Skip to main content
Public beta This website is in public beta – please give your feedback.

Example clinical scenario

A four-year-old girl has been diagnosed with acute lymphoblastic leukaemia (ALL) and the plan is to start induction chemotherapy. The proposed schedule includes treatment with 6-mercaptopurine. As part of the routine work-up, the haematologist requests pharmacogenomic tests for variants in the TPMT and NUDT15 genes. The results identify TMPT variants, which are known to lead to TPMT deficiency. Because the patient is at high risk of myelosuppression, the haematologist and pharmacist decide to start her on a lower dose of 6-mercaptopurine.

When to consider genomic testing

  • 6-mercaptopurine is commonly prescribed for the treatment of ALL and is extensively metabolised by two enzymes: thiopurine methyltransferase, encoded by the TPMT gene, and nudix hydrolase 15, encoded by the NUDT15 gene.
  • Some individuals have variants in the TPMT and/or NUDT15 genes, which lead to reduced enzyme activity and increase the risk of toxicity.
  • Variants in TPMT can lead to higher levels of thioguanine nucleotides, the active metabolite of 6-mercaptopurine; this increases the patient’s risk of experiencing serious adverse effects from 6-mercaptopurine treatment.
  • Individuals with reduced-function variants in NUDT15 are also more sensitive to 6-mercaptopurine toxicity.
  • The main dose-limiting adverse event associated with variants in both genes is myelosuppression.
  • Though frequencies vary across ethnic groups, up to 1 in 300 people have two no-function variants in TMPT, making them TMPT poor metabolisers, while up to 1 in 100 individuals have two no-function NUDT15 variants.
  • TPMT and NUDT15 pharmacogenomic testing should be requested prior to initiation of 6-mercaptopurine therapy.

What do you need to do?

  • Consult the National Genomic Test Directory for cancer. From here, you can access information about individual tests and their associated eligibility criteria. The downloadable spreadsheet lists all available tests, and you can search for the relevant gene by name.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • For this clinical indication, the appropriate test to choose is:
  • Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

Resources

For clinicians

References:

↑ Back to top
  • Last reviewed: 02/07/2024
  • Next review due: 02/07/2025
  • Authors: Dharmisha Chauhan and Rachel Palmer
  • Reviewers: Dr Charlotte Barker, Dr John McDermott, Professor Bill Newman