What is the clinical significance of determining TPMT (thiopurine methyltransferase) phenotype in patients requiring thiopurine drugs, such as azathioprine (Imuran) or mercaptopurine (Purinethol), and how does it guide dosage and treatment?

TPMT Phenotype Testing in Thiopurine Therapy

TPMT testing should be performed before initiating thiopurine therapy to guide dosing and prevent potentially life-threatening myelosuppression in patients with enzyme deficiency. 1

Clinical Significance of TPMT Phenotype Testing

TPMT (thiopurine methyltransferase) is a key enzyme responsible for metabolizing thiopurine drugs such as azathioprine (Imuran) and mercaptopurine (Purinethol). Testing for TPMT phenotype or genotype before starting therapy has significant implications for patient safety and treatment efficacy.

TPMT Deficiency Prevalence and Risk

• Approximately 0.3% (1:300) of patients of European or African ancestry have homozygous TPMT deficiency (little or no enzyme activity) 2
• About 10% of patients have heterozygous TPMT deficiency (intermediate enzyme activity) 2
• Patients with East Asian ancestry have different genetic risk factors, with NUDT15 deficiency being more common (2% homozygous, 21% heterozygous) 2

Myelosuppression Risk Based on TPMT Status

• Homozygous deficiency: 20.8-fold increased risk of thiopurine-induced leukopenia (95% CI, 3.4-126.9) 1
• Heterozygous deficiency: 4.3-fold increased risk of thiopurine-induced leukopenia (95% CI, 2.7-6.9) 1
• Most leukopenia events occur within 8 weeks of starting therapy, though they can occur later 1

Dosing Recommendations Based on TPMT Status

For Patients with Normal TPMT Activity (Wild-type)

• Standard dosing: 2-2.5 mg/kg/day for azathioprine or 1-1.5 mg/kg/day for mercaptopurine 1
• Regular monitoring still required

For Patients with Intermediate TPMT Activity (Heterozygous)

• Reduce dose to 50% of standard dose 1
• These patients can tolerate thiopurines at reduced doses 3

For Patients with Low/Absent TPMT Activity (Homozygous Deficient)

• Either avoid thiopurines completely or use extremely reduced doses (0-10% of standard dose) 1
• Some evidence suggests that very careful dose titration may allow treatment in these patients 4
• Patients typically require 10% or less of the recommended dosage 5

Evidence for TPMT Testing

The American Gastroenterological Association (AGA) conditionally recommends routine TPMT testing before starting thiopurine therapy based on low-quality evidence 1. While population-level benefits may be modest, the potential to prevent severe harm in the small subset of homozygous deficient patients justifies testing.

Three randomized controlled trials comparing TPMT-guided dosing versus standard weight-based dosing found:

• No significant difference in overall hematologic adverse events (RR 0.94; 95% CI 0.59-1.50) 1
• No significant difference in treatment discontinuation rates (RR 1.09; 95% CI 0.94-1.27) 1
• However, in patients with TPMT mutations, guided dosing reduced hematologic adverse events by 89% 1

Implementation in Clinical Practice

Testing Methods

• TPMT phenotype: Measures actual enzyme activity in red blood cells
• TPMT genotype: Detects common mutations (*2, *3A, *3B, *3C alleles)
• Both methods are considered acceptable 1

Important Clinical Considerations

• TPMT testing does not eliminate the need for routine blood count monitoring 1
• Testing may delay therapy by 1-2 weeks, but this is generally inconsequential given the slow onset of action of thiopurines 1
• FDA recommends genotype or phenotype testing before high-dose chemotherapy with thiopurines in pediatric patients 1

Pitfalls to Avoid

• TPMT testing may create a false sense of security - not all cases of leukopenia are related to TPMT status 1
• TPMT status does not predict other adverse events like hepatotoxicity or pancreatitis 1
• Even with normal TPMT, regular monitoring is essential as myelosuppression can occur through other mechanisms

Beyond TPMT: Additional Considerations

• NUDT15 testing is now also recommended, particularly for patients of East Asian ancestry 1
• Reactive thiopurine metabolite monitoring (measuring 6-TGN levels) may be useful in patients with active disease or adverse effects 1
• Target 6-TGN levels between 230-450 pmol/8×10^8 RBCs when used as monotherapy 1

TPMT testing represents an important application of pharmacogenetics that can prevent serious adverse events and optimize thiopurine therapy in patients requiring these medications for inflammatory bowel disease and other conditions.