Flexible dosing with Darbepoetin alfa for the treatment of chemotherapy-induced anemia

Abstract

Anemia is frequent in cancer patients with chemotherapy, and has an important negative effect on health-related quality of life (QoL). Darbepoetin alfa belongs to a new class of erythropoietic proteins with a unique molecular structure and interesting properties compared with classic recombinant human erythropoietin. Darbepoetin alfa is effective for chemotherapy-induced anemia when administered once weekly at a dose of 2.25 mug/kg, as shown in two large phase III placebo-controlled trials in patients with solid tumors and hematological malignancies. Furthermore, it was safe and well tolerated. More recently attention has been focused on optimizing Darbepoetin alfa therapy. Front-loaded dosing was explored to accelerate the hemoglobin (Hb) response and effect on QoL, but this idea could not be confirmed in a large phase III study. Based on the prolonged half-life of Darbepoetin alfa, administration every 3 weeks was appealing. In a large phase III trial, noninferiority of administration of 500 mug every 3 weeks compared with the weekly dosing could be confirmed, both in terms of reduction of red blood cell transfusion, Hb parameters, and QoL. This schedule is very convenient for patients and caregivers as it allows synchronization of erythropoietic therapy and common chemotherapy schedules. Questions for future study are the optimal iron supplementation strategy and the effect of Darbepoetin alfa on outcome. This article reviews the clinical development of Darbepoetin alfa with emphasis on recent data.

Figure 1

Mean hemoglobin over time by chemotherapy cycle in the phase II randomized study with asynchronous (filled circles) or synchronous administration (empty circles) of Darbepoetin alfa administered every 3 weeks. Error bars represent 95% confidence limits. Copyright © 2005. Reproduced with permission from Glaspy J, Henry D, Patel R, et al. 2005. Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa. Eur J Cancer, 41:1140–9.

Figure 2

Red blood cell transfusion rates in four phase III trials with Darbepoetin alfa. Data from two placebo-controlled studies (Vansteenkiste et al 2002; Hedenus et al 2003), the front-loading study (Kotasek et al 2004), and the every 3 weeks dosing study (Canon et al 2006).

Figure 3

Combined analysis of survival from four Darbepoetin alfa studies in chemotherapy-induced anemia.