Incidence and Clinical Significance of NUDT15 enzyme polymorphisms in a London population of paediatric Acute Lymphoblastic Leukaemia (ALL) patients treated at Great Ormond Street Hospital, London.


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Lamia Samrin-Balch1, Sujith Samarasinghe1, Ajay Vora Vora1
1Great Ormond Street Hospital for Children NHS Foundation Trust

Abstract

Background

NUDT15, an enzyme, responsible for mercaptopurine (6MP) metabolism has clinically significant genetic polymorphisms linked to ethnicity (predominantly Asian), causing haematopoietic toxicity. Currently no studies have been done in the ethnically diverse London population to determine the prevalence, trend or clinical relevance in paediatric patients with Acute Lymphoblastic Leukaemia (ALL). Prolonged exposure to 6MP in maintenance ALL treatment is vital for a sustained remission.

Method

83 subjects who have completed ALL treatment were chosen to retrospectively test correlation between ethnicity and NUDT15 polymorphism. In addition to prevalence, clinical effect on 6MP tolerance during maintenance was also explored in relation to NUDT15 variants detected.

In 52 patients, weekly neutrophil results and maximum tolerated 6MP dose as a percentage of the maximum total dose was obtained for the duration of maintenance period.


Results

Results found no significant trend between ethnicity and NUDT15 polymorphisms. Prevalence for NUDT15 polymorphism is between 13-26%, with a notable occurrence in Asian ethnicity subjects (P=0.009). Two clinically relevant variants were detected showing subjects only tolerated a mean 6MP dose of approximately 40% and 60% throughout maintenance. Whilst the groups tested were too small to elicit statistical significance, clinically such a reduced tolerance to 6MP is certainly worth exploring. On average these 2 groups had great fluctuations in neutrophils over the maintenance phase suggestive of poor understanding of the affect of inherited polymorphisms.

Conclusion

In conclusion NUDT15 variant and ethnicity proved no trend, suggesting the need to test all Paediatric ALL patients in London, as prevalence is similar to that of TPMT variants, which are screened as standard of care. Those with a recognised variant tolerated clinically lower 6MP doses than expected.

 

Impact statement

NUDT15 polymorphisms should be tested in all paediatric leukaemia patients receiving 6MP, regardless of ethnicity with a validated enzyme assay in order to ensure adequate maintenance therapy, so patients in remission, remain in remission.