This DGI pertains to the interaction between the thiopurine methyltransferase (TPMT) gene and the thiopurine drugs azathioprine, 6-mercaptopurine, and thioguanine. Extensive literature and FDA warning labels indicate increased risk for myelotoxicity in patients with specific genetic differences in the TPMT gene.
INTERMEDIATE MYELOTOXICITY RISK
Dose reduction and close monitoring is strongly recommended if thiopurine therapy is continued.
HIGH MYELOTOXICITY RISK
Standard dosing of thiopurine therapy is contraindicated and should be stopped. Switching therapy is recommended.
The TPMT gene encodes an enzyme that is involved in the metabolism of thiopruine drugs such as azathioprine, 6-mercaptopurine (6MP) and 6-thioguanine. There are different TPMT gene versions, or variants, and each has a different effect on how well thiopurines work in the body. The variants termed *2, *3a, *3b, and *3c result in a non-functioning or low-functioning TPMT enzyme, which may lead to an increased risk of bone marrow damage called myelotoxicity. Patients who carry ONE copy of a non-functioning or low-functioning variant in TPMT have an intermediate risk for myelotoxicity. Patients who carry TWO copies of non-functioning or low-functioning variants in TPMT have a high risk for myelotoxicity. A thiopurine dose reduction is recommended for patients at intermediate risk. Switching therapy is recommended for patients at high risk.
Studies have shown patients with TPMT variants may be at increased risk for bone marrow damage while on thiopurine therapy. (See Supporting Evidence)
Genotyping for TPMT was performed within a high complexity, certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement act of 1988. This validated clinical Laboratory Developed Test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be >99%.
Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications?
Higgs JE, Payne K, Roberts C, Newman WG. Pharmacogenomics. 2010 Feb;11(2):177-88.
Thiopurine S-methyltransferase (TPMT) metabolizes thiopurine medications, including azathioprine and 6-mercaptopurine. Absent TPMT activity (i.e., in individuals homozygous for a variant TPMT allele) is associated with an increased risk of myelosuppression in patients taking thiopurine drugs. However, it is not clear if there is also an increased risk for patients with intermediate TPMT activity (i.e., in individuals heterozygous for a variant TPMT allele). Aims: To quantify the increased risk of myelosuppression for patients with intermediate TPMT activity. Materials & methods: A systematic review identified published studies, up to 29 September 2008, that explored the relationship between TMPT and hematological adverse drug reactions to thiopurines. Following a critical appraisal of the quality of published studies, a meta-analysis calculated the odds ratio of myelosuppression for patients with intermediate TPMT activity compared with wild-type. Results: A total of 67 studies were identified, the majority retrospective cohort in design. Patients with two TPMT variant alleles who are TPMT deficient have a substantial increase in their risk of myelotoxicity (86% of deficient patients developed myelosuppression). The increase in odds ratio of developing leukopenia for patients with intermediate TPMT activity or one TPMT variant allele compared with wild-type was 4.19 (95% CI: 3.20-5.48). Conclusion: This meta-analysis suggests that individuals with both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelosuppression, compared with individuals with normal activity. However, there is significant variability in the quality of the reported studies and large prospective studies to clarify the size of the effect of TPMT variant alleles on the risk of myelosuppression should be conducted. Accurate risk assessments will provide important data to inform clinical guidelines.
Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.
Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE; Clinical Pharmacogenetics Implementation Consortium. Clin Pharmacol Ther. 2011 Mar;89(3):387-91. Epub 2011 Jan 26.
Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.
Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review.
Booth RA, Ansari MT, Loit E, Tricco AC, Weeks L, Doucette S, Skidmore B, Sears M, Sy R, Karsh J. Ann Intern Med. 2011 Jun 21;154(12):814-23, W-295-8.
Background: The evidence for testing thiopurine S-methyltransferase (TPMT) enzymatic activity or genotype before starting therapy with thiopurine-based drugs is unclear.
Purpose: To examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in adults and children with chronic inflammatory diseases.
Data Sources: MEDLINE, EMBASE, the Cochrane Library, and Ovid HealthSTAR (from inception to December 2010) and BIOSIS and Genetics Abstracts (to May 2009).
Study Selection: Two reviewers screened records and identified relevant studies in English.
Data Extraction: Data on patient characteristics, outcomes, and risk for bias were extracted by one reviewer and independently identified by another.
Data Synthesis: 54 observational studies and 1 randomized, controlled trial were included. Insufficient evidence addressed the effectiveness of pretesting. Genotyping sensitivity to identify patients with low and intermediate TPMT enzymatic activity ranged from 70.33% to 86.15% (lower-bound 95% CI, 54.52% to 70.88%; upper-bound CI, 78.50% to 96.33%). Sparse data precluded estimation of genotype sensitivity to identify patients with low to absent enzymatic activity. Genotyping specificity approached 100%. Compared with noncarriers, heterozygous and homozygous genotypes were both associated with leukopenia (odds ratios, 4.29 [CI, 2.67 to 6.89] and 20.84 [CI, 3.42 to 126.89], respectively). Compared with intermediate or normal activity, low TPMT enzymatic activity was significantly associated with myelotoxicity and leukopenia.
Limitation: Available evidence was not rigorous and was underpowered to detect a difference in outcomes.
Conclusion: Insufficient evidence addresses the effectiveness of TPMT pretesting in patients with chronic inflammatory diseases. Estimates of the sensitivity of genotyping are imprecise. Evidence confirms the known associations of leukopenia or myelotoxicity with reduced TPMT activity or variant genotype.