Vincristine Neuropathy in Children: Squatting (Sitting Cross Legged) Predisposes Common Peroneal Nerves to Be More Severely Affected than Tibial Nerves

Objective The main objective of this article was to evaluate vincristine neuropathy effect on common peroneal and tibial nerves. Methods A retrospective study was conducted in children with vincristine neuropathy between August 2006 and January 2016 at Sultan Qaboos University Hospital. Results Twenty-eight children (15 females and 13 males) were included in the study. The compound muscle action potential of common peroneal nerves was significantly reduced relative to the tibial nerves (p < 0.05)). There was no difference in latency and nerve conduction velocity between the two nerves. Conclusion Children receiving vincristine demonstrate severe peroneal neuropathy compared with tibial nerves. We conclude that squatting posture effects peroneal nerves and postulate that the peroneal nerves are affected more due to the squatting posture. This squatting posture stretches the nerves that are already affected by the toxic effect of vincristine.

Biomarkers of vincristine neuropathy in Kenyan children.

2601 Background: In a U.S. population, cytochrome P450 (CYP) 3A5 high-expressers metabolize vincristine (VCR) more efficiently than low-expressers and vincristine-induced peripheral neuropathy (VIPN) is less common in African-Americans than Caucasians. We test the hypothesis that more children in Kenya are CYP3A5 high-expressers compared to U.S. children and as such experience less VIPN. Methods: This study was conducted in Kenyan children with cancer (n=78) being treated with VCR at Moi University AMPATH Oncology Institute in partnership with Indiana University. Saliva Oragene kits for DNA extraction and genotyping were obtained. Whole blood was collected via finger stick on Whatman protein saver dried blood spot cards for analysis of VCR concentrations. VIPN was assessed prospectively using two neuropathy assessment tools (Modified Total Neuropathy Score (TNS) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0). Results: Compared to 14% in the U.S. sample, 94% of Kenyan subjects are CYP3A5 high-expressers (p<2.2x10-16). Kenyan children have significantly lower VCR plasma concentrations (11.15ng/ml/mg ± 1.051) compared to US (primarily Caucasian) children (13.26ng/ml/mg ± 2.897) one hour following the administration of VCR (p=0.011). By TNS VIPN assessment, 71% of Kenyan children developed VIPN compared to 100% of U.S. children (p=8.8x10-7). CYP3A5 high-expresser genotype is associated with lower TNS VIPN severity scores than low-expresser genotypes (p=0.006). TNS VIPN assessments show that height is positively correlated with severity of VIPN (p=0.025). CTCAE VIPN assessments also showed a positive correlation with height (p=0.036), but did not show any association with CYP3A5 genotype. Conclusions: Kenyan children are more likely to be CYP3A5 high-expressers than U.S. children and as such may metabolize VCR more efficiently. Supporting these data is that Kenyan children experience significantly less VIPN than U.S. children. CYP3A5 genotype and height are independent predictors of VIPN in Kenyan children with cancer. The CTCAE may lack sufficient sensitivity to detect VIPN for use in future studies aimed at optimizing VCR dosing strategies.

Genetic Factors Underlying the Risk of Thalidomide-Related Neuropathy in Patients With Multiple Myeloma

Purpose To indentify genetic variation that can modulate and predict the risk of developing thalidomide-related peripheral neuropathy (TrPN). Patients and Methods We analyzed DNA from 1,495 patients with multiple myeloma. Using a custom-built single nucleotide polymorphism (SNP) array, we tested the association of TrPN with 3,404 SNPs. The SNPs were selected in predicted functional regions within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and adverse effects associated with myeloma and its therapy. Patient cases and controls were derived from two large clinical trials that compared thalidomide with conventional-based treatment in myeloma patients (Medical Research Council Myeloma-IX and HOVON-50/GMMG-HD3). Results We report TrPN associations with SNPs—ABCA1 (rs363717), ICAM1 (rs1799969), PPARD (rs2076169), SERPINB2 (rs6103), and SLC12A6 (rs7164902)—where we show cross validation of the associations in both trials. To investigate whether TrPN SNP associations were related to exposure to thalidomide only or general drug-related peripheral neuropathy, we performed a second analysis on patients treated with vincristine. We report SNPs associated with vincristine neuropathy, with a seemingly distinct underlying genetic mechanism. Conclusion Our results are consistent with the hypothesis that an individual's risk of developing a peripheral neuropathy after thalidomide treatment can be mediated by polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system. These findings will contribute to the development of future neuroprotective strategies with thalidomide therapy and the better use of this important compound.