Gene Variant Linked to Vincristine Neurotoxicity in Paediatric ALL

Microtubule-related gene predicts neurotoxicity in children given vincristine during acute lymphoblastic leukaemia treatment

medwireNews: Researchers have identified a single nucleotide Polymorphism (SNP) variant that is significantly associated with the likelihood and severity of vincristine-induced peripheral neuropathy (VIPN) in paediatric patients with acute lymphoblastic leukaemia (ALL).

CEP72 encodes a centrosomal protein essential for microtubule formulation, the target process of vincristine, explain William Evans, from St Jude Children’s Research Hospital in Memphis, Tennessee, USA, and co-workers.

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

The genome-wide analysis was performed on DNA samples from two studies of 222 patients aged a median of 6.0 years and 99 patients aged a median of 11.4 years. All patients received between 36 and 39 doses of vincristine 1.5 or 2.0 mg/m2.

Children homozygous for the T risk Allele of the CEP72 gene were significantly more likely to experience at least one episode of grade 2 to 4 neuropathy than those carrying the CC or CT Genotype, at 56.0% versus 21.4%.

Patients with the CEP72 TT genotype also had, on average, a 2.7-fold higher grade of neuropathy than those with the CC or CT genotypes, at 1.23 versus 0.45, as well as a shorter time to grade 2 to 4 neuropathy, at an average of 225 versus 307 days.

The risk T allele was significantly less common in African–American patients than in those of other ethnicities, “consistent with the reported lower incidence of vincristine-induced neuropathy in black patients”, Evans et al observe.

Laboratory analysis demonstrated that sensitivity to vincristine in stem cell-derived neurons and human ALL cell lines increased with reduced expression of CEP72. And primary leukaemia cell lines created from newly diagnosed ALL patients who were homozygous for the risk T allele were significantly more sensitive to vincristine than those created from CT or CC patients.

Howard McLeod, from Moffitt Cancer Center in Tampa, Florida, USA, suggests in an accompanying editorial that while vincristine may be unavoidable in paediatric leukaemia treatment, this increased sensitivity may make dose reduction possible without compromising efficacy.

He acknowledges that it is yet unclear whether CEP72 is associated with VIPN in adult ALL, or in the treatment of lymphomas or solid tumours.

Nevertheless, Howard McLeod suggests: “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.

“This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN.”

References

Diouf B, Crews KR, Lew G, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphboblastic leukemia. JAMA 2015; 313(8): 815–823. doi:10.1001/jama.2015.0894

McLeod HL. Precision medicine to improve the risk and benefit of cancer care. Genetic factors in vincristine-related neuropathy. JAMA 2015; 313(8): 803–804. doi:10.1001/jama.2015.1086

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