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NUDT15 variant linked to mercaptopurine intolerance in pediatric ALL
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Children with acute lymphoblastic leukemia who harbored the novel NUDT15 variant received a lower average dose intensity of mercaptopurine, according to study results.
The findings suggest the NUDT15 variant may be a genetic predictor of mercaptopurine intolerance in these patients, researchers wrote.
“Mercaptopurine is highly effective in ALL and essential for the cure of this aggressive cancer,” researcher Jun J. Yang, PhD, associate member in the department of pharmaceutical sciences at St. Jude Children’s Research Hospital, told HemOnc Today. “However, it also has a narrow therapeutic index with common toxicities. Identifying genetic risk factors for mercaptopurine toxicity will help us better understand how this drug works and also potentially enable clinicians to individualize therapy based on patients’ genetic make-up.”
Jun J. Yang
Yang and colleagues evaluated data from 657 children with newly diagnosed ALL who were enrolled on a Children’s Oncology Group clinical trial designed to evaluate racial differences in exposure to mercaptopurine. Results of this trial showed that only East Asian ancestry was significantly associated with mercaptopurine dose intensity (P˂.001), and patients with greater East Asian ancestry tolerated lower dose intensities.
In the current analysis, researchers observed a previously reported finding that the rs1142345 loci in TPMT had a genome-wide significant association with mercaptopurine dose intensity. One patient was homozygous for this variant allele (CC genotype) and tolerated a dose intensity of 6%, compared with average dose intensities of 65.7% for patients with the CT genotype (n=39) and 83.5% for the wild-type TT genotype (n=617).
Yang and colleagues also found the nonsynonymous variant rs116855232 in NUDT15 was associated with dose intensity. Two patients with this TT genotype only tolerated 8.3% of the protocol standard dose of mercaptopurine, whereas patients with the TC genotype (n=31) had an average dose intensity of 63% and patients with wild-type genotype at this single-nucleotide polymorphism (n=624) had an average dose intensity of 83.5%.
The novel risk variant occurred most frequently in East Asian (9.8%) and Hispanic (3.9%) children. It occurred rarely in Europeans (0.2%) and was monomorphic in Africans.
“In addition to confirming the role of TPMT, we have identified another important genetic risk factor — a genetic variation in a gene called NUDT15 — for mercaptopurine intolerance,” Yang said. “Patients carrying the variant version of NUDT15 are exquisitely sensitive and required up to 90% reduction of the normal dose of this drug.”
The analysis included a validation cohort of 371 children with ALL enrolled on the St. Jude Total Therapy XV protocol. The rs116855232 loci in NUDT15 also was significantly associated with mercaptopurine dose intensity in this population (P=.024).
Researchers then evaluated the combined effects of TPMT and NUDT15 variants. All patients homozygous for either TPMT or NUDT15 risk variants (n=3) and those heterozygous for both TPMT or NUDT15 risk variants (n=4) were mercaptopurine intolerant, or required at least a 50% reduction from the protocol-planned dose.
“Research is ongoing in our laboratories to figure out exactly how NUDT15 is involved in mercaptopurine sensitivity, and also what the clinical action should be — if any — when a patient is found to carry the risk variant,” Yang said. “The long-term goal is to use these findings to improve chemotherapy safety and effectiveness.” –by Alexandra Todak
Jun J. Yang, PhD, can be reached at St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS313, Memphis, TN 38105; email: Jun.Yang@stjude.org
Disclosure: The researchers report research funding from Merck Sharpe & Dohme, as well as royalties on patents related to TMPT genotyping.
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