Association of an Inherited Genetic Variant With Vincristine-Related Peripheral Neuropathy in Children With Acute Lymphoblastic Leukemia

Abstract

Importance With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is compelling need to mitigate treatment toxicities that can compromise quality of life. Peripheral neuropathy is the major dose-limiting toxicity of the microtubule inhibitor vincristine, an anticancer agent given to every child with ALL. Objective Identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. Design, Setting and Participants All patients had been enrolled in one of two prospective clinical trials for childhood ALL that included treatment with 36–39 doses of vincristine. Genome-wide single nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in all patients from whom DNA was available (n=321 patients); 222 patients (median age at 6.0 years, range 0.1–18.8 years) enrolled between 1994–1998 on the St. Jude Children’s Research Hospital protocol Total XIIIB (St. Jude cohort) with toxicity followed through January 2001, and 99 patients (median age 11.4 years, range 3.0–23.8 years) enrolled between 2007–2010 on the Children’s Oncology Group protocol AALL0433 (COG cohort) with toxicity followed through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. Exposures Treatment with vincristine at a dosage of 1.5 or 2.0 mg/m2 as a component of protocol directed chemotherapy for childhood ALL. Main Outcomes and Measures Vincristine-induced peripheral neuropathy was assessed at each clinic visit using the National Cancer Institute Common Terminology Criteria for Adverse Events and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life-threatening (grade 4). Results Grade 2–4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (n=64 of 222) in the St. Jude cohort and in 22.2% of patients (n=22 of 99) in the COG 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 p =6.3 × 10−9). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%, 95% CI 11.6%–19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 patients (56%, 95% CI 41.2–70.0) developed at least one episode of grade 2–4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotype (58 of 271 patients; 21.4%, 95% CI 16.9–26.7); p=2.4×10−6. The severity (grade) of neuropathy was greater (2.4-fold by Poisson regression (p<0.0001), 2.7-fold based on mean grade of neuropathy (1.23 [95% CI 0.74 – 1.72] versus 0.45 [95% CI 0.3 – 0.6]; t test p=0.004)) in patients homozygous for the CEP72 risk allele (TT genotype), compared to patients with the CC or CT genotype. The CEP72 promoter SNP was show...

Inherited genetic variation in childhood acute lymphoblastic leukemia

“…In a genome-wide study, a higher frequency of neuropathy has been associated with a promoter variant in CEP72 (rs924607). 90 The frequency of the risk allele was lower in individuals with African ancestry compared with the other ancestral groups, consistent with a lower incidence of vincristine neuropathy in African American patients. 91 A candidate-gene study found that variants in ABCB1, ACTG1, and CAPG were associated with vincristine neurotoxicity during ALL therapy, 92 although other candidate-gene studies found no associations with ABCB1 variants, despite its likely role in vincristine transport.…”

How I treat acute lymphoblastic leukemia in older adolescents and young adults

“…CEP72 regulates the localization of centrosomal proteins and proper bipolar spindle formation, and knockdown in human ALL cells is associated with augmented vincristine effects. 71 Similarly, the risk of glucocorticoid-induced osteonecrosis in children with ALL is associated with single nucleotide polymorphisms in ACP1, which regulates osteoblast differentiation. 72 Although further study is needed, one could envision testing for these polymorphisms prior to treatment and adjusting doses based on individual results.…”

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

“…22 No protocols recommend discontinuation of vincristine except in cases of paralysis (occasionally caused by Charcot-Marie-Tooth disease), but several protocols recommend dose reduction in CTCAE grade 3-4 cases of paraesthesia or motor paralysis. This toxic eff ect is addressed by all treatment protocols with the CTCAE grading, except for one group applying the Balis scale.…”