TPMT deficiency is an autosomal recessive trait associated with severe hematopoietic toxicity when patients are treated with standard doses of the antineoplastic agents 6-mercaptopurine (6MP) or 6-thioguanine (6TG), or the immunosuppressant azathioprine (AZA) (Lennard et al., 1989). ... TPMT deficiency is an autosomal recessive trait associated with severe hematopoietic toxicity when patients are treated with standard doses of the antineoplastic agents 6-mercaptopurine (6MP) or 6-thioguanine (6TG), or the immunosuppressant azathioprine (AZA) (Lennard et al., 1989). The thiopurines are pro-drugs that require extensive metabolism in order to exert their cytotoxic action. Azathioprine is non-enzymatically reduced to 6MP. 6MP and 6TG are activated by HPRT (308000) and subsequent steps to form cytotoxic thioguanine nucleotides (TGNs) which are incorporated into DNA and/or RNA, causing DNA-protein cross-links, single-strand breaks, interstrand cross-links, and sister chromatid exchange. TPMT functions mainly to inactivate these drugs; thus, a deficiency of TPMT results in increased conversion to toxic TGNs, which can result in myelosuppression (Coulthard and Hogarth, 2005). However, 6MP is unique in that it can also be converted via TPMT into a methyl-thioinosine 5-prime monophosphate (MeTIMP), a metabolite that inhibits de novo purine synthesis and likely contributes to the cytotoxic effect of 6MP (Vogt et al., 1993; Krynetski et al., 1995; Coulthard and Hogarth, 2005).
Lennard et al. (1987, 1990) found a significant negative correlation between erythrocyte cytotoxic TGNs and TPMT activity among children with acute lymphoblastic leukemia (ALL) treated with 6MP. Two of 3 adult patients with very high TGN concentrations and ... Lennard et al. (1987, 1990) found a significant negative correlation between erythrocyte cytotoxic TGNs and TPMT activity among children with acute lymphoblastic leukemia (ALL) treated with 6MP. Two of 3 adult patients with very high TGN concentrations and 6MP-induced leukopenia had no detectable TPMT activity, presumed to be an inherited deficiency of the enzyme (Lennard et al., 1987). Children with low concentrations of TGNs had higher TPMT activity and a higher subsequent relapse rate (Lennard et al., 1990). Lennard et al. (1987, 1990) concluded that individuals with inherited low TPMT activity may be at risk for increased TGNs and acute myelosuppression when treated with standard doses of thiopurine drugs. In addition, genetically determined TPMT activity may regulate the cytotoxic effect of 6MP and thus influence outcome of therapy for childhood ALL. Lennard et al. (1989) reported 5 patients treated with standard doses of azathioprine who developed acute myelosuppression. Compared to control patients who did not develop myelosuppression, the 5 patients had very low TPMT activities and abnormally high levels of cytotoxic thioguanine nucleotides, consistent with inherited low TPMT activity. Evans et al. (1991) reported an 8-year-old girl who developed severe hematopoietic toxicity with conventional oral doses of 6-mercaptopurine for treatment of ALL. Lennard et al. (1993) reported 2 unrelated children with ALL taking 6MP who developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular TPMT activity and both produced higher cytotoxic drug metabolites at decreased 6MP dosage compared to other patients taking 100% of the dose. Lennard et al. (1993) concluded that both children had the recessive trait lacking TPMT activity and noted the importance of recognizing such individuals in order to avoid fatal bone marrow failure through inadvertent overdosage. Schutz et al. (1993) reported azathioprine-induced myelosuppression in a heart transplant recipient with TPMT deficiency. Liepold et al. (1997) reported a 14-year-old girl who developed severe pancytopenia 7 weeks after starting azathioprine for HLA-B27-associated juvenile spondylarthritis (see 106300). She was found to have toxic levels of 6-thioguanine nucleotides and was TPMT-deficient. Withdrawal of azathioprine allowed recovery 8 weeks later. Black et al. (1998) found that 6 (9%) of 67 patients with autoimmune disease taking AZA were heterozygous for a mutant TPMT allele. Five of the 6 patients discontinued treatment within 1 month because of low leukocyte levels. The authors concluded that TPMT heterozygotes taking AZA are at increased risk for adverse side effects. Of 23 patients who developed excessive toxicity while taking 6MP or AZA, Evans et al. (2001) found that 6 were homozygous for TPMT deficiency, 9 were heterozygous, and 8 had normal TPMT activity (homozygous wildtype). The 65% frequency of homozygous or heterozygous individuals among these patients was significantly greater than the expected 10% in the general population. Hematologic toxicity occurred in more than 90% of the patients, while hepatotoxicity occurred in 6 (26%) patients. Dosage adjustment in these patients resulted in tolerance of treatment without toxicity. Schwab et al. (2002) found that 3 (60%) of 5 patients who developed hematopoietic toxicity from azathioprine had 1 or more TPMT variant alleles. Evans (2002) commented that this overrepresentation of TPMT variant alleles in patients developing hematopoietic toxicity with thiopurine therapy was consistent with their findings (Evans et al., 2001). In addition, both studies showed that hematopoietic toxicity can occur in TPMT heterozygotes, not just homozygous-deficient patients. Kurzawski et al. (2005) reported a 38-year-old Polish man who underwent allogenic kidney transplant due to chronic glomerulonephritis and was treated with AZA among other immunosuppressive agents. Two months later, he developed severe myelosuppression and AZA was withdrawn. Upon reintroduction of AZA 2 weeks later, the patient again developed myelosuppression. After final withdrawal of AZA, the kidney was still functioning 10 years after transplant.
