In the fight against childhood leukemia, small variables can have big effects in the successful outcomes for patients’ lives. This is most apparent in the
latest findings by researchers at St. Jude Children's Research Hospital, who described four genetic mutations that affect chemotherapy intolerance in acute leukemia. The discovery could set the stage for genetics-oriented, personalized chemotherapy doses for leukemia patients in the future.
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer, and involves the overproduction of immature white blood cells in the bone marrow. These cancerous cells invade the blood and other organ systems, causing massive cell death and damage in a short amount of time.
Mercaptopurines, anti-cancer medications under the class of thiopurines, are widely used in the effective treatment of ALL. However, due to toxicity, some patients cannot tolerate full doses of the drug. This limits the efficacy of the treatment and reduces the chances for positive outcomes.
To find the genetic cause of mercaptopurine intolerance, researchers from St. Jude led an international effort to conduct a genome wide association study of 270 children with ALL. They found that four mutations in the
NUDT15 gene were significantly associated with mercaptopurine intolerance. Patients who carry one or more variations in
NUDT15 were more sensitive to mercaptopurine toxicity and required at least a 50% reduction in the dose of the chemotherapeutic agent.
The
NUDT15 gene makes nucleoside diphosphate, an enzyme that’s important in metabolizing thiopurines and reducing the amount of toxicity of the drug. The four high-risk mutations in this gene reduce
NUDT15 function by 74.4 to 100%. This significant loss in function of the enzyme causes a toxic build-up of the chemo drug and triggers excessive cell death.
Mutations in this gene are more common in patients of East Asian and Hispanic ancestry, and less common in those with European or African ancestry. These results corroborate nicely with previous clinical data showing that patients of Asian ancestry cannot tolerate the same high mercaptopurine doses as used in the US or Europe.
Earlier last year, the research team published similar findings in another gene,
TPMT, wherein genetic variants also increased sensitivity for thiopurines toxicity. From that study, doctors now do routine testing for
TPMT variants and adjust the thiopurines doses based on the patient’s genetic profile. The current study is heading in the same forward direction. “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," said Jun J. Yang, senior study leader, and associate member of the St. Jude Department of Pharmaceutical Sciences.
Based on this work, ALL patients could be screened for high-risk genetic variants in the
NUDT15 gene. A genetic profile could then guide doctors to determining the optimal dose of thiopurines that has the highest anti-cancer effects at the lowest toxicity to healthy cells. Formulating the optimal drug doses for each variant will be the crucial next steps. Meanwhile, this personalized chemotherapy also has the potential to be expanded to include inflammatory diseases, like ulcerative colitis and Crohn's disease, for which thiopurines are often prescribed.
"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,” said Ching Hon-Pui, co-author and chair of the St. Jude Department of Oncology.
Additional source:
St. Jude press release
