An inherited genetic mutation in the CEP72 gene appears to predispose carriers to develop peripheral neuropathy when they are treated with vincristine, according to a report published online Feb. 24 in JAMA.
The genetic variation, a single nucleotide polymorphism (SNP) in the T allele at rs924607 in the promoter region of the CEP72 gene, was identified in a genome-wide association study that analyzed DNA samples from 321 children with acute lymphoblastic leukemia who received standard vincristine therapy while participating in two prospective clinical trials. Carriers had both a higher incidence and a greater severity of vincristine-induced peripheral neuropathy than noncarriers. Moreover, the risk of neuropathy increased in a linear fashion as the number of copies of the risk allele increased, said Barthelemy Diouf, Pharm.D., Ph.D., of the hematological malignancies program in the department of pharmaceutical sciences, St. Jude’s Children’s Research Hospital, Memphis, and his associates.
Vincristine is one of the most frequently used and effective agents for treating leukemias, lymphomas, brain tumors, and solid tumors in both children and adults. If the findings of this preliminary study are replicated in future research, they “may provide a basis for safer dosing of this widely prescribed anticancer agent,” the investigators noted.
Vincristine-induced peripheral neuropathy is characterized by pain as well as sensory and motor dysfunction that causes extensive morbidity, including impaired manual dexterity, impaired balance and deep-tendon reflexes, and altered gait. At present there is no way to identify which patients will develop this toxicity and no strategy for mitigating it.
The disorder occurs at different rates in various races and is known to develop less frequently in African-Americans than in members of other racial groups.
To explore whether there might be a genetic basis for this discrepancy and to identify possible polymorphisms associated with the disorder, Dr. Diouf and his associates performed a genome-wide association study using germline DNA samples collected from children participating in two clinical trials. One cohort involved children with newly diagnosed ALL who were enrolled in 1994-1998 (222 patients); the other cohort involved children with relapsed ALL who were enrolled in 2007-2010 (99 patients). All the study participants were followed for toxic effects through 2011. Vincristine-induced peripheral neuropathy developed in 28.8% of the first cohort and 22.2% of the second.
The researchers found 5,051 typed SNPs and 10,195 imputed SNPs that occurred with some frequency in both study groups, but only rs924607 on the CEP72 gene on chromosome 5 was significantly related to the development of vincristine-induced peripheral neuropathy. In the first cohort, 20 of 32 patients (62%) with the TT genotype had at least one episode of the disorder, as did 8 of 18 patients (44%) in the second cohort. Fewer patients with the CC or CT genotypes (21%) did so, indicating a dose-response relationship between the number of copies of the risk allele and the likelihood of developing vincristine-induced neuropathy.
In this analysis of the data, the alleic odds ratios for the development of neuropathy among rs924607 carriers were 2.43 in the first cohort and 4.1 in the second, the investigators reported (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0894]).
Another analysis showed that the cumulative incidence of all neuropathy episodes differed significantly by CEP72 genotype in both study cohorts. Similarly, the cumulative incidence of severe neuropathy episodes also was significantly higher in patients homozygous for the CEP72 risk allele. Approximately 55% of patients with the TT genotype developed grade 2-4 neuropathy, compared with only 20% of those with the CC or CT genotype.
In addition, the median time to the first episode of neuropathy was significantly shorter in carriers than in noncarriers of the CEP72 polymorphism. The average time was 225 days in patients with the TT genotype, compared with 307 days in those with the CT or CC genotype. The grade (severity) of neuropathy also correlated with the number of copies of the risk allele patients carried: It was nearly three times higher in patients with the TT genotype and 1.5 times higher in those with the CT or CC genotypes than in noncarriers.
African-American patients were less likely to carry the CEP72 polymorphism than were other racial groups, which is consistent with their lower incidence of vincristine-induced neuropathy, Dr. Diouf and his associates said.
If these findings are verified in other patient populations, it could lead to a new approach for identifying patients who are susceptible to vincristine-induced neuropathy. As important, the data also suggest that the leukemia cells of patients who are homozygous for the CEP72 risk allele are more sensitive to vincristine than are the leukemia cells of other patients. If that is confirmed, “it may be 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” the drug, they added.