Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor

Abstract

Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR’s clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient’s quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into individualized therapies. In this review, we discussed the potential associations between genetic variants in genes contributing to the pharmacokinetics/pharmacodynamics of VCR and VIPN incidence and severity in patients with acute lymphoblastic leukemia. Of note, genetic variants in the CEP72 gene have great potential to be translated into clinical practice. Such a genetic biomarker may help clinicians diagnose VIPN earlier. Besides, genetic variants in other genes, such as CYP3A5, ABCB1, ABCC1, ABCC2, TTPA, ACTG1, CAPG, SYNE2, SLC5A7, COCH, and MRPL47, have been reported to be associated with the VIPN, but more evidence is needed to validate the findings in the future. In fact, a variety of complex factors jointly determine the VIPN. In implementing precision medicine, the combination of genetic, environmental, and personal variables, along with therapeutic drug monitoring, will allow for a better understanding of the mechanisms of VIPN, improving the effectiveness of VCR treatment, reducing adverse reactions, and improving patients’ quality of life.

Vincristine Side Effects With Concomitant Fluconazole Use During Induction Chemotherapy in Pediatric Acute Lymphoblastic Leukemia

“…Disparate results currently exist as to whether fluconazole increases the rates of vincristine-associated neuropathy. However, older age has been identified by some studies as a risk factor for the development of neuropathy in patients receiving both vincristine and fluconazole 17,18 . The results of our study add to the growing body of literature supporting the idea that advanced age does increase the risk of developing vincristine-induced peripheral neuropathy (VIPN).…”

“…The 2011 cohort study by Schie et al 16 found increased neurotoxicity with vincristine and azole coadministration; however, the majority of subjects received itraconazole with only 1 subject receiving fluconazole. As fluconazole is a weaker, noncompetitive inhibitor of several human CYP proteins and does not significantly inhibit P-gp as compared with itraconazole or posaconazole, there seem to be fewer adverse drug reactions between it and vincristine 4,17 . Disparate results currently exist as to whether fluconazole increases the rates of vincristine-associated neuropathy.…”

The Battlefield of Chemotherapy in Pediatric Cancers

“…Nevertheless, in 2020, an investigation among 150 pediatric patients with ALL and Wilm’s tumors showed that significant side effects of the vincristine regimen are mostly neurotoxic, which is at a mild to moderate level [ 65 ]. In recent years, more and more studies have revealed the deep connection between genetic polymorphisms and VIPN [ 66 , 67 , 68 ]. The CEP72 genetic variant is an optimistic VIPN signature marker since the CEP72 gene encodes centrosome proteins that participate in the development of microtubules.…”

Neurotoxicity Associated with Treatment of Acute Lymphoblastic Leukemia Chemotherapy and Immunotherapy

“…Patients with preB ALL who expressed CYP3A5 showed less vincristine-induced peripheral neuropathy (VIPN), generated more M1, and had lower metabolic rates than those who did not express CYP3A5 [ 32 ]. The CEP72 gene genetic variations have a lot of therapeutic potential [ 33 ]. Another genetic variant possibly related to the vincristine response is lower NHP2L1 mRNA expression in leukemia cells derived from children with recently diagnosed ALL, which was substantially related to enhanced sensitivity to VCR in B- and T-cell leukemia [ 34 ].…”