Vincristine is neurotoxic and causes VIPN; the damaged nerve fibers send incorrect signals to the pain center, resulting in neuropathic pain [20–22]. There are three main clinical manifestations of VIPN: peripheral nerve injury, autonomic nerve symptoms, and cranial nerve symptoms. The chief manifestations of peripheral nerve injury are extremity weakness and movement limitation, including clawing hand and walking difficulty, and some severe cases may even lead to paralysis [23]. Peripheral nerve injury can also manifest as shallow sensory abnormalities and neuralgia, such as needling, burning, and numbness. In addition, autonomic nerve injury can manifest as abdominal pain, constipation, and intestinal stasis. In severe cases, paralytic intestinal obstruction has been reported [24]. Finally, the primary manifestations of cranial nerve injury are tinnitus, drooping eyelids, diplopia, jaw pain, temporary blindness, facial paralysis, and hoarseness [25–27].
The risk of VIPN may vary in different populations [6]. The overall risk of VIPN may be affected by the treatment regimen, single dose of vincristine, frequency of vincristine use, ethnicity, combination of drugs, genes, and other factors. It has been reported that the incidence of VIPN in children is 20.8–98% [28], and the incidence of VIPN in the 74 children in this study is 58.1%, which is consistent with the relevant literature. In view of the high incidence of VIPN in children with ALL, clinicians should pay close attention to the occurrence of VIPN, and timely and accurate treatment should be given to reduce the impact of VIPN on children and their quality of life.
The CEP72 gene, which encodes a centrosomal protein, includes two alleles at rs924607: T and C. The CEP72 variant (T allele at rs924607) is a transcription repressor in the promoter region of the NKX63 binding site, which leads to the decreased expression of CEP72 mRNA. The decreased mRNA level also leads to the decreased expression of CEP72 in human nerve cells or leukemia cells. Thus, the CEP72 variant increases a patient’s sensitivity to vincristine [13, 17]. Diouf et al. and Stock et al. found that genetic polymorphisms in the CEP72 rs924607 gene were associated with an increased risk of VIPN in leukemia. Both studies show that children with the CEP72 TT genotype had an increased risk of VIPN compared to children with the CEP72 CC /CT genotype [13, 17]. However, the studies of Gutierrez-Camino et al. and Zgheib et al. did not find that the TT genotype of CEP72 was related to the occurrence of VIPN [14, 16]. The results of this study showed that the genetic polymorphism of CEP72rs924607 is associated with the occurrence of VIPN; that is, the T allele is a risk gene for VIPN. With the increase of the risk allele, the incidence of VIPN in children with ALL increases. Our results are consistent with the conclusion that the CEP72 rs924607 gene polymorphism is correlated with the occurrence of VIPN by Diouf et al. and Stock et al. but not consistent with the study results of Gutierrez-Camino et al. and Zgheib et al. Both Diouf et al. and Stock et al. conducted prospective studies on American subjects, while Gutierrez-Camino et al. conducted a retrospective study on Spanish subjects, and Zgheib et al. conducted a retrospective study on Saudi Arabian subjects. The variation in research results may be due to differences in ethnicities, research methods and chemotherapy methods. It is possible that the CEP72 rs924607 gene polymorphism in Asian and North American populations has the same effect on the incidence of VIPN, but more studies with a large sample size are needed to confirm this idea. This may be a suitable direction for future research.
Furthermore, this study found that the polymorphism of the CEP72 rs924607 gene had no statistical significance in the severity of VIPN, which is inconsistent with the study of Diouf et al. in 2015 [13]. Studies have shown that the severity of VIPN varies by race, with white people having a higher risk and severity of VIPN than African Americans, but a higher survival rate [29]. The conclusion of this study is inconsistent with the study of Diouf et al. because the chemotherapy regimen and the study population are different. Additionally, the sample size of this study is small, and differences between ethnicities cannot be excluded.
Thus, in terms of VIPN type, peripheral nerve injury had the highest incidence and cranial nerve injury had the lowest, which is consistent with the fact that peripheral nerve injury is the most common neurotoxic manifestation mentioned in the Chinese Expert Consensus on Vinblastine in the Treatment of Malignant Lymphoma [24]. In this study, no correlation was found between the CEP72rs924607 gene polymorphism and VIPN type. Previous studies have not found a relationship between the gene polymorphism of CEP72rs924607 and VIPN type. The reason for the lack of a relationship between gene polymorphism of CEP72rs924607 and VIPN type may be because the T risk allele affects cell sensitivity to vincristine. However, this sensitivity may only affect the occurrence of VIPN but not the type of VIPN.
VIPN is a toxic side effect of vincristine in the treatment of ALL, resulting in a decreased quality of life. Common treatment methods include fasting, gastrointestinal decompression, nutritional support, enemas, and lactulose defecation, which are further combined with the use of B vitamins and other nutritional supplements. Due to the individual differences, after drug withdrawal and treatment, neurotoxic adverse reactions usually last for a long time and gradually disappear, taking several months at most, but a small portion of them persist [24]. The treatment methods of VIPN in this research center included observation, use of neurotrophic drugs (such as mecobalamine), analgesics (such as ibuprofen), enemas (such as ceramide and lactilose), and other (such as fasting and protection of the stomach). No death or residual peripheral neuropathy was found, and the prognosis of VIPN was generally good.
Finally, this research studied the relationship between VIPN and the CEP72 rs924607 gene in ALL patients. Limitations of the study included a small sample size and small number of patients with homozygous CEP72 risk alleles. At the same time, it is inevitable that some children with subclinical neuropathy will be omitted during the evaluation process, and the grade of some patients with mild neuropathy may be underestimated. In future clinical studies, we will make improvements through the following methods. First, we will start prospective follow-up of patients at the time of ALL diagnosis and conduct timely and effective tracking and recording. Second, we will evaluate peripheral neuropathy using instrumental measurement and a joint assessment scale, which will make the phenotyping and classification of peripheral neuropathy more accurate. and make the study more rigorous.