Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”
