Etoposide and etoposide phosphate hypersensitivity in children: Incidence, risk factors, and prevention strategies

Abstract

Introduction Etoposide is critical in treating pediatric cancers, although hypersensitivity can be severe and treatment-limiting. Reported rates of hypersensitivity range from 2% to 51%. Hypersensitivity data for etoposide phosphate, a newer product, are lacking. The primary objective of this study was to assess etoposide and etoposide phosphate hypersensitivity incidence. Secondary objectives included evaluation of potential risk factors for hypersensitivity and strategies to prevent recurrence. Methods This retrospective cohort study evaluated pediatric patients who received initial etoposide phosphate or etoposide dose between August 2012 and July 2017. The primary outcome was documentation of hypersensitivity within four months of initial dose. Potential risk factors evaluated included age, allergies, dose, infusion rate, infusion concentration, and premedication. Results Of 246 patients, hypersensitivity reactions occurred in five of 54 patients (9.3%) who received etoposide phosphate and 52 of 192 patients (27.1%) who received etoposide ( p = 0.0061). For etoposide, the mean initial infusion rate was 64.6 ± 40.9 mg/m2/h for patients with hypersensitivity and 49.5 ± 33.4 mg/m2/h without hypersensitivity ( p = 0.0886). Etoposide phosphate rate was not associated with hypersensitivity. Recurrent hypersensitivity occurred in one of nine patients (11.1%) who received etoposide desensitization and one of 38 patients (2.6%) who changed formulation to etoposide phosphate. Conclusions Etoposide was associated with more hypersensitivity than etoposide phosphate in pediatric patients. Etoposide hypersensitivity was associated with higher infusion rates, but not etoposide phosphate. Differences in hypersensitivity incidence and infusion rate influence indicate a formulation-effect. Etoposide hypersensitivity recurrence may be prevented by changing to etoposide phosphate formulation. During etoposide phosphate shortages, etoposide desensitization may prevent recurrent hypersensitivity.

Six‐step etoposide desensitization protocol: A pediatric, adolescent, and young adult case series

“…The reported incidence of etoposide hypersensitivity for pediatric patients ranges from 27% to 51% 19,21–22 . Hypersensitivity reactions may occur at any time and are not limited to the first etoposide exposure, as demonstrated in this case series where the majority of patients received and tolerated three or more doses prior to initial hypersensitivity reaction.…”

“…4,13,16,18 Etoposide phosphate has lower hypersensitivity incidence. 19 However, additional options are needed due to increasing drug shortages. 24,25 From 2005 to 2011, drug shortages in the United States almost quadrupled.…”

“…Recently, etoposide hypersensitivity reactions have been managed by changing formulation to etoposide phosphate or initiating desensitization protocols 4,13,16,18 . Etoposide phosphate has lower hypersensitivity incidence 19 . However, additional options are needed due to increasing drug shortages 24,25 .…”

“…At our institution, etoposide phosphate formulation is traditionally used to allow continuation of first‐line therapy. Incidence of etoposide phosphate hypersensitivity is significantly lower than etoposide (9.3% vs 27.1%) 19 . Occasionally, etoposide phosphate manufacturer supply is insufficient.…”

“…Incidence of etoposide phosphate hypersensitivity is significantly lower than etoposide (9.3% vs 27.1%). 19 Occasionally, etoposide phosphate manufacturer supply is insufficient. During shortages, etoposide desensitization is utilized to prevent hypersensitivity recurrence.…”