Azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine (TG) are thiopurine drugs. These agents are indicated for the treatment of various diseases including hematologic malignancies, inflammatory bowel disease (IBD), rheumatoid arthritis, and as immunosuppressants in solid organ transplants. Thiopurine drugs are metabolized, in part, by thiopurine methyltransferase (TPMT). TPMT displays genetic polymorphism resulting in null or decreased enzyme activity. At least 20 polymorphisms have been identified, of which, TPMT *2, *3A, *3B, *3C, and *4 are the most commonly studied. These polymorphisms have been associated with increased myelosuppression risk. TPMT genotyping may be useful to predict this risk.
Approximately 86-97% of patients have the TPMT *1/*1 (wild-type) genotype.  These patients have normal TPMT enzyme activity. Approximately 3-14% of patients have the heterozygous TPMT genotype and possess one TPMT variant allele. These patients may experience moderate to severe myelosuppression; therefore, thiopurine drug dose reduction may be warranted.  The population prevalence of patients who have the homozygous TPMT variant genotype is low (approximately 1 in 178 to 1 in 3,736 patients).  However, these patients have the highest risk of developing severe myelosuppression, which may lead to life-threatening complications such as sepsis.  These patients may not be candidates for treatment with a thiopurine drug, or the drug dose should be reduced by at least 10-fold. 
The TPMT genotype assay uses polymerase chain reaction (PCR) amplication followed by single nucleotide primer extension to detect the TPMT *1, *2, *3A, *3B, and/or *3C alleles.  The TPMT genotype assay requires a whole blood sample.
Public Health Importance
Thiopurine-induced myelosuppression can result in increased morbidity, hospitalization and/or treatment discontinuation.  Myelosuppression increases an individual’s risk of developing an infection and sepsis.  The incidence of mild leukopenia is approximately 5-25%.  Rare, but severe leukopenia can develop suddenly and unpredictably in approximately 3% of patients.  A 27-year analysis showed that AZA contributed to the incidences of myelosuppression in 5% of patients.  Over an 18-year period, 2% of patients with IBD experienced 6-MP-induced leukopenia that resulted in hospitalization.  The incidence of myelosuppression occurred more frequently during the first eight weeks after treatment initiation, and was more likely to occur with a higher drug dose.  It should be noted that while the TPMT genotype test may predict myelosuppression risk, the test should not replace complete blood count (CBC) monitoring to detect myelosuppression during treatment with thiopurine drugs.  Given that TG carries the risk of myelosuppression  , CBC monitoring is also necessary for this drug.
Published Reviews, Recommendations and Guidelines
Systematic evidence reviews
The Agency for Healthcare Research and Quality (AHRQ) concluded that “there is currently insufficient evidence regarding the effectiveness of determining TPMT status prior to thiopurine treatment in terms of improvement in clinical outcomes and incident myelotoxicity in comparison with routine monitoring of full blood counts and adverse events.” 
Recommendations by independent groups
Guidelines by professional group
Christine M. Nguyen and Margaret A.S. Mendes are funded by the Veterans Affairs San Diego Healthcare System. Joseph D. Ma is funded by the University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences.
The authors have declared that no competing interests exist.
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