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Inherited gene variant increases neuropathy risk in children with ALL
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Children with acute lymphoblastic leukemia who had an inherited polymorphism in the promoter region of CEP72 demonstrated a greater risk for vincristine-related peripheral neuropathy, according to study results.
The condition also appeared more severe in this subgroup of patients, results showed.
Because cure rates for childhood ALL exceed 85%, efforts must be made to minimize treatment toxicities — including vincristine-induced peripheral neuropathy (VIPN) — that can reduce quality of life, according to study background.
William E. Evans, PharmD, of the hematological malignancies program in the department of pharmaceutical sciences at St. Jude Children’s Research Hospital, and colleagues conducted their study to assess whether specific genetic germline variants are associated with incidence or severity of VIPN in pediatric patients with ALL.
William E. Evans
The researchers performed a genome-wide association study of patients involved in one of two prospective clinical trials for childhood ALL. In both trials —St. Jude Total XIIIB and Children’s Oncology Group AALL0433 — participants underwent treatment with 36 to 39 doses of vincristine.
The analysis included 222 patients (median age, 6 years; range, 0.1-18.8) from the St. Jude trial and 99 patients (mediate age, 11.4 years; range, 3-23.8) from the COG trial.
All participants received peripheral neuropathy assessments based on NCI criteria, with incidence graded as mild (grade 1), moderate (grade 2), serious or disabling (grade 3) or life-threatening (grade 4).
About one-quarter (26.8%) of the overall study population developed grade 2 to grade 4 VIPN.
Researchers observed a significant association between a single nucleotide polymorphism in the promoter region of the CEP72 gene and VIPN (P = 6.3x10-9). This SNP had a minor allele frequency of 37%, and 16% of patients (95% CI, 11.6-19.5) were homozygous for the risk allele (TT at rs924607).
Twenty-eight of 50 (56%; 95% CI, 16.9-26.7) patients with the high-risk CEP72 genotype (TT at rs924607) experienced at least one case of grade 2 to grade 4 neuropathy, compared with 21.4% (95% CI, 16.9-26.7) of patients with CEP72 CC or CT genotypes.
“We discovered that an inherited variant of the CEP72 gene was associated with a higher risk and greater severity of vincristine neuropathy in two groups of children with ALL,” Evans told HemOnc Today. “Those children who inherited two copies of the high-risk CEP72 gene had a significantly higher likelihood — about 3.5-fold — of developing vincristine neuropathy and had a more severe form of neuropathy (about 2.5-fold higher severity).”
Results also showed leukemia cells from patients who inherited two copies of the CEP72 risk allele were more sensitive to vincristine, Evans said.
“[This suggests] it may be possible to treat these patients with a lower dose of vincristine to reduce their neuropathy without compromising the treatment of their leukemia — a possibility we plan to test in our next clinical trial at St. Jude,” Evans said.
The results of subsequent investigations could have considerable implications.
“If future studies show that these patients can be safely treated with a lower dosage of vincristine, we may be able to personalize treatment to reduce this toxicity without compromising the anticancer effects of vincristine, as we now do routinely for mercaptopurine using TPMT genotype,” Evans said. “It will also be important to extend these studies to adults and to children with other cancers.”
Despite the findings, it remains unclear whether vincristine can be removed from treatment options for children with CEP72 variants, Howard L. McLeod, PharmD, senior member of the DeBartolo Family Personalized Medicine Institute at Moffitt Cancer Center, wrote in an accompanying editorial.
Also, no other treatments “reproducibly modulate the incidence or severity” in patients with genetic predispositions to VIPN, McLeod wrote.
“As with many factors associated with severe toxicity, it will be difficult to conduct a prospective study in which preemptive interventions are performed,” McLeod wrote. “It is also unclear if CEP72 variants also are associated with VIPN in treatment of adult ALL, lymphomas and solid tumors.
“However, there is value in the association of CEP72 with VIPN,” he added. “The ability to 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. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.” – by Anthony SanFilippo
For more information:
William Evans, PharmD, can be reached at Pharmaceutical Sciences, MS 313, Room I-5108, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; email: william.evans@st.jude.org.
Disclosure: The researchers report no relevant financial disclosures. McLeod reports stock options for Cancer Genetics Inc.
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