Alves et al. (1999) analyzed 24 children who received curative therapy of ALL with thiopurine drugs. Four of them were shown to be heterozygous for the TPMT*3A allele; all 4 patients exhibited signs of severe hepatic toxicity during ... Alves et al. (1999) analyzed 24 children who received curative therapy of ALL with thiopurine drugs. Four of them were shown to be heterozygous for the TPMT*3A allele; all 4 patients exhibited signs of severe hepatic toxicity during treatment. Stanulla et al. (2005) evaluated TPMT genotype and early treatment response to oral 6MP in 814 patients with childhood ALL. Genotype analysis showed that 755 (92.8%) patients were TPMT wildtype, 55 (6.8%) were heterozygous, and 4 (0.5%) were homozygous for mutant TPMT alleles, with the following allele frequencies: wildtype TPMT*1, 96.12%; TPMT*2, 0.25%; TPMT*3A, 2.95%; TPMT*3C, 0.56%; TPMT*9, 0.06%; TPMT*11, 0.06%. The 4 patients homozygous for a mutant TPMT genotype were treated with a 10-fold reduced dose of 6MP to prevent hematopoietic toxicity and were excluded from further analysis. The heterozygous patients did not receive an adjusted dose. Detection of minimal residual disease, as measured by PCR-based detection, on day 78 after 4-week treatment with 6MP showed that the heterozygous TPMT patients had a 2.9-fold reduction in minimal residual disease compared to patients with the wildtype alleles; 9.1% of heterozygotes had detectable minimal residual disease compared to 22.8% of wildtype homozygotes. The findings indicated that TPMT genotype has a substantial impact on minimal residual disease after 6MP administration. Stanulla et al. (2005) concluded that TPMT heterozygotes may not benefit from 6MP dose reduction during the induction consolidation phase of treatment for childhood ALL.
In a patient with TPMT deficiency reported by Evans et al. (1991), Krynetski et al. (1995) identified a mutation in the TPMT gene (187680.0001). The mutation was heterozygous in both the proposita and her mother and absent in ... In a patient with TPMT deficiency reported by Evans et al. (1991), Krynetski et al. (1995) identified a mutation in the TPMT gene (187680.0001). The mutation was heterozygous in both the proposita and her mother and absent in the father. The authors concluded that the patient had a second inactivating mutation. Krynetski et al. (1995) commented that a reliable method to determine TPMT genotype is important, given the potentially fatal nature of hematopoietic toxicity when full doses of 6MP or AZA are given to TPMT-deficient patients. In a 14-year-old girl who developed severe pancytopenia after starting AZA for HLA-B27-associated juvenile spondylarthritis, Liepold et al. (1997) identified homozygosity for the TPMT*3A allele (187680.0002). Family studies showed that the mother was also homozygous for the deficiency while other family members were heterozygous. In a patient with AZA-induced myelosuppression after renal transplant, Kurzawski et al. (2005) identified compound heterozygosity for 2 variants in the TPMT gene (TPMT*3A and TPMT*3C; 187680.0005). Stanulla et al. (2005) stated that 20 TPMT variant alleles, TPMT*2-TPMT*18, associated with decreased enzyme activity had been identified. More than 95% of decreased TPMT activity can be explained by the most frequent mutant alleles TPMT*2 and TPMT*3(A-D).