72 patients out of a total of 115 patients with subsequent secondary malignant neoplasms after treatment for childhood ALL on seven consecutive BFM protocols (ALL-BFM 79, 81, 83, 86, 90, 95, and 2000) did not reveal a higher frequency of TPMT alleles associated with lower TPMT activity among these patients (208). Also, in stratified analyses by entities of secondary malignant neoplasms, no significant associations with TPMT alleles conferring lower enzyme activity have been observed. 

Given the potential mortality and known morbidity associated with febrile neutropenia, it may seem surprising that the routine use of TPMT genotyping in defining dose regimens for children with cancer did not gain early wide spread acceptance in the broader community of pediatric oncologists [15], There are several... 

TPMT genotype polymorphisms (TPMT 2, 3A, 3B, and 3C) have been studied in 108 patients with vascuhtis associated with positive antineutrophil cytoplasmic antibodies (ANCA), who were given azathioprine and followed for 47 months [144. Adverse reactions (leukopenia, anemia, thrombocytopenia, gastrointestinal adverse reactions including hepatitis, and hypersensitivity reactions) did not differ between patients who were heterozygous and those who were homozygous or between the ter-tiles of patients who were homozygous. 

The frequencies of TPMT mutant alleles have been studied retrospectively in 147 Japanese patients with inflammatory bowel disease taking azathioprine, of whom 144 were wild-type for TPMT (TPMT 1/ 1) and three carried a mutant TPMT allele (TPMT 1/ 3C) [145 ]. The incidence of adverse reactions to azathioprine was 38/ 114 in the wild-type group. Leukopenia occurred in 16% of the patients with wild-type TPMT. The authors concluded that determination of TPMT genotype may not be useful in Japanese patients in predicting adverse reactions to azathioprine. 

Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Thiopurinemethyltransfer-ase (TPMT) genotype and TPMT activity in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis relation to azathioprine maintenance treatment and adverse effects. Ann Rheum Dis 2009 68(5) 758-9. 

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