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Gene Variant Linked to Peripheral Neuropathy Caused By Common Chemo Drug for Pediatric Leukemia

ARTICLE IN BRIEF

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THE RESEARCH TEAM included (left to right) Kristine R. Crews, PharmD; Barthelemy Diouf, PhD; and William E. Evans, PharmD.

A specific genetic variant was found to increase both the incidence and severity of peripheral neuropathy as a side effect of the widely used chemotherapy drug vincristine in children treated for acute lymphoblastic leukemia.

Researchers have identified a specific inherited variant in the promoter region of the CEP72 (centrosomal protein 72kDA) gene that may increase both the incidence and severity of peripheral neuropathy as a side effect of the widely used chemotherapy drug vincristine in children treated for acute lymphoblastic leukemia (ALL).

The trial included 222 pediatric patients enrolled in the St. Jude Total XIIIB clinical trial between 1994 and 1998, and 99 children and adolescents enrolled in a Children's Oncology Group (COG) study on ALL relapse.

In 321 pediatric ALL patients, 50, or 16 percent, had inherited two copies of the high-risk variant in the CEP72 gene (TT at rs924607).

Twenty-eight of 50 (56 percent) of the children who had inherited both alleles of the high-risk CEP72 genotype developed at least one episode of grade 2 (moderate), grade 3 (serious/disabling) or grade 4 (life-threatening) symptoms of peripheral neuropathy (95% CI, 41.2%-70.0%). In comparison, only 58 of 271 patients (21.4 percent) of the children who had the CEP72 CC or CT genotypes developed comparable episodes of peripheral neuropathy (95% CI, 16.9%-26.7%).

The children with two copies of the high-risk CEP72 genotype had a 2.7-fold greater risk for vincristine-induced peripheral neuropathy than those who had not inherited both high-risk alleles, the study authors said.

The findings may not only help better identify at-risk children, but doctors may be able to decrease the dose of the drug without sacrificing its efficacy, according to corresponding author William E. Evans, PharmD, of St. Jude Children's Research Hospital in Memphis, TN.

“Laboratory experiments in leukemia cells and neurons derived from pluripotent stem cells demonstrated that lower CEP72 expression from the variant increases cellular sensitivity to the cancer-fighting properties of vincristine,” he told Neurology Today. “This suggests that it might be possible to lower the vincristine dose without compromising the likelihood of cure in these patients.”

Vincristine, approved in 1963, is one of the most commonly used and most effective drugs for treating leukemia, lymphoma, and brain and solid tumors in both children and adults. However, an estimated 25 percent of treated patients develop peripheral neuropathy and must often reduce or discontinue treatment. And while severe peripheral neuropathy can delay or otherwise compromise the likelihood of a cure in such patients, there has been no way to identify those most likely to develop peripheral nerve damage, said Dr. Evans.

A clinical trial in newly diagnosed pediatric ALL patients will begin later this year at the hospital, as will two other studies, one of which will examine the possible role of the variant in adult survivors of ALL who develop peripheral neuropathy many years after exposure to vincristine. The other will seek to determine optimal dose reduction in children with the variant.

Dr. Evans said the investigators, in collaboration with a team at the University of Chicago, are awaiting approval from an institutional review board to to conduct a case-control analysis of the CEP72 variant in adults who did or did not develop vincristine-induced neuropathy.

STUDY METHODOLOGY

In the study, published in the Feb. 24 issue of the Journal of the American Medical Association, genome scans for one million common genetic variants were performed for all children and adolescent patients, including those without vincristine-induced peripheral neuropathies (VIPN). Each of the subjects' treatment involved between 36 and 39 doses of the chemotherapy agent.

The laboratory studies were led by researcher Barthelemy Diouf, PhD. Kristine R. Crews, PharmD, was another important contributor, and investigators at a large number of other cancer hospitals also participated in the research.

“We are already getting a great response to our findings, and are excited about the upcoming clinical trials,” Dr. Evans told Neurology Today. “Peripheral neuropathy in these patients is the canary in the coal mine, in terms of vincristine's effects. We now know that something is wrong that makes some patients more vulnerable to neuropathies. Next we need to find out if we can prevent this toxicity without compromising cure rates by giving these high-risk patients lower doses, while also investigating the relationship of this variant in adult-onset peripheral neuropathy.”

EXPERTS COMMENT

In an accompanying editorial, Howard L. McLeod, PharmD, said the new study is another step toward the emergence of personalized medicine.

“Genetic variants, gene expression, and other patient factors allow for more objective selection of therapeutic regimens, individualized dosing of drugs, and the possibility of avoiding drug toxicity,” said Dr. McLeod, medical director of the DeBartolo Family Personalized Medicine Institute at the University of South Florida Moffitt Cancer Center in Tampa.

“As therapies begin to prolong life ... risk of toxicity takes on a greater degree of importance in care management,” he wrote. “Taking steps to avoid acute and chronic adverse drug reactions can guide choices among apparently equal treatment options, which is especially important in the context of effective therapy because active therapy can be compromised due to debilitating toxic effects, especially neurotoxicity.”

