Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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TPMT and the Thiopurine Drugs
TPMT testing before initiation of drug therapy is one of the first clinical examples of
use of PGx testing in patient care. The thiopurine drugs are frequently prescribed for
additional indications other than acute lymphoblastic leukemia (ALL), such as rheumatoid
arthritis, inflammatory bowel disease, and other autoimmune conditions, and
also for immune suppression following organ transplants. Accumulated evidence has
well documented that 6-mercaptopurine (6-MP, launched in the United States in 1953)
dramatically improves the cure rate of ALL children, 22 but that severe myelosuppression
(or leukopenia) or fatal sepsis is the most severe, even life-threatening adverse
drug reaction associated with the use of purine drugs, such as 6-MP 23 and azathioprine
(AZT, used as an immunosuppressant in transplant patients since the 1950s). 24 Isolated
in 1980, thiopurine S-methyltransferase (TPMT) has been identified as the key catabolic
enzyme responsible for the inactivation of thiopurine drugs, including 6-MP, 25
and thus TPMT-inherited deficiency (due to germline mutations) is associated with
severe hematopoietic toxicity (such as myelosuppression) when treated with standard
doses of 6-MP. 26–29 Clinical studies have observed that 0.3% of white subjects could
be at increased risk of suffering thiopurine-induced myelosuppression due to the presence
of two deficient copies of the TPMT gene, which are termed as a poor metabolizer
phenotype, 27,30,31 and that approximately 10% of patients who have intermediate
levels of TPMT activity would also be at increased risk of myelosuppression from
standard doses of thiopurine drugs, 30 although their severe toxicity would be less likely.
Therefore, it is necessary to identify or predict whether an individual patient could be
an intermediate or poor metabolizer phenotype of TPMT before starting thiopurine
drugs, and lower dosage or alternative drugs would be prescribed for patients with
intermediate TPMT activity levels or deficient metabolizers.
In terms of the fact that the consequences for a patient who is not tested for
TPMT before use of thiopurine drugs could be life-threatening, phenotyping or
genotyping assay of TPMT prior to thiopurine treatment may have a favorable costeffectiveness
ratio in ALL patients. 12 Phenotyping assay of TPMT in humans is performed
as described elsewhere, 32 using red blood cells as the source of the enzyme
TPMT, and phenotypic monitoring of TPMT through red blood cell counting may
reduce the drive to implement TPMT genotyping testing. However, the drawbacks of
the phenotyping assay include labor-intensive, time-consuming, required expensive
instrumentation; and it is impractical in patients receiving transfusions. In contrast,
the PCR-based RFLP genotyping of TPMT is used to determine the presence of
TPMT-deficient alleles, which has been validated to predict the TPMT activity levels
and to further predict the risk of severe neutropenia for 6-MP and AZT. 27
TPMT testing before initiation of drug therapy is one of the best examples of
PGx that is not only clinically useful but also cost-effective. In Europe (United
Kingdom, Ireland, Germany, and the Netherlands), the actual level of implication
was estimated to be 12% according to a multicenter survey. 1 When stratified by the
biomarker, TPMT is one of the most common biomarkers evaluated in a total of
34 eligible articles about economic evaluation of PGx strategies published from 1999
to 2009. 14 In a CEA study, screening for TPMT before treating rheumatoid arthritis
patients with AZT indicated that TPMT genotyping was relatively cost-effective. 33