Predictive Assay for Chemotherapy-Induced Peripheral Neuropathy Associated with Vinca Alkaloids in Lymphoid Malignancies

Introduction: Vinca alkaloids, such as vincristine, are important anticancer agents mainly employed in the treatment of hematological cancers. The principal mechanism for the antineoplastic activity is microtubule disruption. However, these agents also cause damage to mitochondria which leads to oxidative stress and production of reactive oxygen species (ROS). Other chemotherapeutic drugs that are suggested to cause peripheral neuropathy by this mechanism, i.e., increased oxidative stress, include taxanes and platinum compounds. Oxidative damage to peripheral neurons can cause damage to myelin sheath, mitochondrial proteins, and other antioxidant enzymes, resulting in hyperexcitability of peripheral neurons. This nerve damage results in the commonly seen dose-limiting neurological side effect chemotherapy-induced peripheral neuropathy (CIPN). Hence, assessment of biomarkers for peroxidation, myelin repair/maintenance, and red-ox balance (glutathione recycling) can be helpful in monitoring the on-set and course of peripheral neuropathy. We hypothesize that chemotherapeutic agents with similar effects on mitochondria (vinca alkaloids, taxanes and platinum compounds) will produce a specific pattern of glutathione recycling in patients prone to CIPN.

Methods: Patients who had given written consent to participate in this exploratory single-centered, prospective IRB approved study contributed a blood sample prior to each treatment cycle. At each visit, the Rotterdam Symptoms Check-List (RSCL) was filled out and reported symptoms confirmed by comparison to notes in medical records.

Whole blood was analyzed for glutathione recycling capacity using the bioactive probe hydroxyethyldisulfide (HEDS) and incubated at room temperature for 2 hours with gentle mixing. Prior to spectrophotometric determination, blood cells and proteinaceous thiols will be removed from the sample by acid precipitation and centrifugation. The final spectrophotometric reading will be converted into ME produced using the conversion factor provided in the assay kit Rockland Inc). Recycling capacity was compared to self-reported grade of CIPN.

Results: Thus far we have enrolled 276 patients with an average age of 63.69 years (±12.85 STDEV; Range; 25-91). Patients are predominantly of Caucasian heritage (80.8%) along with 18.1 % African American and 1.1% Asian heritage. Females constitute 53.26 % of the cohort. To date we have 150 patients with more than 24 months of follow-up and among these patients, 5.5% had no reported symptoms of CIPN. Of those with severe CIPN (NCCN grade 3) neuropathy, 71% had a reduction in GSH recycling of greater than or equal to 40% from pre-treatment level. The reduced glutathione recycling capacity preceded on-set of symptoms by approximately 4 weeks. The majority of patients demonstrating this pattern of glutathione recycling had persistence CIPN that lasted for 6-18 months before an improvement was noted in medical records. We are currently assessing the value of adding biomarkers for lipid peroxidation and/or myelin formation/maintenance to further improve the likelihood ratio and AUROC values for the test.

Conclusions: This data suggests the importance of GSH recycling in the ability to predict risk of CIPIN. Patients whose pre-treatment baseline was less than 1 or progressively dropped by at least 40%, seem to be at most risk for CIPN. Further, this may predict persistence of CIPN even after cessation of chemotherapy. Most patients in this cohort received taxanes or platinum therapy. However, given the similarity in mechanism and results from an early assessment of lymphoma patients treated with vinca alkaloids that resulted in similar outcomes with reduced glutathione recycling capacity suggest the possible use of this test to predict CIPN among lymphoma patients.