TMPT & NUDT15 Pharmacogenomic testing in paediatric and adult ALL

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6-MP is a prodrug that is metabolised to active thioguanine nucleotides which are incorporated into DNA. Thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are key enzymes in the metabolism and inactivation of 6-MP and its active metabolites. Individuals with lower enzymatic activity are more likely to experience toxicity such as severe bone marrow suppression. TPMT and NUDT15 enzyme activity is modulated by common genetic variants which are inherited in an autosomal co-dominant manner and associated with lower enzymatic activity. These single nucleotide polymorphisms (SNPs) are seen at variable frequencies across ethnicities.

Pharmacogenomic testing for TPMT and NUDT15 polymorphisms in ALL patients is now included on the NHSE Genomic Test Directory. This update reflects well established practice in the treatment of childhood ALL, most recently as part of the ALLTogether protocol. Adult dosing guidance has recently been published by BOPA.

TPMT and NUDT15 testing is provided by a limited number of GLHs in England. Bristol (SWGLH) is the provider for the North West. Please send a peripheral blood sample (5ml in EDTA) and a completed SWGMS test request form specifying TPMT/NUDT15 testing (NGTD reference M91.80 and M91.81 respectively) to the Bristol Genetics Laboratory, North Bristol NHS Trust, Pathology Building, Southmead Hospital, Southmead Road, Westbury-On-Trym, Bristol BS10 5NB.

Alternatively please send the sample to the NWGLH using this form for onward referral.