JAMA: Vincristine peripheral neuropathy linked to CEP72 variability
Vincristine is a widely used cytotoxic agent for cancer treatment in adults and children. A significant portion of patients treated with vincristine experience dose-limiting neuropathies including pain, sensory, and motor dysfunction. As cure rates are rising for many types of cancers, it is important to identify factors that may affect patients’ risk for developing acute and chronic drug toxicities such as vincristine-induced neuropathies.
Diouf and colleagues conducted a genome-wide association study of individuals included in clinical trials for acute lymphoblastic leukemia (ALL) who were treated with vincristine. Among 222 children with ALL, researchers found that a single-nucleotide polymorphism (SNP) in the promoter region of CEP72 was linked with increased risk and severity of peripheral neuropathy associated with vincristine use.
Specifically, researchers noted, “Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the [Children’s Oncology Group] cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3×10−9).” In addition, 56% of patients (28 of 50) with the high-risk CEP72 genotype developed at least 1 episode of grade 2 to 4 neuropathy, which was significantly higher than the rate in patients with low-risk genotypes (21.4% [58 of 271]; P = 2.4×10−6). “Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine,” researchers wrote.
In an accompanying editorial, Howard L. McLeod, PharmD, 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.” In addition, Mcleod noted that availability of this information can inform discussion of relative “risks and benefits of [vincristine] therapy with patients and their family members.”
Diouf B et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313:815-23.
McLeod H. Precision medicine to improve the risk and benefit of cancer care: genetic factors in vincristine-related neuropathy [editorial]. JAMA. 2015;313:803-4.