Peripheral Neuropathy in Non-Hodgkin Lymphoma Patients Receiving Vincristine With and Without Aprepitant/Fosaprepitant

John B. Bossaer, PharmD BCOP BCPS
Associate Professor
Bill Gatton College of Pharmacy
East Tennessee State University
Johnson City, TN

Vincristine is a widely used agent in hematologic malignancies. Its efficacy and lack of myelosuppression make it an ideal antimicrotubule agent to include in combination chemotherapy regimens. Despite the widespread use of vincristine, dose-limiting peripheral neuropathy can occur. Risk factors for peripheral neuropathy include hepatic dysfunction (e.g., elevated total bilirubin) and concomitant use of CYP3A4 inhibitors (e.g., azole antifungals).

The antiemetic agent aprepitant and its IV formulation prodrug, fosaprepitant, are moderate CYP3A4 inhibitors. Aprepitant/fosaprepitant’s CYP3A4 inhibition is illustrated by the dosing of dexamethasone, a CYP3A4 substrate, with and without concomitant aprepitant (12 mg vs. 20 mg, respectively).¹ It has been widely assumed that no significant drug-drug interaction between vincristine and aprepitant/fosaprepitant occurs. This assumption likely stems from a small pharmacokinetic study (N = 12) demonstrating similar plasma concentrations of vinorelbine when it is given with and without aprepitant.² Vinorelbine, also a vinca alkaloid, has minor differences in metabolism and elimination compared to vincristine, but both are primarily metabolized via CYP3A4.

However, Okada and colleagues identified aprepitant use as a risk factor for early-onset (after the first cycle) vincristine-induced peripheral neuropathy in Japanese patients receiving cyclophosphamide doxorubicin vincristine prednisone (CHOP)–like chemotherapy regimens.³ Given the biological plausibility of an aprepitant/fosaprepitant-vincristine interaction via CYP3A4 inhibition and these recent clinical data from Okada and colleagues, we decided to investigate the possibility of such an interaction in our patient population. Anecdotally, the ratio of local oncologists who routinely prescribe neurokinin-1 (NK-1) antagonists (aprepitant and fosaprepitant are the only NK-1 agents on formulary) with CHOP-like regimens is approximately 50:50. Therefore, we believed that a retrospective cohort study of CHOP-like chemotherapy patients who did or did not receive aprepitant/fosaprepitant would be feasible.

We retrospectively reviewed electronic medical records from July 1, 2010, to June 30, 2018, of all adults who received standard-dose vincristine-based chemotherapy regimens for non-Hodgkin lymphoma (NHL).⁴ The primary objective of our study was the incidence of early-onset peripheral neuropathy, with a secondary endpoint of cumulative rate of peripheral neuropathy. The incidence of peripheral neuropathy was determined by reviewing medical records for documented neuropathy symptoms or initiation of treatment for peripheral neuropathy (e.g., gabapentin). We determined that 186 patients would be needed to have 80% power to detect a 20% difference in early-onset peripheral neuropathy between the aprepitant/fosaprepitant group and the group that did not receive an NK-1 antagonist. Fisher’s exact test was used to analyze primary and secondary endpoints with a one-side alpha of 0.05.

Ultimately, 115 patients were eligible for evaluation. The most common reason for exclusion was a cancer other than NHL (n = 23), multiple doses of vincristine/cycle (n = 12), lost to follow-up (n = 9), death (n = 9), and prior vincristine use (n = 8). More patients received aprepitant/fosaprepitant (n = 71) than did not (n = 44). However, baseline demographics were similar between the two groups regarding concomitant use of other 3A4 inhibitors such as fluconazole, vincristine dose, and age. There were fewer patients with diabetes in the aprepitant/fosaprepitant group (21.2% vs. 38.6%; p = .04). CHOP, rituximab-CHOP (R-CHOP), and rituximab cyclophosphamide vincristine prednisone (R-CVP) were the most common chemotherapy regimens in both groups (80.2% and 72.7%, respectively). There was no difference in the rate of early-onset peripheral neuropathy between groups (26.7% vs. 22.7%; p = .627). However, more overall peripheral neuropathy was seen in the aprepitant/fosaprepitant group (56% vs. 36%; p = .036). All cases of peripheral neuropathy were mild (grade 1).

The results suggest that CYP3A4-inhibiting NK-1 antagonists (aprepitant, fosaprepitant, netupitant) increase the risk of vincristine-induced peripheral neuropathy. However, one must consider the quality of evidence and balance that with the efficacy of NK-1 antagonists in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). Certainly, our study suffers from several notable limitations. First and foremost, retrospective studies are subject to confounding variables, and any such results should be interpreted as hypothesis-generating rather than practice-changing. In addition, we included patients who were receiving treatment with common 3A4 inhibitors (such as fluconazole and diltiazem) to better represent real-world practice. Although the use of such drugs was well balanced between the groups, this inclusion may still confound results. Finally, our study was small and underpowered for our primary endpoint.

Given the quality of the evidence and the fact that all cases of peripheral neuropathy were mild, clinicians should feel comfortable using aprepitant or fosaprepitant with vincristine-containing regimens in patients at high risk of CINV. Given the frequency that CHOP-like regimens are administered with and without NK-1 antagonists at cancer centers around the country, similar studies should be conducted to better delineate the risk of vincristine-induced peripheral neuropathy with CYP3A4-inhibiting NK-1 antagonists. If you are reading this, please consider conducting such a study! Future considerations should include the possibility that longer 3A4 inhibition with aprepitant (given orally for 3 days) or netupitant (with a longer half-life) is a greater risk than fosaprepitant (given IV for 1 day), as well as the possible risk with vincristine-intensive regimens (e.g., EPOCH). One might also consider making a comparison of rolapitant use versus aprepitant/fosaprepitant, because rolapitant is not a 3A4 inhibitor. Of course, a prospective study with similar cohorts would be ideal and would provide clinicians with higher-quality evidence.

References

1. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74:17-24.
2. Loos WJ, de Wit R, Freedman SJ, et al. Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients. Cancer Chemother Pharmacol. 2007;59:407-412.
3. Okada N, Hanafusa T, Sakurada T, et al. Risk factors for early-onset peripheral neuropathy caused by vincristine in patients with a first administration of R-CHOP or R-CHOP-like chemotherapy. J Clin Med Res. 2014;6:252-260.
4. Edwards JK, Bossaer JB, Lewis PO, Sant A. Peripheral neuropathy in non-Hodgkin’s lymphoma patients receiving vincristine with and without aprepitant/fosaprepitant. J Oncol Pharm Pract. 2019. Published online ahead of publication on August 25, 2019.