THIOPURINE TOXICITY — TPMT & NUDT15

Thiopurine Toxicity — TPMT and NUDT15 variants that cause life-threatening bone marrow failure from azathioprine, mercaptopurine, and thioguanine at doses that are well-tolerated by most patients.

Whole genome sequencing provides complete TPMT and NUDT15 genotyping simultaneously — the two genes that together explain the vast majority of severe thiopurine toxicity, including the NUDT15 variants that explain toxicity in East Asian patients who test TPMT-normal.

TPMT
NUDT15

About this condition

Thiopurine Toxicity — TPMT & NUDT15

Thiopurines — azathioprine (Imuran), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) — are immunosuppressive and cytotoxic agents widely used in hematological malignancies (acute lymphoblastic leukemia), inflammatory bowel disease, autoimmune diseases, organ transplantation, and as maintenance therapy in rheumatoid arthritis. The primary toxicity risk is severe, potentially fatal myelosuppression — bone marrow failure resulting in life-threatening neutropenia, thrombocytopenia, and anemia. Two pharmacogenes are responsible for the majority of clinically significant thiopurine toxicity: TPMT (thiopurine S-methyltransferase) and NUDT15 (nudix hydrolase 15).

TPMT inactivates thiopurines; deficient TPMT activity allows accumulation of cytotoxic thioguanine nucleotides at levels that cause severe myelosuppression. Approximately 10% of the population is TPMT intermediate metabolizers (heterozygous for a loss-of-function variant), and approximately 0.3% are poor metabolizers (homozygous). FDA labeling for azathioprine and 6-MP includes TPMT testing guidance. NUDT15 degrades thioguanine triphosphate; loss-of-function NUDT15 variants similarly lead to accumulation of toxic metabolites. Critically, NUDT15 variants are common in East Asian, South Asian, and Hispanic populations but rare in European ancestry — explaining the observation that many East Asian patients develop severe thiopurine toxicity despite normal TPMT genotyping. NUDT15*2 (p.Arg139Cys) is the most common pathogenic variant.

CPIC provides Level A (highest evidence) guidelines for both TPMT and NUDT15 with thiopurines, recommending dose reductions for intermediate metabolizers in both genes and alternative therapy or dramatically reduced dosing for poor metabolizers. The combination of TPMT*3A compound heterozygosity, NUDT15 homozygous loss-of-function, or any combination of TPMT poor metabolizer and NUDT15 poor metabolizer genotypes creates the highest toxicity risk, approaching complete inability to tolerate even very low thiopurine doses. Testing both genes simultaneously — as whole genome sequencing provides — is essential because TPMT-normal patients may have NUDT15 variants that explain their toxicity.

NUDT15 variants are responsible for most thiopurine toxicity in East Asian, South Asian, and Hispanic patients who test TPMT-normal. A single-gene TPMT test misses the primary toxicity driver in these populations.

Gene locus: TPMT (6p22.3), NUDT15 (13q14.2)

TPMT-only testing misses NUDT15 — the primary thiopurine toxicity gene in East Asian and South Asian patients. CPIC Level A guidelines require both genes. Whole genome sequencing covers both in a single test.

Testing only TPMT misses the toxicity driver in East Asian patients

TPMT*3A — the most common TPMT loss-of-function allele — has a carrier frequency of approximately 5% in Europeans but less than 1% in East Asian populations. NUDT15*2 — the most common NUDT15 loss-of-function allele — has frequencies of approximately 8-14% in East Asian populations but is very rare in Europeans. Multiple documented cases exist of East Asian patients who experienced severe thiopurine-induced myelosuppression after testing TPMT-normal, subsequently found to be NUDT15 poor metabolizers. Until NUDT15 testing was added to standard pharmacogenomics panels, these patients had no mechanism-based explanation for their toxicity. Whole genome sequencing routinely calls complete star-allele diplotypes for both TPMT and NUDT15.

The combination phenotype — TPMT intermediate plus NUDT15 intermediate — creates unexpectedly severe toxicity

CPIC guidelines note that patients who are intermediate metabolizers for both TPMT and NUDT15 — a combination that can occur in any population — face toxicity equivalent to poor metabolizer status for either gene alone. This synergistic toxicity risk is only captured when both genes are genotyped simultaneously. A patient who tests 'TPMT intermediate — consider dose reduction' but is not also tested for NUDT15 may receive a thiopurine dose that is too high if they are also NUDT15 intermediate. Whole genome sequencing provides both diplotypes simultaneously, enabling the combined phenotype assessment that CPIC explicitly recommends.

Thiopurine Toxicity — TPMT and NUDT15 variants that cause life-threatening bone marrow failure from azathioprine, mercaptopurine, and thioguanine at doses that are well-tolerated by most patients.

Thiopurine Toxicity — TPMT & NUDT15

TPMT-only testing misses NUDT15 — the primary thiopurine toxicity gene in East Asian and South Asian patients. CPIC Level A guidelines require both genes. Whole genome sequencing covers both in a single test.

Testing only TPMT misses the toxicity driver in East Asian patients

The combination phenotype — TPMT intermediate plus NUDT15 intermediate — creates unexpectedly severe toxicity

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