TPMT Activity in Azathioprine-Induced Myelosuppression
Most patients who develop myelosuppression on azathioprine have normal or near-normal TPMT activity, not low activity as might be expected. 1
Expected TPMT Results in Myelosuppression Cases
The Counterintuitive Reality
- 73% of patients with severe azathioprine-induced myelosuppression have completely normal TPMT genotype with no detectable mutations 2
- Only 27% of patients who develop myelosuppression have any TPMT genetic variants 2
- Among those with variants: 17% are heterozygous (intermediate activity) and only 10% are homozygous deficient 2
Clinical Pattern by TPMT Status
Homozygous TPMT deficiency (absent activity):
- Represents only 0.3% of the population 1, 3
- 86% of these patients develop myelosuppression if given standard doses 4
- Myelosuppression occurs rapidly, typically within 1.5 months 2
- This is the only group reliably predicted by TPMT testing 1
Heterozygous TPMT deficiency (intermediate activity):
- Represents approximately 10% of the population 3
- Myelosuppression occurs in 14.3% of these patients (vs 3.5% with normal TPMT) 1
- Timing is variable, ranging from 1 to 18 months after starting therapy 2
- Odds ratio for leukopenia is 4.19 compared to wild-type 4
Normal TPMT activity:
- This is the most common scenario in patients who develop myelosuppression 1
- Myelosuppression can occur anywhere from 0.5 to 87 months after starting therapy 2
- Cannot be predicted by TPMT testing 1
Why TPMT Testing Fails to Predict Most Cases
The disconnect between TPMT status and myelosuppression occurs because:
- Alternative metabolic pathways (xanthine oxidase) remain intact in most patients 1, 3
- Variable penetrance of TPMT deficiency alleles exists 1
- Azathioprine may induce TPMT activity through substrate induction 1
- Other factors influence metabolism including race, age, and concurrent medications 1
- Cirrhosis itself causes cytopenia independent of azathioprine toxicity 1
Critical Clinical Implications
TPMT testing cannot replace hematologic monitoring:
- Complete blood counts must be performed weekly for the first month, twice monthly for months 2-3, then monthly thereafter 1, 3
- This monitoring is mandatory regardless of TPMT status 1, 5
- Pretreatment TPMT testing only identifies the small minority (0.3%) at extreme risk 1, 5
When to suspect TPMT deficiency:
- Severe pancytopenia occurring within the first 6-8 weeks of therapy suggests homozygous TPMT deficiency 2, 6
- Later-onset myelosuppression (>2 months) is more likely unrelated to TPMT status 2
- Consider TPMT testing in patients with severe or recurrent myelosuppression 7, 3
Bottom Line for Clinical Practice
If your patient develops myelosuppression on azathioprine, the TPMT result will most likely be normal 1, 2. Only if myelosuppression is severe and occurs very early (<6 weeks) should you strongly suspect TPMT deficiency 2, 6. The FDA label explicitly states that death from pancytopenia has occurred in patients with absent TPMT activity 3, but these cases represent a small minority of all azathioprine-induced myelosuppression.