TPMT: the enzyme that decides how much thiopurine is too much
TPMT is one of the oldest pharmacogenetic tests in routine clinical use, and one of the few where the consequence of getting it wrong is measured in weeks in hospital rather than in a drug that underperforms.
Also known as: thiopurine S-methyltransferase.
What TPMT does
The enzyme methylates thiopurine drugs, which is a way of diverting them down a harmless route before they can be converted into the metabolites that act on dividing cells. Bone marrow is full of dividing cells. If TPMT activity is low, more of each dose takes the active route, the active metabolites build up in red cells and marrow, and blood counts fall. The drug still works; there is simply far more of it doing the work than the dose implies.
The metabolizer groups
TPMT is graded by diplotype rather than by an activity score. Two working copies make a normal metabolizer. One reduced or absent copy makes an intermediate metabolizer, which is roughly one person in ten of European ancestry. Two make a poor metabolizer, which is rare, on the order of one in three hundred. CPIC also uses possible intermediate metabolizer for combinations where one allele's function is not settled, and Indeterminate where the pair cannot be graded at all. The lower the activity, the smaller the safe dose.
Medications where it matters
azathioprine (Imuran)
Azathioprine is used long term in inflammatory bowel disease, autoimmune hepatitis, transplant medicine and several rheumatological conditions, so a lot of people take it for years. Reduced TPMT activity is the reason a starting dose that suits most people can drop someone else's white cell count. The published guidance below is written in terms of starting dose, not in terms of avoiding the drug.
| If your result is | Published CPIC guidance |
|---|---|
| Indeterminate | Per CPIC (A): "Based on NUDT15, initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment." |
| Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment." |
| Normal Metabolizer | Per CPIC (A): "Initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment." |
| Poor Metabolizer | Per CPIC (A): "Consider alternative nonthiopurine immunosuppressant therapy." |
| Possible Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment." |
mercaptopurine (6-MP)
Mercaptopurine is central to childhood acute lymphoblastic leukaemia maintenance, where treatment runs for years and dose intensity matters for outcome. This is the setting where TPMT testing became standard practice, and where the dose reductions in the guidance below are largest.
| If your result is | Published CPIC guidance |
|---|---|
| Indeterminate | Per CPIC (A): "Based on NUDT15, initiate therapy with standard starting dose of mecaptopurine (e.g., 75 mg/m2/day for malignancy or 1.5 mg/kg/day for nonmalignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if starting dose is ≥75 mg/m2/day (for malignancy) or ≥1.5 mg/kg/day (for nonmalignancy). If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust mercaptopurine doses based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing mercaptopurine over other agents." |
| Normal Metabolizer | Per CPIC (A): "Initiate therapy with standard starting dose of mecaptopurine (e.g., 75 mg/m2/day for malignancy or 1.5 mg/kg/day for nonmalignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Poor Metabolizer | Per CPIC (A): "For malignancy: initiate therapy with drastically reduced starting doses. Reduce starting dose by 10-fold and reduce frequency to thrice weekly instead of daily (e.g. 10 mg/m2/day given 3 days/week). During therapy, adjust mercaptopurine doses based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 4-6 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignancy: consider alternative nonthiopurine immunosuppressant therapy." |
| Possible Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if starting dose is ≥75 mg/m2/day (for malignancy) or ≥1.5 mg/kg/day (for nonmalignancy). If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust mercaptopurine doses based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing mercaptopurine over other agents." |
thioguanine (6-TG)
Thioguanine is the least used of the three but travels the same metabolic road, so the same enzyme sets the same problem. It is included here because a TPMT result that changes azathioprine dosing changes this one too.
| If your result is | Published CPIC guidance |
|---|---|
| Indeterminate | Per CPIC (A): "Based on NUDT15, initiate therapy with standard starting dose of thioguanine (e.g., 40 mg/m2/day for malignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if standard starting dose is ≥40 mg/m2/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of thioguanine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing thioguanine over other agents." |
| Normal Metabolizer | Per CPIC (A): "Initiate therapy with standard starting dose of thioguanine (e.g., 40 mg/m2/day for malignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Poor Metabolizer | Per CPIC (A): "Initiate therapy with drastically reduced starting doses. Reduce starting dose by 10-fold and reduce frequency to thrice weekly instead of daily. During therapy, adjust thioguanine doses based on degree of myelosuppression and disease-specific guidelines. It usually takes at least 4-6 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents." |
| Possible Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if standard starting dose is ≥40 mg/m2/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of thioguanine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing thioguanine over other agents." |
Is this in your raw DNA file?
TPMT is not part of the standard chip or variant-file report. It is a Deep Read gene, read from aligned reads in a BAM or CRAM file. The reason is the shape of the gene: CPIC's TPMT table covers dozens of star alleles built from combinations of variants, and calling them apart needs sequence rather than a handful of chip positions. Where the reads do not resolve a diplotype, the result is Indeterminate. If you are about to start a thiopurine, this is a case where a clinical TPMT test ordered by the prescriber, often alongside an enzyme-activity measurement, is the right tool and a re-analysis of your own file is not a substitute for it.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
Is TPMT in my 23andMe or AncestryDNA raw data?
Some TPMT positions appear on some consumer chips, but the gene is graded on star-allele combinations that a chip cannot resolve. Aimosti reads TPMT from aligned reads as part of the Deep Read panel, and reports Indeterminate where the data does not settle the diplotype.
My doctor already ordered a TPMT test. Does this add anything?
Not for the decision in front of you. A clinical TPMT test, particularly one that measures enzyme activity rather than genotype alone, is what should drive your dosing. A genotype result from your own file is context, and it is worth knowing the two can disagree, because activity is affected by things other than the gene.
Why is NUDT15 mentioned alongside TPMT?
Because CPIC's thiopurine guidance grades both genes together. Low activity in either one raises the same risk, and a normal TPMT result does not rule out a NUDT15 problem. The guidance shown on this page assumes a typical NUDT15 result; the NUDT15 page covers the other side.
Does a normal TPMT result mean thiopurines are safe for me?
It means one known risk factor is absent. Thiopurines still require blood-count monitoring in everyone, because most of the reasons counts fall have nothing to do with this gene.