Characterization of the peripheral neuropathy associated with brentuximab vedotin treatment of Mycosis Fungoides and Sézary Syndrome

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is common, frequently limits chemotherapy dosing, and negatively impacts quality of life. The National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0, and the Total Neuropathy Score clinical version (TNSc) are both validated scores to quantify peripheral neuropathy (PN), with the TNSc being more sensitive to clinical changes. Mycosis fungoides and Sézary syndrome (MF/SS) are characterized by a chronic course, where current therapies are generally non-curative and treatment toxicities have the potential for significant lasting effects. Brentuximab vedotin (BV) is an antibody-drug-conjugate composed of an anti-CD30 monoclonal antibody linked to the microtubule-disrupting agent, monomethyl auristatin E, with a known associated CIPN. In our phase II clinical trial of BV in MF/SS, 25 (69%) of 36 patients developed PN, with 18 (50%) developing Clinically Significant PN, CTCAE v4.0 grade 2 or higher. The median time to grade 2 PN was 15 weeks (range 0.4-48) after the initial dose. By Kaplan-Meier calculation, the median time to improvement from Clinically Significant PN was 30 weeks from the last BV dose. Seventy-four percent had improvement by 24 months. We found that TNSc scores significantly correlated with CTCAE grade, with Spearman correlation coefficient 0.68 (p < 0.001). By logistic regression, for each 100 mg increase in BV total dose, the likelihood of developing Clinically Significant PN increased by 23% (95% CI 4-46%). Improved monitoring of CIPN associated with BV is of paramount importance in the MF/SS population.

Keywords: Brentuximab vedotin; Chemotherapy-induced peripheral neuropathy; Mycosis fungoides; Neuropathy; Sézary syndrome; Total neuropathy score.

Fig. 1

Development and resolution of PN. a Swimmer’s plot illustrating the time course of the 25 patients who developed PN. Kaplan–Meier illustrations of the resolution or improvement of b any PN, and c clinically significant (≥Gr 2) PN

Fig. 2

Comparison of CTCAE grade with TNSc. a The correlation between CTCAE grade and TNSc is statistically significant, the Spearman correlation coefficient is 0.68 (p < 0.001). b Time course of peripheral neuropathy in 11 patients from the start of trial by TNSc and CTCAE grade

Fig. 3

a Photomicrograph of sural nerve in longitudinal section demonstrating a mild loss of myelinated fibers and no inflammatory infiltrate. Hematoxylin and eosin. Bar 100 microns. b Anti-CD30 immunohistochemistry shows no positivity. Bar 100 microns