Presentation: Patient requiring 6-mercaptopurine for acute lymphoblastic leukaemia

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.

• 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.

• 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:
  • M91 Haematological tumours.
    • Clinical indication: acute lymphoblastic leukaemia.
    • Test codes: M91.80 TPMT and M91.81 NUDT15 (always check the latest test directory to ensure the test code is correct).
    • Test description: Single nucleotide polymorphism/Small variant detection (simple targeted mutation testing).
  • For DNA-based tests, an EDTA sample is required.
  • For further information about how to order this test in your institution, contact your local Genomic Laboratory Hub.
  • The ALLTogether clinical study protocol for children and young adults should be consulted for dosing advice for paediatric ALL patients with TPMT or NUDT15 variants.
  • At the time of writing, dosing guidance for adult ALL patients with TPMT or NUDT15 variants is also available.
• 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.

For clinicians

• ALLTogether: Clinical study protocol: 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) (PDF, 426 pages) (please check locally for the latest approved version in use at your institution)
• UK Clinical Pharmacy Association: Guideline for 6-mercaptopurine dosing based on TPMT and NUDT15 genotypes
• US National Library of Medicine ClinicalTrials database: A treatment protocol for participants 0–45 years with acute lymphoblastic leukaemia

References:

• 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