Gene variant increases risk and severity of nerve disorder linked to vincristine

Children with acute lymphoblastic leukemia who had a certain gene variant experienced a higher incidence and severity of peripheral neuropathy after receiving treatment with the cancer drug vincristine, according to a study in JAMA (2015; doi:10.1001/jama.2015.0894).

Cancer remains the leading cause of death by disease in US children despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and as cure rates have surpassed 85%, it becomes increasingly important to lessen the toxicities of treatment that adversely affect quality of life and longevity.

Vincristine is one of the most widely used and effective anticancer agents for treating leukemias in both adults and children. The dose-limiting toxic effect of vincristine is peripheral neuropathy (damage to the nerves), characterized by neuropathic (nerve) pain and impaired manual dexterity, balance, and altered gait. Currently, there are no reliable means of identifying patients at high risk of vincristine­induced neuropathy or strategies to reduce this drug toxicity.

William E. Evans, PharmD, of St. Jude Children's Research Hospital in Memphis, Tennessee, and colleagues performed a genome-wide association study to determine whether there are genetic variants associated with vincristine-induced neuropathy. The study included patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine.

Genetic analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years) enrolled in 1994-1998 in a St. Jude Children's Research Hospital cohort; and 99 patients (median age, 11.4 years) enrolled in 2007-2010 in a Children's Oncology Group (COG) cohort.

Grade 2 (moderate) to 4 (life threatening) vincristine-induced neuropathy during therapy occurred in 28.8% of patients (64/222) in the St. Jude cohort and in 22.2% (22/99) in the COG cohort.

The researchers found that an inherited variant in the gene CEP72 was associated with a higher incidence and severity of vincristine-related peripheral neuropathy in children with ALL. Among patients with the gene variant, 28 of 50 (56%) developed at least one episode of grade 2 to 4 neuropathy, compared with 21% (58/271) of other patients.

“If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent,” the authors wrote.

”It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect,” said Howard L. McLeod, PharmD, of the Moffitt Cancer Center in Tampa, Florida in an accompanying editorial (doi:10.1001/jama.2015.1086).

 “However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). 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,” stated McLeod.

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