Vincristine-induced neuropathy: Long term follow-up of lymphoma survivors treated with CHOP or dose-adjusted EPOCH chemotherapy

Abstract Introduction: The incidence of Vincristine-induced neuropathy (VIN) occurs in up to 70% of non Hodgkin Lymphoma (NHL) survivors treated with front-line lymphoma regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and infusional dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), administered with or without rituximab (R) (Su et al., 2025). The pathogenesis of chemotherapy-induced neuropathy differs for the various chemotherapy agents. Vincristine interferes with microtubule formation, an essential component of nerve fiber axons, leading to mitotic arrest and neuronal injury (Kim et al., 2020). Clinical manifestation of VIN ranges from mild paresthesia (numbness or tingling) to severe deficits that require dose reductions, potentially limiting therapeutic options (Cavaletti et al., 2023; Huehnchen et al., 2022). Symptoms can persist even after treatment is finished, increasing the risk of falls and negatively impacting both long-term quality of life (QOL) and activities of daily living (ADLs). Limited data is available related to persistent VIN in lymphoma survivors. We therefore evaluated long-term neuropathy outcomes in patients with lymphoma treated with CHOP or EPOCH chemotherapy. Methods: We conducted a single-site, prospective study at The Ohio State University Arthur G. James Cancer Hospital, a large, tertiary National Cancer Institute (NCI) designated Comprehensive Cancer Center. The protocol was approved by the Institutional Review Board. Written, informed consent was obtained from participants receiving first-line CHOP or EPOCH chemotherapy prior to enrollment. Longitudinal outcomes for VIN included clinician-assessed and patient-reported outcome measures (PROs), and serum neurofilament-light (Nf-L) levels. Initially, data was collected at 3-times: T1 (baseline, before cycle 2); T2 (before cycle 4); and T3 (before cycle 6). A post-treatment visit (T4) was added to assess long-term VIN outcomes following treatment. Consent and questionnaire completion occurred remotely. Participants completed the PROs, and clinical records were reviewed for any additional chemotherapy and concomitant medications. Additionally, the electronic medical record was evaluated for neuropathy-related terms and additional details, including onset, persistence, symptoms, or resolution since completion of the initial chemotherapy. Results: Data was collected from 26 participants (CHOP n =17, EPOCH n =9) at T1. After further examination, one participant (CHOP) was determined to be ineligible due to baseline neuropathy. The number of participants decreased at each time point related to disease progression (T2: 21; CHOP n = 13, EPOCH n = 7) (T3: 15; CHOP n = 9, EPOCH n = 6). At the post treatment visit (T4), data was collected from six of the 11eligible participants. Time since finishing treatment was approximately 3.5 years (range 38-42 months). All participants were female, and 50% received EPOCH. Participants receiving EPOCH were more racially diverse (33% white vs. 100% white in the CHOP cohort), with a younger mean age (age 43 vs. 66). At T3, vincristine was reduced by 50% in three cases, although the dose reduction was prompted by constipation rather than neuropathy; however, grade 1 neuropathy (CTCAE; Common Terminology Criteria for Adverse Events) was also documented. Four participants experienced neuropathy at T3, including one grade 2 case (ID 1014). This was the only participant referred to neurology; the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire CIPN twenty-item scale (EORTC QLQ-CIPN20) score increased from 25 to 36 at T4. Conclusions: Overall, neuropathy outcomes varied in our cohort. For most, CIPN20 scores were stable to improved between T3 and T4, yet 3 participants (mean age 68.7) reported persistent numbness and tingling in their feet and toes. Increasing age has been reported as a risk factor for development of chemotherapy induced neuropathy with one study reporting persistence of symptoms in the post-treatment phase (Bulls et al., 2019; Hershman et al., 2016). Results from our study suggest that VIN can persist well into survivorship for lymphoma patients, adversely impacting long-term QOL. We plan to perform a follow-up, larger study to investigate underlying pathological mechanisms and inform potential therapeutic options.