Inherited gene variation helps explain drug toxicity in patients of East Asian ancestry

Approximately 10% of young leukemia patients of East Asian ancestry inherit a gene variation associated with reduced tolerance of an indispensable drug for acute lymphoblastic leukemia (ALL), the most common childhood cancer.

Researchers reported that patients who inherited either one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine. Patients with the NUDT15 variant required their mercaptopurine dose reduced by as much as 92%. At standard doses, patients developed side effects that caused treatment delays and threatened their chance for cure.

The study was led by scientists from St. Jude Children's Research Hospital in Memphis, Tennessee, and the findings were published in the Journal of Clinical Oncology (2015; doi:10.1200/JCO.2014.59.4671).

The finding should aid efforts to improve identification and treatment of patients who need reduced doses of mercaptopurine. The drug is the backbone of chemotherapy that has helped transform the outlook for young patients with ALL. At St. Jude, 94% of patients with newly diagnosed ALL now become long-term survivors.

In this study, patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than those from other racial and ethnic groups. Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared with 3.9% of Hispanic patients. The variant was more rare among those of European or African ancestry. East Asia includes China, Japan, and Korea.

"Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry. Even at very low doses, the patients often develop toxicity that delays treatment, but until now the genetic basis of the problem was unknown," said first and corresponding author Jun J. Yang, PhD, an assistant member of the St. Jude Department of Pharmaceutical Sciences.

St. Jude is a pioneer in the field of pharmacogenetics, which focuses on how inherited differences in the makeup of genes influence patients' drug responses. This study confirmed previous St. Jude research that showed variations in another gene, TPMT, were also associated with an increased risk of mercaptopurine toxicity. St. Jude patients are now routinely tested for the TPMT variants, and the results help determine the mercaptopurine dose patients receive.

The TPMT variants did not completely explain mercaptopurine toxicity. The TPMT variants are less common in persons of East Asian ancestry. TPMT carries instructions for a protein of the same name. Some patients with normal TPMT still cannot tolerate standard doses of the drug. "That suggested there are other inherited genetic risk factors at play," Yang said.

Six percent of the patients in this study who required more than a 50% reduction in mercaptopurine inherited neither the TPMT nor NUDT15 variants. "Other factors, both genetic and nongenetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL," said senior author Mary Relling, PharmD, chair of the St. Jude Department of Pharmaceutical Sciences.

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