Pre-therapy testing

Before starting patients on therapy, testing can identify individuals at risk for excessive myelosuppression or severe hematopoietic toxicity when taking thiopurine drugs (e.g., azathioprine or 6-mercaptopurine) due to low thiopurine methyltransferase (TPMT) activity.

Both enzyme and genotype testing can be performed prior to therapy initiation. Current literature does not clearly demonstrate superiority of one test over the other; however, enzyme testing can detect individuals with increased metabolism and rare variants not included in genotype testing. Research demonstrates genetic variants in Nudix hydrolase 15 (NUDT15) also affect thiopurine toxicity.¹ NUDT15 can only be tested through the genotype test. Therefore, both the genotyping assay and the enzyme assay are considered complementary and are recommended.

Key testing

• TPMT3 | Thiopurine Methyltransferase Activity Profile, Erythrocytes
  • Measures enzyme activity in a patient’s blood to determine thiopurine metabolization.
  • Offers TPMT activity in three separate reactions, which do not interfere with one another and compete for TPMT.
  • Offers greater specificity than measuring TPMT activity with only a single analyte analysis, enabling more conclusive results.
  • Uses multivariate pattern recognition software (CLIR) that aids post-analytical interpretation to detect TPMT phenotype pattern differences, drive precise medicine, and reduce clinical uncertainty.
• TPNUQ | Thiopurine Methyltransferase (TPMT) and Nudix Hydrolase (NUDT15) Genotyping, Varies
  • Uses a patient’s genetic information to determine thiopurine metabolization.
  • Evaluates both the TPMT gene and NUDT15, which can have genetic variants strongly associated with thiopurine-related toxicity.
  • Including NUDT15 as part of testing is especially important when clinicians are treating more diverse populations, as deficiency is most common among East Asian (22.6%), South Asian (13.6%), and Native American (12.5%–21.2%) populations.²

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Testing after therapy initiation

Testing after initiation of therapy enables clinicians to optimize therapy and identify elevated metabolite concentrations that may result in toxicity. Additionally, clinicians should order testing as needed for dose changes, flare-ups, signs of toxicity, and suspicion of noncompliance, as well as in patients who do not respond to therapy as expected.

Key testing

• THIO | Thiopurine Metabolites, Whole Blood

Advantages

• Optimizes therapy through identification of elevated metabolite concentrations.
• Facilitates understanding of therapy response when there are flare-ups, signs of toxicity, and suspicions of noncompliance.
• Is recommended 4 weeks after starting treatment to ensure patient compliance and to look for early risk of toxicity; 12-16 weeks after beginning therapy when TGN metabolites have reached a steady state; and annually.

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References

1. Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016 Apr;48(4):367-73.
2. Moyer, A. NUDT15: A bench to bedside success story. Clin Biochem. 2021;9211:1-8.