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DR. WILLIAM E. EVANS: “Laboratory experiments in leukemia cells and neurons derived from pluripotent stem cells demonstrated that lower CEP72 expression from the variant increases cellular sensitivity to the cancer-fighting properties of vincristine. This suggests that it might be possible to lower the vincristine dose without compromising the likelihood of cure in these patients.”

In cancer research, for example, efforts to minimize neurotoxic side effects of chemotherapy agents “have yet to produce a robust approach for managing this adverse drug event without negatively altering patient outcome,” he stated.

As with all translational research, an important challenge is how and when to adopt any new findings into clinical practice, according to Dr. McLeod.

“There are no current treatment options available that modulate the incidence or severity in a patient with a genetic predisposition for vincristine-induced peripheral neuropathy. As with many factors associated with severe toxicity, it will be difficult to conduct a prospective study in which preemptive interventions are performed. It is also unclear if CEP72 variants also are associated with VIPN in treatment of adult ALL, lymphomas, and solid tumors.”

However, there is value in the association between CEP72 and neuropathy, he said. “The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members.”

Cristian M. Ionita, MD, a clinical associate professor of neurology in the Division of Pediatric Neurology at Seattle Children's Hospital, has treated a number of children with vincristine-associated peripheral neuropathies.

“I am a neurologist, so I only see the tip of the iceberg — the most severe cases involving the weakest patients. But in every case, reducing the dose of the drug has resulted in functional gains, although many still experience some milder symptoms,” he told Neurology Today in a telephone interview.

He mentioned one of his cases, a young boy with very little muscle mass who responded well once his vincristine dose was reduced.

“He finished treatment and it has now been four or five years. The last time I saw him he was still in remission, and his neuropathy was manageable,” he said.

“I think if a child has this variant, their doctor might want to try a smaller dose of vincristine, although I am not sure whether or not this is contraindicated. The few kids I have seen, though, all improved with a lower dose. Vincristine was taken away for a few months, then started up again on the lower dose, and their peripheral neuropathy symptoms gradually abated. There was some permanent damage, but their functional ability improved significantly.”

It is important to understand the difference between milder peripheral neuropathy — without significant muscle weakness — and more advanced cases when it comes to functional impact on a child, he noted. The functional cost of peripheral neuropathy and quality of life for children with severe neuropathy must also be considered. The cost of genetic screening is not very high, considering the cost of chemotherapy, physical therapy, and related care to help improve muscle weakness. “I personally think it is worth the cost,” he said.

Sindhu Ramchandren, MD, a professor of neurology and director of the Pediatric and Adult CMT and MDA program at the University of Michigan in Ann Arbor, had a different view on the study findings, however.

“I think this study is extremely timely because it represents the divergence from the ‘one size fits all’ approach of most clinical trials. Too often we do not consider individual variability in treatment responses and risk variability,” she told Neurology Today in a telephone interview.

In a 2009 study published in the Journal of the Peripheral Nervous System, Dr. Ramchandren and colleagues found that most children treated with vincristine did not experience debilitating long-term neuropathy symptoms over time.

“We examined 37 ALL survivors between the ages of eight and 18 years of age two years after treatment,” she said. “Self-reported symptoms, standardized examinations, and nerve conduction studies showed that while 29 percent had abnormal nerve conduction results, most did not have subjective symptoms. Even though motor proficiency scores were lower than the norm, they did not correlate with motor function status or quality of life.”

Dr. Ramchandren also agreed with Dr. McLeod's editorial. “Taking vincristine out of children's chemotherapy regimen is really not an option because it is so effective,” she said. “I would be very reluctant to suggest that parents base treatment decisions on their child's variant status.

EXPERTS: ON A GENETIC VARIANT ASSOCIATED WITH PERIPHERAL NEUROPATHY IN ACUTE LYMPHOBLASTIC LEUKEMIA TREATMENT

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DR. CRISTIAN M. IONITA: “I am a neurologist, so I only see the tip of the iceberg — the most severe cases involving the weakest patients. But in every case, reducing the dose of the drug has resulted in functional gains, although many still experience some milder symptoms.”

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DR. SINDHU RAMCHANDREN: “Taking vincristine out of childrens chemotherapy regimen is really not an option because it is so effective. I would be very reluctant to suggest that parents base treatment decisions on their childs variant status.”

LINK UP FOR MORE INFORMATION:

•. Barthelemy D, Crews KR, Evans WE, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia http://jama.jamanetwork.com/article.aspx?articleid=2130318. JAMA 2015;313:815–823.
    •. McLeod HL. Precision medicine to improve the risk and benefit of cancer care genetic factors in vincristine-related neuropathy http://jama.jamanetwork.com/article.aspx?articleid=2130297. JAMA 2015;313:803–804.
      •. Renbarger JL, McCammack KC, Rouse CE, Hallm SD. Effect of race on vincristine-associated neurotoxicity in pediatric acute lymphoblastic leukemia patients http://onlinelibrary.wiley.com/doi/10.1002/pbc.21435/abstract. Pediatr Blood Cancer 2008;50:769–771.
        •. Ramchandren S, Leonard M, Mody RJ, et al. Peripheral neuropathy in survivors of childhood acute lymphoblastic leukemia http://onlinelibrary.wiley.com/doi/10.1111/j.1529-8027.2009.00230.x/abstract. J Periph Nerv Syst 2009;3:184–189.