A previously unknown variant of a gene called CEP72 has been linked to increased risk and severity of vincristine-induced peripheral neuropathy (VIPN) in children with acute lymphoblastic leukemia (ALL). The study was published onlineFebruary 24 in the Journal of the American Medical Association.
"Those children who inherited two copies of the high-risk CEP72gene had about 3.5-fold likelihood of developing vincristine neuropathy, and had a more severe form of neuropathy,” commented lead author William Evans, PharmD, of St. Jude Children's Research Hospital, Memphis, Tennessee.
"If reproduced, this finding may lead to a diagnostic test to identify those patients at highest risk of vincristine-induced neuropathy," Dr Evans told Medscape Medical News.
The study also found that children with two copies of the variant were more sensitive to vincristine.
"If future studies confirm this finding, it may be possible to treat those patients with the high-risk CEP72 genotype with a lower dosage of vincristine to reduce this toxicity without compromising the anticancer effects of vincristine," Dr Evans explained.
"As we advance cure rates beyond 85% for children with ALL, the most common cancer in children, it is important to focus on improving quality of life," Dr Evans pointed out. “Reducing treatment toxicities is important because some side effects can persist for decades after treatment is completed, compromising quality of life and, potentially, longevity."
Every child with ALL receives vincristine about 30 to 40 times during 2 or more years of treatment, he continued. About 25% of patients who receive vincristine develop VIPN, which can cause loss of sensation, numbness, pain, and problems with motor skills. VIPN also limits vincristine dosage and can potentially disrupt therapy.
Vincristine interferes with microtubule formation, ultimately causing cell death. Normally, the CEP72 gene codes for a protein essential for microtubule formation, Dr Evans explained. The high-risk variant of CEP72 is associated with lower expression of the CEP72 protein. This increases cell sensitivity to vincristine, causing greater cell damage, he continued.
Genome-Wide Study
Dr Evans and colleagues carried out a genome-wide association study in 321 children from two separate cohorts.
The study included 222 children (median age, 6.0 years) with newly diagnosed ALL who had enrolled between 1994-1998 in a St. Jude Children's Research Hospital clinical trial (with follow-up through January 2001).
The genome study also included 99 children (median age, 11.4 years) with relapsed ALL who had enrolled between January 2007-2010 in a Children's Oncology Group (COG) trial (with follow-up through May 2011).
Both patient cohorts received from 36 to 39 doses of vincristine, at doses up to 2.0 mg/m2.
Researchers assessed VIPN clinically using National Cancer Institute criteria.
Results showed that 50 of 321 children (16%) were homozygous for the high-risk variant. Of these, 56% (28 of 50) developed at least one episode of grade 2 to 4 VIPN, compared with 21.4% (58 of 271; P = 2.4 x 10-6) with low-risk genotypes.
Children with the high-risk variant were between 2.4 and 4 times more likely to develop VIPN (St. Judes' OR: 2.43 ; COG OR: 4.1). They also experienced from 2.4- to 2.7-fold greater severity of VIPN, compared with those with low-risk genotypes.
Laboratory studies in human neurons and leukemia cells revealed that decreasing CEP72 gene expression resulted in increased sensitivity to vincristine.
Genetic analyses showed that the frequency of the high-risk variant was lower among children of African ancestry. This is "consistent" with the clinical observation of a lower incidence of VIPN in African Americans, according to the authors.
Searching for the "Sweet Spot"
In a linked editorial, Howard L. McLeod, PharmD, of the Moffitt Cancer Center, in Tampa, Florida, emphasized that these results could enhance personalized medicine for children treated with vincristine, and perhaps even for adults. Currently, much of the research on biomarkers has focused on more recent drugs and on improving benefit rather than reducing toxicity.
"Both vincristine and peripheral neuropathy have been underevaluated," Dr McLeod commented to Medscape Medical News. "One of the main points [of this study] is that old drugs need to have the same rigorous assessment for biomarkers as the new drugs."
"Currently, there's no sugar daddy for the old drugs. Drug companies or NIH will pay to find biomarkers for a new drug, but vincristine? It's as old as Harold Varmus (the 75-year-old Nobel laureate who is the current director of the National Cancer Institute)," he commented. "So it's a neglected area. These drugs work, and they could probably work better."
"It would be an advance if we could use the full dose of vincristine to get the best effect," he added. "There's nothing worse than having therapy that's successfully working, and then having to stop it because of neuropathy."
Although this approach may not be ready for "prime time," Dr McLeod anticipates a brighter future.
"I'm hopeful that the other large clinical trials in the UK, Germany, etc, will ask, Is this genetic variant relevant in their large data sets?" he emphasized. "Other studies should be done to identify inhibitors or modulators of this gene. If there's a 'sweet spot' where we could protect the nerves and not diminish the antileukemia effect, that would provide a change to therapy."
The authors report no relevant financial relationships. Dr McLeod reports having stock options from Cancer Genetics Inc.
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