Thiopurines

Azathioprine and 6-MP are widely prescribed as immunosuppressants for a range of non-malignant indications including inflammatory bowel disease (IBD) and rheumatoid arthritis. 6-MP and thioguanine are indicated in haematological malignancy.

• Thiopurines are antimetabolites, acting as ‘rogue’ nucleotides, which become incorporated into DNA and disrupt DNA synthesis in rapidly dividing cells.
• TPMT and NUDT15 enzymes play a key role in metabolising either active thiopurine metabolites or thioguanine to inactive metabolites.
• Genetic variants of TPMT or NUDT15 can result in poorly functioning or non-functioning enzymes, which result in an accumulation of active thiopurine metabolites, called thioguanine nucleotides. This increases the risk of serious adverse effects, including severe myelosuppression.
• Three TPMT genetic variants account for around 90% of genetic causes of a poor or non-functioning TPMT enzyme.
• A patient’s metaboliser status is calculated based on their NUDT15 and TPMT gene alleles. Note that a patient may have one or more variants in TPMT and/or NUDT15.
• The prevalence of clinically significant NUDT15 and TPMT variation differs between ancestries and populations:
  • TPMT deficiency is the main genetic cause of thiopurine intolerance in patients of European and African; and
  • genetic variation in NUDT15 is responsible for most thiopurine-related myelosuppression in patients of Asian ancestry, and is also common in Hispanic populations.
• When considering prescribing thiopurines, pharmacogenomic results should be considered alongside other clinical factors such as organ function and drug interactions.
• Note that the current standard genomic tests may not detect rarer variants of TPMT and NUDT15, although these may still be clinically significant.

Patients receiving MP-6 for acute lymphoblastic leukaemia

• Testing for TPMT and NUDT15 genetic variation is available via the National Genomic Test Directory for patients initiated on MP-6 for acute lymphoblastic leukaemia (ALL).
• For patients with clinically significant variants in TPMT and/or NUDT15, a lower thiopurine starting dose is generally recommended, although in some cases prescription of an alternative agent may be advised.
• Specific prescribing recommendations are available from the latest versions of the relevant ALL treatment protocols for adults and children (always follow the latest protocols used by your institution):
  • at the time of writing, the ALLTogether1 clinical trial protocol should be consulted for dosing advice for paediatric ALL patients with TPMT or NUDT15 variants; and
  • dosing guidance for adult ALL patients with TPMT or NUDT15 variants is available from the British Oncology Pharmacy Association (BOPA).

Patients prescribed thiopurines for other indications

• TPMT and NUDT15 genomic testing for thiopurines for other indications is not currently included in the National Genomic Test Directory and is not routinely funded.
• Despite this, patients may present with pharmacogenomic information from other healthcare systems, clinical trials or direct-to-consumer genomic testing (caution should be exercised when interpreting results from non-validated genomic tests).

For clinicians

• ALLTogether: A treatment study protocol of the ALLTogether Consortium for children and young adults (1–45 years of age) with newly diagnosed acute lymphoblastic leukaemia (ALL)
• British Oncology Pharmacy Association: Guideline for 6-mercaptopurine dosing in adult acute lymphoblastic leukaemia based on TPMT and NUDT15 genotypes (PDF, 13 pages)
• NHS England: National Genomic Test Directory
• US National Library of Medicine ClinicalTrials database: A treatment protocol for participants 0–45 years with acute lymphoblastic leukaemia

References:

• Hindorf U and Appell ML. ‘Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function’. Journal of Crohn’s and Colitis 2012: volume 6, issue 6, pages 655–659. DOI: 10.1016/j.crohns.2011.11.014
• Lennard L, Cartwright CS, Wade R and others. ‘Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia’. British Journal of Clinical Pharmacology 2013: volume 76, issue 1, pages 125–136. DOI: 10.1111/bcp.12066
• Walker GJ, Harrison JW, Heap GA and others. ‘Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease’. Journal of the American Medical Association 2019: volume 321, issue 8, pages 773–785. DOI: 10.1001%2Fjama.2019.0709
• Warner B, Johnston E, Arenas-Hernandez M and others. ‘A practical guide to thiopurine prescribing and monitoring in IBD’ Frontline Gastroenterology 2018: volume 9, pages 10–15. DOI: 10.1136/flgastro-2016-100738