Pharmacogenomics of Vincristine‐Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

Abstract

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN.

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations

“…Interestingly, the frequencies of both of the above-mentioned lead SNPs, rs4427239 and rs55898176, were substantially lower in the Swiss MIN cases compared to MIA cases and similar to the frequencies observed in controls (Supplementary Table S6). The allele frequencies of these SNPs in the MIN cases thus did not follow an intermediate distribution between the frequencies in the MIA cases and the controls, as has been observed for genetic associations with other adverse drug reactions for cases with intermediate severity [87]. If these signals indeed represent true causal associations, a potential underlying mechanism involving the intergenic locus on chromosome 9, or the SVEP1 locus in agranulocytosis may not apply to metamizole-induced neutropenia.…”

Analyses of Adverse Drug Reactions–Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database

“…The CPNDS is composed of clinicians in many disciplines, including clinicians with expertise in areas such as clinical pharmacology, pediatric oncology, audiology, and medical genetics and researchers with expertise in several disciplines including genomics, computer science, molecular biology, statistics, economics, and pharmacology. The multidisciplinary nature of the team has led to clinically prioritized questions and achievable research projects, [8][9][10][11][12][13][14][15][16][17][18][19][20][27][28][29][30] including recently published studies on pharmacogenomics biomarkers of interferon-β-induced hepatic toxicity 28 and vincristineinduced peripheral neuropathy 29 (Table 4). Looking toward the future, the CPNDS aims to expand the number of ADRs targeted for pharmacogenomic analyses and to work together with researchers worldwide for the replication of pharmacogenomic findings in independent patient cohorts.…”

Optimizing the use of the hyperCVAD regimen: Clinical vignettes and practical management

“…In addition to MTX serum level monitoring, serum creatinine and urine output should be evaluated daily. If patients experience increased MTX levels or delayed clearance, the leucovorin dose and/or frequency should be increased based on an established nomogram . Care should be taken to confirm MTX clearance and adequate renal function (serum creatinine <1.5 mg/dL) before starting HDAC to avoid serious toxicity.…”

“…A genetic polymorphism in the promoter region of the CEP72 gene has been associated with increased sensitivity to vincristine. 9 Pediatric patients homozygous for the risk allele (TT) at SNP rs924607 experienced greater cumulative incidence (61% vs 23%; P < .001) and a 2.7-fold higher median grade of vincristine-induced PN compared with those with the CC or CT genotypes. 10 Among adult patients with the CEP72 TT genotype, 75% developed PN compared with 44% with the CT or CC genotypes (P = .02).…”

“…If patients experience increased MTX levels or delayed clearance, the leucovorin dose and/or frequency should be increased based on an established nomogram. 9 Care should be taken to confirm MTX clearance and adequate renal function (serum creatinine <1.5 mg/dL) before starting HDAC to avoid serious toxicity. Renal impairment increases the risk of cerebellar neurotoxicity with HDAC due to the impaired clearance of the neurotoxic metabolite Ara-UTP.…”