AsianScientist (Mar. 14, 2016) – An international group of researchers has discovered genetic variants that make children with acute lymphoplastic leukemia (ALL) suffer excess side effects during routine treatment. The discovery could pave the way for potential genetics-guided precision medicine for ALL, the most common childhood cancer. The findings were published online in Nature Genetics.
The study involved 270 children with ALL and is a collaboration between the National University of Singapore Yong Loo Lin School of Medicine, Unidad De Oncologia Pediatric in Guatemala, the Japanese Pediatric Leukemia/Lymphoma Study Group and St Jude Children’s Research Hospital in the United States.
One in five Singaporean children undergoing chemotherapy for ALL has an inherited genetic variation of NUDT15 that makes them sensitive to standard doses of chemotherapy. These children, along with other Asian children, were found to suffer from prolonged fever and infections when given mercaptopurine, a chemotherapy drug that is the cornerstone of successful pediatric ALL treatment. This is despite dosages that were much lower than the recommended levels in the United States.
By screening for NUDT15 variants in children with ALL, doctors can potentially personalize their chemotherapy doses based on their genotype and avoid toxicity without compromising treatment effectiveness.
The researchers found four NUDT15 variants that alter the metabolism of mercaptopurine, a member of a class of chemotherapy medication that is widely used as anti-cancer and immunosuppressant drugs, and which is crucial for curing ALL.
Patients with these genetic variants are particularly sensitive to the drugs. They are intolerant of standard drug dosages and are at risk for treatment-disrupting toxicity. This is very common among Asians, with one in five Singaporean children and up to one in three Japanese children at risk. The scientists also found that the genetic variations are also common in other populations across Asia and those of Hispanic ethnicity.
The research in Singapore involved 76 ALL patients and was led by Associate Professor Allen Yeoh from the NUS Medicine’s Department of Pediatrics. Most Asian children are particularly sensitive to mercaptopurine, tolerating only two-thirds of the dose of mercaptopurine used for American children, explained Yeoh.
“About 20 percent of Singaporean children tolerate even lower doses—about one third of the dose used in America—while one in 80 children are extremely sensitive, tolerating only five percent of the usual dose.
“For many years, dosing Asian children with mercaptopurine was very much a hit-and-miss, causing unnecessary side effects of infections and fever in the sensitive ones and probably under-dosing the majority because of fear of side effects,” said Yeoh.
A St Jude’s news announcement on the findings said the researchers have shown that the NUDT15 enzyme helps to balance mercaptopurine activity by reducing the supply of the active drug metabolite that triggers cell death. This check-and-balance mechanism helps to prevent the excessive death of white blood cells that put patients at high risk for infections and other serious complications.
The study team showed the high-risk NUDT15 variants cause a 74.4 to 100 percent loss of NUDT15 function and a toxic build-up of the drug at standard doses.
“This study is key to the development of more effective, personalized mercaptopurine therapy because it provides a clear explanation of how variations in the NUDT15 gene change drug metabolism and cause toxicity in patients,” said Dr. Jun J. Yang, an associate member of the St Jude Department of Pharmaceutical Sciences, who led the international effort.
“We are planning clinical studies to move these findings from the laboratory to the clinic with the hope to guide individualized therapy in the future,” Yang added.
The article can be found at: Moriyama et al. (2016) NUDT15 Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity.
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Source: National University of Singapore ; Photo: Shutterstock.
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