Debilitating anemia resulting from both the disease and its treatment is common in patients who have cancer. Treating chemotherapy-induced anemia with erythropoiesis-stimulating proteins such as epoetin alfa(Drug information on epoetin alfa) (Epogen) and darbepoetin alfa(Drug information on darbepoetin alfa) (Aranesp) has been shown to increase hemoglobin (Hgb) levels, reduce the need for red blood cell transfusions, and improve quality of life.[2-13] Darbepoetin alfa has a greater sialic acid-containing carbohydrate content than epoetin alfa, which results in a longer serum half-life and greater potency. This makes it possible to dose less frequently without any loss of efficacy. In particular, the ability to administer darbepoetin alfa every 3 weeks (q3wk) would provide a convenient therapeutic option for patients, caregivers, and health care providers, because most patients are treated with 3-week cycles of chemotherapy.Of interest with the less-frequent dosing schedules of darbepoetin alfa is the effect of chemotherapy-induced myelosuppression on the efficacy of erythropoiesis stimulation, which could influence the timing of the administration of darbepoetin alfa. Phase II and III clinical trials have been conducted to evaluate the efficacy of darbepoetin alfa q3wk in a variety of settings and to determine the optimal timing of administration of darbepoetin alfa with chemotherapy.
Clinical Development of q3wk Dosing of Darbepoetin Alfa for Chemotherapy-Induced Anemia
A pilot randomized placebo-controlled dose-finding phase II study showed that darbepoetin alfa q3wk ameliorated anemia in patients with solid tumors. Patients were eligible for the study if they were being treated with cyclic chemotherapy, had a life expectancy of at least 6 months, and had Hgb levels of 11 g/dL or less. They were randomized to darbepoetin alfa (at a dose of 4.5, 6.75, 9, 12, 13.5, or 15 µg/kg) or to placebo q3wk by subcutaneous (SC) injection. No dose increases for inadequate responses were permitted during the double-blind phase of the study, which lasted for a total of 12 weeks.
There was a dose response in terms of the percentage of patients with a Hgb response (defined as an increase in Hgb level of 2 g/dL or more in the absence of red blood cell transfusions in the previous 28 days) with darbepoetin alfa 4.5 µg/kg (24%) to 12 µg/kg (62%); no additional effects were seen with doses higher than 12 µg/kg. The response rate in the placebo group was 14%. There were hematopoietic responses (defined as a Hgb response or a Hgb level of 12 g/dL or higher in the absence of red blood cell transfusions in the previous 28 days) in more than half of patients treated with darbepoetin alfa 6.75 µg/kg (52%) and in 31% of those treated with placebo. There were red blood cell transfusions in fewer patients treated with darbepoetin alfa (19% to 30%) than with placebo (46%). The q3wk darbepoetin alfa schedule was well tolerated, with a safety profile comparable to that of placebo.
The results of this study indicate that q3wk dosing of darbepoetin alfa, at doses similar to those in more-frequent schedules, can increase Hgb to the target levels and reduce transfusion requirements.
The interplay between the effects of chemotherapy and erythropoiesis-stimulating proteins was explored in a randomized study that compared q3wk darbepoetin alfa given on a synchronous or asynchronous schedule relative to the chemotherapy in patients with nonmyeloid malignancies. Patients treated with chemotherapy q3wk who had anemia (pretreatment Hgb level 9-11 g/dL) were randomized to darbepoetin alfa at a dosage of 6.75 µg/kg q3wk by SC injection on the same day as their chemotherapy (synchronous dosing) or on day 15 of the chemotherapy cycle (asynchronous dosing). To ensure that delays and modifications in the chemotherapy, which was given for up to 16 weeks, did not confound the study outcomes, changes in the Hgb levels were assessed at 6 weeks.