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Improvements in hemoglobin levels and fatigue after Darbepoetin alfa in patients with myelodysplastic syndromes

Interim data from a Phase 2 study evaluating the use of 500 mcg of Aranesp ( Darbepoetin alfa ) administered every three weeks to treat anemia in patients with a bone marrow disorder known as myelodysplastic syndrome ( MDS ).

Low-risk MDS patients receiving Aranesp every three weeks, who had no prior erythropoietic therapy, exhibited an overall response of 70 percent, increased hemoglobin levels and improvements in patient-reported fatigue.

Myelodysplastic Syndrome ( MDS ), also known as pre-leukemia or "smoldering" leukemia, encompasses a group of disorders in which the bone marrow does not produce enough blood cells. MDS is associated with abnormal blood counts or poorly functioning blood cells and often results in anemia, neutropenia and thrombocytopenia. Approximately 21,000 new cases of MDS are diagnosed each year in the United States.
MDS is more prevalent in men and Caucasians, and primarily occurs in people older than 60.

" During the course of their disease, the majority of MDS patients develop clinically significant anemia, which can lead to fatigue and the need for red blood cell transfusions," said Janice Gabrilove, at Mount Sinai School of Medicine, New York and the study's lead investigator. " Currently, there are no recombinant erythropoietic products approved for the treatment of anemia in MDS patients. These results are encouraging."

Results for the 13-week test period were presented for 189 of 209 patients enrolled and included erythroid response, achievement of target hemoglobin, incidence of transfusion and patient reported fatigue. Sixty-nine percent of these patients ( n=130 ) had no prior erythropoietic agent use.

In the group that had no previous treatment with an erythropoietic agent, 70 percent of patients had an erythroid response, with 49 percent classified as major response ( defined as greater than or equal to 2 grams per deciliter increase from baseline hemoglobin or transfusion independence ).
Sixty-seven percent of patients achieved the target hemoglobin level of 11 g/dL. Nineteen percent in the erythropoietin-naive group had at least one transfusion during the 13-week observation period.

In the group previously treated with an erythropoietic agent ( n= 59 ), 44 percent experienced an erythroid response, with 24 percent classified as major. Forty-five percent of patients achieved the target hemoglobin level of 11 g/dL, and 29 percent had at least one transfusion.

During the 13-week test period, 78 percent of patients experienced at least one adverse event. Seventeen percent ( n= 33 ) of patients experienced a serious adverse event, with fatigue, asthenia, and diarrhea as the most common. Six percent ( n=12 ) had treatment-related adverse events, with injection-site pain and diarrhea the most common ( n=2 for each ). No thrombotic events have been reported to date in this study.

This Phase 2, single-arm study of approximately 200 low-risk MDS patients ( those with a low risk of progressing to acute myeloid leukaemia ) was designed to assess treatment of anemia in this patient population with Aranesp 500 mcg administered every three weeks. The primary endpoint of the study was the proportion of patients achieving an erythroid response ( defined in accordance with the International Working Group Response Criteria ) during the 13-week test period. Secondary endpoints included changes in hemoglobin level from baseline, incidence of transfusions and impact on patient reported fatigue.

Aranesp is a recombinant erythropoietic protein, which contains two additional sialic acid-containing carbohydrate chains compared to the Epoetin alfa molecule and remains in the bloodstream longer than Epoetin alfa because it has a longer half-life.

Aranesp was approved by the U.S. Food and Drug Administration ( FDA ) in September 2001 for the treatment of anemia associated with chronic renal failure, also known as chronic kidney disease ( CKD ), for patients on dialysis and patients not on dialysis.
In July 2002, Aranesp was approved by the FDA for the treatment of chemotherapy-induced anemia in patients with non-myeloid malignancies.

Aranesp is contraindicated in patients with uncontrolled hypertension.
Erythropoietic therapies may increase the risk of thrombotic events and other serious events.
The target hemoglobin ( Hb ) should not exceed 12 g/dL. If the Hb increase exceeds 1.0 g/dL in any 2-week period, dose reductions are recommended. In a study with another erythropoietic product, where the target Hb was 12 - 14 g/dL, an increased incidence of thrombotic events, disease progression, and mortality was seen.

Pure red cell aplasia ( PRCA ) has been observed in patients treated with recombinant erythropoietins. This has been reported predominantly in patients with chronic renal failure.
Aranesp should be discontinued in any patient with evidence of PRCA and the patient evaluated for the presence of antibodies to erythropoietin products.
The most commonly reported side effects in clinical trials were fatigue, edema, nausea, vomiting, diarrhea, fever, and dyspnea.

Source: American Society of Hematology ( ASH ) 47th Annual Meeting, 2005