Effect of Dose Reductions on Response to 500-μg Darbepoetin alfa Administered Once Every 3 Weeks for the Treatment of Chemotherapy-Induced Anemia: Analysis from a Randomized, Double-Blind, Active-Controlled Trial.

Background: Darbepoetin alfa (Aranesp®; DA) is an erythropoiesis-stimulating protein (ESP) effective for treating chemotherapy-induced anemia (CIA). Every-3-week (Q3W) administration has been shown to be effective in treating CIA in a randomized, double-blind, double-dummy, active-controlled phase 3 study of 705 patients (pts) (EHA 2005 Meeting: Poster# 0471). We performed an exploratory analysis from this study to investigate the effect of dose reductions/withholding on Hb levels with the extended Q3W dosing compared with QW dosing. Dose titration is important to ensure efficient control of hemoglobin (Hb) levels and to minimize adverse events resulting from rapid increases in Hb.

Methods: The study enrolled pts ≥18 years of age, diagnosed with anemia (Hb <11g/dL) and nonmyeloid malignancy with ≥12 wks of planned chemotherapy. Pts were randomized 1:1 to 500 μg Q3W or 2.25 μg/kg/wk (QW) DA for 15 weeks. Randomization was stratified by tumor type, screening Hb (<10 or ≥10g/dL), and region; adjusted KM estimates represent weighted averages obtained for each randomization strata. Dose reductions were prespecified to 60% of previous dose (40% reduction) if ≥1-g/dL Hb increase in 2 wks occurred in the absence of transfusion, or if Hb was ≥13 g/dL (dose reinstated if Hb ≤12 g/dL); ie, the Q3W dose was initially reduced to a fixed dose of 300 μg. An exploratory piecewise mixed effect (PME) model was developed to investigate the effect of these dose reductions on Hb levels of pts treated with 500 μg Q3W (Naumova et al 2001). The PME model allowed the slope to change before and after the 1st dose reduction, insuring that these 2 lines intersected at the time of titration, and adjusted for study stratification factors. Hb values within 28 days of a transfusion were excluded from the analysis.

Results: A high proportion of pts in both Q3W and QW groups had their dose reduced (adjusted KM: 74% [95% CL: 69, 80] for the Q3W group, and 75% [95% CL: 70, 80] for the QW group), predominantly as a result of an Hb increase ≥1 g/dL in 2 wks. The average weekly dose over the entire study was 129.6 (SD 34.7) μg for the Q3W group and 113.0 (SD 42.7) μg for the QW group. The median time to 1st dose reduction was 43 days for the Q3W group (36 days for the QW group), when the mean Hb concentration was 11.15 g/dL. The PME model for Q3W revealed an increase in Hb up to the 1st dose reduction at a mean rate of 0.048 g/dL/day (0.34 g/dL/wk). After 1st dose reduction, Hb was maintained at a relatively steady level until the end of treatment phase with a subsequent slower increase of 0.004 g/dL/day (0.028 g/dL/wk). Examination of Hb profiles after dose withholding from Hb ≥13 g/dL showed no differences between Q3W and QW groups. The safety profiles for the Q3W and QW groups were similar, with no increase in cardiovascular/thromboembolic events associated with rapid increases in Hb.

Conclusions: DA administered using a fixed dose Q3W can safely and effectively treat CIA. The PME model confirms that the starting dose of 500 μg Q3W, accompanied by dose reductions in the range of 25–50%, maintains Hb levels in pts with CIA.