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New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.
Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.
One in 3 Japanese patients in this study carried the variations.
And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.
In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.
With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.
In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.
“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.
The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.
“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”
The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.
Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine. 
Photo courtesy of the CDC
New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.
Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.
One in 3 Japanese patients in this study carried the variations.
And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.
In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.
With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.
In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.
“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.
The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.
“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”
The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.
Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.
Photo courtesy of the CDC
New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.
Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.
One in 3 Japanese patients in this study carried the variations.
And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.
Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.
In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.
With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.
In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.
“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.
The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.
“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”
The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.
Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.