ARANESP Is Effective and More Convenient for Controlling Anemia

SAN FRANCISCO—The anemia drug darbepoetin alfa (ARANESP) effectively alleviates anemia, boosting hemoglobin counts and reducing the need for red blood cell transfusions, according to the results of two separate studies.

In a study conducted among 177 patients with solid tumors, darbepoetin raised hemoglobin more than 2 g/dL. Weekly doses of darbepoetin were tested for 12 weeks at five different doses concurrently with chemotherapy. Darbepoetin is a supersialated protein that binds to the erythropoietin receptor and stimulates erythropoiesis by the same mechanism as rHuEPO. The control group received rHuEPO for 6 weeks, along with chemotherapy.

"The bottom line is that darbepoetin worked. It increased the blood counts of patients significantly. And the higher the dose of darbepoetin, the more the blood counts improved," said lead researcher John Glaspy, MD, MPH, director of the Bowyer Oncology Center at the University of California at Los Angeles.

Darbepoetin was given in doses of 0.5, 1.0, 1.5, 2.25, and 4.5 µg/kg/week starting with the first cycle of chemotherapy. At the lowest dose (5 µg/kg), darbepoetin boosted hemoglobin by a mean of .96 g/dL. The mean change in hemoglobin counts at the highest dose (4.5 µg/kg) was 2.6 g/dL.

The study showed dose-dependent trends in the mean change of hemoglobin and the proportion of patients achieving a hemoglobin response and correction. At 2.25 µg/kg, 50% of patients achieved a hemoglobin correction and at 4.5 µg/kg, this rose to 70%.

Quality-of-Life Issues

As part of the study, participants answered questions on a Health Related Quality of Life (HRQOL) survey at 1 week, and again at 4, 8, and 12 weeks after chemotherapy and anemia therapy had begun. Selected domains of HRQOL were measured by the Functional Assessment of Cancer Therapy (FACT) Anemia and FACT-General scale. The results revealed that the patients’ functional abilities and fatigue score increased as their hemoglobin went up with darbepoetin therapy. At 0 change in hemoglobin, the average fatigue score was -1.5, while at more than 2 g/dL change in hemoglobin, the score improved to 5.1.

The number of red blood cell transfusions needed by patients on each drug was also dramatically different—22% of patients on rHuEPO compared to only 2% to 7% of patients on darbepoetin. Yet, as Dr. Glaspy noted: "The object of the study was not to compare darbepoetin with rHuEPO. We need to find out if darbepoetin is effective and maintain a database on rHuEPO."

Although not yet approved by the Food and Drug Administration, darbepoetin has been shown to have a two- to threefold longer serum terminal half-life than rHuEPO in patients with chronic renal failure. Dr. Glaspy’s work has also shown that darbepoetin has an extended serum terminal half-life in oncology patients receiving chemotherapy. In this study, darbepoetin was given only once weekly, while rHuEPO has to be administered 1 to 3 times weekly.

Underreported Diagnosis

Darbepoetin was well tolerated by most patients in the study. "Our data showed that darbepoetin is a safe drug," Dr. Glaspy said. The type and frequency of adverse events in patients receiving darbepoetin were consistent with those experienced by patients with cancer receiving cytotoxic chemotherapy and comparable to those of patients receiving rHuEPO. The most frequently reported adverse events in both treatment groups included fatigue, nausea, vomiting, diarrhea, and fever. No anti-darbepoetin antibodies were detected.

All the patients in the study were anemic at outset, had more than a 6-month life expectancy, had solid tumors, were iron replete, and had adequate renal and liver function. None had more than two red blood cell transfusions within 4 weeks of randomization, and no rHuEPO therapy within 8 weeks of randomization.

Anemia is generally considered an underreported diagnosis in cancer patients. Yet the incidence of anemia in cancer patients may be as high as 50% to 60%. Cancers associated with the highest incidence of anemia include lymphomas, lung cancer, and ovarian or genitourinary tumors. There currently are no universal guidelines for the treatment of anemia in cancer patients.

The results of the study indicate that darbepoetin may be effective in treating the anemia in cancer patients, according to Dr. Glaspy. "We know that darbepoetin works in the setting of our study. Additional data with higher doses of the drug should give us an even better picture of darbepoetin’s safety and efficacy," Dr. Glaspy concluded.

Reduction in Dosing

In a multicenter international study, darbepoetin was shown to be effective when given just once every 3 weeks to patients with solid tumors. This represents a substantial reduction in the dosing schedule compared to rHuEPO, administered 1 to 3 times every week.

"The potential for being able to treat anemia in cancer patients with injections substantially less often than currently given could dramatically increase the number of anemia patients treated for this underrecognized disease," said lead researcher Dusan Kotasek, MD, of the Ashford Cancer Centre in Ashford, Australia. Only about one third of anemic cancer patients on chemotherapy receive treatment for anemia, Dr. Kotasek explained.

Dose-dependent Trend

In the double-blind placebo-controlled study of 163 patients (131 received darbepoetin, 32 received placebo), there was a dose-dependent response to darbepoetin when compared with placebo. The incidence of red blood cell transfusions also decreased as the dose of darbepoetin was increased.

Patients receiving darbepoetin were treated at doses of 4.5, 6.75, 9, or 13.5 µg/kg over 12 weeks. At the highest dose, hemoglobin counts rose an average of 1.5 g/dL, and in some patients, hemoglobin counts went up as much as 2 or 2.5 g/dL. The frequency of blood transfusions in the darbepoetin group was 22% to 25%; half that seen in placebo patients (44%).

"You have to achieve a fairly high dose to see a real benefit, especially in hemoglobin response," Dr. Kotasek stated. "We believe that we haven’t yet reached the most effective dose. If we gave higher doses, we could probably get even better results." Dr. Kotasek said he and fellow researchers will aim to increase the darbepoetin dose given to patients in continuing studies.

Patient Characteristics

More than two thirds of the study participants were female with a wide range of cancers, including breast, gynecologic, and gastrointestinal cancers. All patients were receiving chemotherapy and had developed anemia. None of the patients had received rHuEPO therapy within 8 weeks of randomization, and none had more than two red blood cell transfusions within 4 weeks of randomization.

Dr. Kotasek and fellow scientists revealed that darbepoetin was very well tolerated by patients when given once every 3 weeks. There were no unusual side effects, and adverse events were consistent with those experienced by patients with cancer undergoing chemotherapy, and comparable to those of patients receiving rHuEPO. No darbepoetin antibodies were detected, and trough concentrations of the drug indicated no evidence of accumulation over time.

Fewer Injections

The use of darbepoetin could make it much easier for patients to receive anemia therapy, Dr. Kotasek said. "They would be getting fewer injections—and avoiding any unneeded jabs. There wouldn’t be the need for additional supervision at more frequent anemia therapy sessions. And darbepoetin could be given in a timely manner during the patient’s chemotherapy appointments. It would be very convenient," Dr. Kotasek remarked.

"Giving darbepoetin to cancer patients with anemia is certainly an effective way of maintaining hemoglobin and avoiding blood transfusions, and our research indicates that it’s very safe," he added.