A gene variant linked to peripheral neuropathy (peripheral nerve damage) increases the risk of severe forms of this toxicity after treatment with the chemotherapy drug vincristine, a cytotoxic agent used as leukemia therapy for adults and children. Children with acute lymphoblastic leukemia (ALL) who expressed a variant of the CEP72 gene had an increased risk of severe vincristine-induced peripheral neuropathy, according to a study published in the Journal of the American Medical Association.
Compared to patients who carried one or no copy of this gene variant, those who had two copies of the variant had about 2.4-fold more severe neuropathy (P < .001). Furthermore, those who had two copies of the variant were about 3.5-fold more likely to develop neuropathy.
The work, if validated, suggests that those patients who harbor two copies of this risk variant, may be able to receive a safer dose of vincristine to mitigate the peripheral neuropathy.
To determine whether any genetic variants are associated with neuropathy following treatment with vincristine, William E. Evans, Pharm.D., of St. Jude Children’s Research Hospital in Memphis, and colleagues performed a genome-wide association study of patients included in two prospective clinical trials of childhood ALL. Children in these trials were treated with 36 to 39 doses of vincristine. The analysis included 321 patients: 222 with a median age of 6 who took part in a trial at St. Jude Children’s Research Hospital between 1994 and 1998, and 99 patients with a median age of 11.4 years who were part of a Children’s Oncology Group (COG) trial between 2007 and 2010. These patients were treated with a 1.5 or 2.0 mg/m2 dose of vincristine.
The variant is an inherited polymorphism in the promoter region of the CEP72 gene. The CEP72 gene encodes a centrosomal protein that functions during microtubule formation. Vincristine inhibits formation of microtubules which results in cell death. About one-quarter of patients who are treated with this chemotherapy develop peripheral neuropathy.
With a cure rate for childhood ALL over 85%, researchers are attempting to better mitigate both short- and long-term toxicities for these patients that affect quality of life and long-term health.
Peripheral neuropathy is one of the dose-limiting toxicities of vincristine. Neuropathy can lead to numbness, pain, loss of sensation in the arms and legs, and can also lead to issues with manual dexterity and balance. This toxicity can lead to disruption of treatment that is potentially curative.
Fifty of the 321 (16%) patients carried two copies of this risk allele. Among those patients with the high-risk allele, 56% (28 of 50) had at least one episode of grade 2 to grade 4 neuropathy--greater than the 21.4% rate (58 of 271 patients) of this adverse event among patients who had one or no copies of the allele (P = 2.4×10−6).
The higher risk allele results in lower expression of the CEP72 protein. In laboratory experiments providing support for the association observed in the genomics analysis, neurons with lower expression levels of CEP72 were much more sensitive to vincristine as were human ALL cell lines. Additionally, the researchers showed that leukemia cells from newly diagnosed ALL patients with two copies of the risk allele were also more sensitive to vincristine compared to cells expressing one or no risk allele copy (P = .02).
“Because our data suggest that the leukemia cells of patients who are homozygous for the CEP72 risk allele are more sensitive to vincristine, it maybe possible to treat these patients with a lower dose of vincristine to decrease the risk or severity of neuropathy without compromising the antileukemic effects of vincristine, a possibility that merits assessment in future clinical trials,” stated the authors in their discussion.
These results still need to be validated in a larger cohort.