Gene Variant Associated with Ability to Tolerate Medication in Leukemia


Specific changes in certain genes confer the ability to tolerate the medicine mercaptopurine (MP) in the treatment of acute lymphoblastic leukemia (ALL). Ultimately, these genetic variances can help drive individualizing treatment so improve survival outcomes for children with ALL. These results were recently published in the Journal of Clinical Oncology.

Leukemia is a type of cancer that forms in the blood cells. There are several different types of leukemia; ALL is a fast-growing type of leukemia that requires aggressive treatment strategies.

A common and effective drug often used to treat ALL is MP. However, for some patients, this drug is difficult to tolerate as it causes side effects so severe that the doses must be reduced dramatically. Once doses are reduced, the effectiveness of the drug killing cancer cells is also decreased.

Researchers recently conducted a genome-wide association study (GWAS) to determine if any genetic variances correlated with differences in the ability to tolerate MP among patients with ALL.

The study included approximately 1,000 children from clinical trials. The dose-intensity of MP delivered to patients was recorded and associated genetic variances were determined.

Patients with a specific genetic variant in NUDT15 had a much greater intolerance to MP, compared to patients without the variant.
The NUDT15 variant was most common in East Asians and Hispanics, which perhaps aids in explaining race differences in outcomes of therapy.
Variants within specific genes identified patients who could only tolerate an average of 8.3% of the dose of MP, compared with up to 83.5% of the planned dose.
The researchers concluded that the “variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.”

Further studies are warranted as the way in which cancer treatment is progressing includes greater individualizing treatments.

Reference: Yang J, Landier W, Yang W, et al. Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia. Journal of Clinical Oncology. Published online before print January 26, 2015, doi:10.1200/JCO.2014.59.4671.