TPMT genotype-guided dosing for thiopurines

• TPMT *2 (rs1800462, A80P): no-function. ~0.2% allele frequency.
• TPMT *3A (rs1800460 + rs1142345, A154T + Y240C): no-function. Most common deficient allele in European descent (~3.5% allele frequency).
• TPMT *3B (A154T alone): no-function. Rare.
• TPMT *3C (rs1142345, Y240C alone): no-function. More common in African and East Asian populations.
• NUDT15 *3 (rs116855232, R139C): no-function. Common in East Asian (~10%) and Hispanic populations.

• Normal metabolizer: full dose.
• Intermediate metabolizer (TPMT *1/*2, *1/*3A, *1/*3B, *1/*3C, or NUDT15 *1/*3): start at 30-80% of standard dose; titrate to ANC and TGN levels.
• Poor metabolizer (homozygous or compound heterozygous no-function for TPMT or NUDT15): avoid thiopurines, or use markedly reduced dose (~10% of standard) with intensive marrow monitoring.

Pre-treatment TPMT (+ NUDT15 in East Asian / Hispanic patients, increasingly universal) genotyping is the standard. The most consequential indications:

• Pediatric ALL maintenance (6-MP backbone): poor metabolizers on standard dose develop life-threatening pancytopenia within days to weeks. Pre-treatment testing is now mandatory in essentially all pediatric leukemia centers.
• Adult ALL / lymphoblastic lymphoma maintenance: same logic.
• Inflammatory bowel disease (azathioprine, 6-MP): similar PGx risk; routinely tested.
• Autoimmune (RA, SLE, transplant): similar logic.

Thiopurine metabolite monitoring (6-TGN, 6-MMP levels) is complementary for ongoing dose optimization.

TPMT-thiopurine PGx is one of the most established pharmacogenomic relationships in medicine. CPIC Level A. FDA label warning. Universal pre-treatment testing in pediatric ALL has changed expected toxicity rates substantially. NUDT15 was added to the guidelines after demonstrating significant contribution to thiopurine toxicity, particularly in non-European populations where TPMT alone underestimates risk.

Thiopurine metabolism is complex: TPMT genotype, NUDT15 genotype, ITPA polymorphisms, xanthine oxidase activity (relevant when allopurinol is co-administered), and TGN levels all contribute. Allopurinol + thiopurine combination requires substantial thiopurine dose reduction (~75%) regardless of TPMT genotype because of xanthine-oxidase-mediated shunt into TGN.

Should every patient get TPMT testing?

Yes. CPIC strongly recommends pre-treatment TPMT genotyping for all patients starting thiopurines. Pediatric ALL centers universally test. Adult IBD, transplant, and autoimmune practices increasingly do so.

Is NUDT15 needed in addition to TPMT?

Strongly recommended, especially in East Asian and Hispanic patients where NUDT15 *3 prevalence is high and TPMT alone misses substantial risk. Many centers now combine TPMT + NUDT15 into a single thiopurine PGx panel.

What about co-administration with allopurinol?

Allopurinol inhibits xanthine oxidase, shunting thiopurine metabolism toward TGN (the active and toxic metabolite). Combination requires ~75% thiopurine dose reduction regardless of TPMT/NUDT15 genotype. The combination is intentionally used in some IBD contexts to overcome thiopurine 'hypermethylator' phenotype.

• Relling MV et al. CPIC Guideline for TPMT and NUDT15 Genotypes and Thiopurine Dosing. Clin Pharmacol Ther 2019; 105:1095-1105.
• CPIC TPMT guideline.

• DPYD + 5-FU →
• CYP2C19 + clopidogrel →