John Glaspy, MD, MPH
University of California School of Medicine
In the last decade, the treatment of mild to moderate anemia with epoetin-α in cancer patients has led to significant improvements in patient energy, activity and overall quality of life. The optimal approach to anemia management in these patients remains unknown. A greater understanding of dose response, effects of iron supplementation on response and the effects of anemia correction on radiation and chemotherapy efficacy require further study.
Darbopoetin-α, or Novel Erythropoeisis Stimulating Protein, stimulates erthropoeisis by binding to the human erythropoetin receptor. It has enhanced in-vivo activity relative to epoetin-α due to a significantly greater serum half-life. The increased half-life is due to increased sialic acid content. In pre-clinical studies, the serum half-life of darbopoetin-α has been shown to be three times that of erythropoetin-α, suggesting that less-frequent dosing and more flexible scheduling may be possible. Pharmakokinetic studies show that the mean half-life of subcutaneously injected darbopoetin-α in human patients is 32.6 hours.
A dose finding study in patients with solid tumors showed a clear dose response, with the highest dose level (4.5ug/kg/wk) associated with the shortest time to response and the highest response rate. Hemoglobin response was defined as an increase in the hemoglobin level by 2.0 g/dL or more in the absence of transfusion. Doses of 1.5 and 2.25ug/kg/wk produced results similar to those achieved with epoetin-α given at 150U/kg given three times weekly. Darbopoetin-α was well tolerated in all trials with a side effect profile indistinguishable from epoetin-α. No evidence of neutralizing antibody formation was seen.
A phase 3 trial of darbopoetin-α versus placebo in lung cancer patients showed a greatly reduced need for red cell transfusions during cancer treatment. Hematopoetic response rates, defined as an increase in hemoglobin by 2.0 g/dL over baseline or attainment of a hemoglobin level > 12.0g/dL, was 66% with darbopoeitin-α and 24% with placebo. A phase 2 study of darbopoetin-α given once every two weeks compared to conventionally dosed erythropoetin-α showed similar hemoglobin responses. A darbopoetin-α dose of 3.0ug/kg showed the most similarity in response to that of erythropoetin-α. A placebo-controlled study of darbopoetin-α given every three weeks also showed a similar rate and magnitude of response compared to erythropoetin-α.
In conclusion, data indicates that darbopoetin-α has at least equivalent efficacy as erythropoetin-α in raising hemoglobin levels in patients undergoing treatment for various hematologic and solid tumors. Its longer half-life and less frequent dosing will likely have an impact on patient compliance and quality of life. New data suggesting that maintenance of hemoglobin levels may improve overall survival and lead to less cognitive decline during cancer therapy lend increasing weight to further study of novel erythropoesis stimulating cytokines.