TPMT and NUDT15 genotyping before thiopurines

What it measures. Thiopurines (mercaptopurine and thioguanine) are the backbone of maintenance therapy in acute lymphoblastic leukaemia. Two enzymes protect the marrow from them. Thiopurine methyltransferase (TPMT) inactivates the drugs; about one in ten Europeans carries one low-activity allele and one in three hundred carries two. NUDT15 removes the active thioguanine nucleotides from the DNA-building pool; its low-activity variants are common in East Asian and Hispanic populations, where they explain most severe thiopurine toxicity, and were identified only in 2014 to 2015. Either deficiency lets active metabolites build up in marrow cells.

Evidence and guidelines. TPMT enzyme measurement and genotyping have been used in leukaemia protocols since the 1990s, and the Clinical Pharmacogenetics Implementation Consortium first published dose tables in 2011, adding NUDT15 in the 2018 update: normal metabolisers get the protocol dose, intermediate metabolisers start at 30 to 80 per cent, and poor metabolisers at around 10 per cent given three times a week, with adjustment by blood counts. The FDA labels for mercaptopurine and thioguanine describe TPMT and NUDT15 testing, and the UK and most paediatric leukaemia groups test at diagnosis. The same tests are used before azathioprine in autoimmune disease and transplantation.

Who should have it and what changes. Every patient starting thiopurine maintenance, ideally at leukaemia diagnosis so the result is ready. A poor metaboliser result cuts the starting dose to a tenth; an intermediate result cuts it by a third to a half; otherwise the standard dose is used with the usual monitoring of blood counts, which continues in everyone because genotype explains only part of the variation. Testing costs tens of pounds and takes days; enzyme activity (phenotype) is an alternative when genotype is unavailable but is unreliable after a transfusion.