Leukemia Cure Jeopardized by Drug Toxicity from Genetic Variations

Inherited genetic variations leave acute lymphoblastic leukemia patients sensitive to drugs and at risk for toxicity.

Potential curative treatments for pediatric leukemia may be in jeopardy as a result of severe drug toxicity determined by inherited genetic variations, a recent study found.

The study, published in Nature Genetics, focused on how inherited gene variations can lead to toxicity.

The clinical trials were performed at Unidad De Oncologia Pediatric in Guatemala, National University of Singapore, and the Japanese Pediatric Leukemia/Lymphoma Study Group. Researchers enrolled 270 children with acute lymphoblastic leukemia (ALL).

During the study, investigators focused on thiopurines, which is used as an anti-cancer and immunosuppressing drug.

The results of the study showed that 4 inherited variations in the NUDT15 gene alter thiopurine metabolism leaving patients sensitive to drugs and at risk for toxicity.

The NUDT15 gene reduces the supply of the active drug metabolite that leads to cell death by helping to balance thiopurine activity. This helps prevent excessive white blood cell death that increases the risk for infections and complications in patients.

The high risk NUDT15 variants cause a 74.4% to 100% loss of NUDT15 function, as well as a toxic buildup of the drug.

"This study is key to the development of more effective, personalized ALL therapy because it provides a clear explanation of how variations in the NUDT15 gene change drug metabolism and cause toxicity in patients," said Jun J. Yang, PhD, an associate member at St. Jude. "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."

Data also suggested that variations are common in Asian populations and in those with Hispanic ethnicity. In fact, 1 in 3 Japanese patients carried the high risk variations found in the current study.

In 2015, researchers published a different study that linked a NUDT15d variant most commonly found in patients with East Asian ancestry to reduced tolerance of mercaptopurine.

"While it was clinically recognized that patients of Asian ancestry often cannot tolerate mercaptopurine dosages commonly used in the US and Europe, the pharmacological basis was unknown," said study author Ching Hon-Pui, MD. "This exciting study breaks down a critical barrier to further tailoring the use of this important drug and will likely aid the implementation of precision medicine approaches to improve the quality of care in children with ALL."

In the 2015 study, the NUDT15 variants predicted enzyme activity and showed a tolerance to mercaptopurine. Also, in 285 children with newly diagnosed ALL, researchers found NUDT15 variants were more sensitive to thiopurines.

"That suggests we can screen for NUDT15 variants and potentially to plan mercaptopurine doses according to each patient's genotype before the therapy starts. This way, we hope to avoid toxicity without compromising treatment effectiveness," Yang said.

Although future studies are needed to determine the exact doses needed to be administered to patients with different NUDT15 variants, researchers are still exploring different variants in NUDT15 and other genes, which influences the safety and effectiveness of chemotherapy.