By Laurie Munk

A look backward and a look forward characterized the session on “Growth Factors as Drugs, Part I: Erythropoietin” (9103-S), presented jointly by John Adamson, MD, from the University of California at San Diego, and Charles Bennett, MD, PhD, MPP, from Northwestern University. The event was an ASH/AABB joint program.

After noting several historical milestones in the development of erythropoietin (EPO), Adamson reviewed the basic cellular and molecular biology of the glycoprotein.

·                      Its molecular weight is 64,000 kDa.

·                      It contains 165 amino acids.

·                      Approximately 40% of its mass is carbohydrate.

·                      It is essential for the production of red cells.

He observed that greater than 95% of EPO is made in the kidneys — produced by peritubular capillary lining cells in the renal cortex. The production is inversely related to the oxygenation of tissues. EPO interacts with specific receptors on a multitude of target cells including erythroid and megakaryocytic progenitor cells,

vascular endothelial cells and cells in many other tissues. For erythroid progenitors, the interaction causes terminal differentiation and maturation of the progenitor cells and the premature release of marrow reticulocytes into the peripheral circulation.

The function of putative receptors on other cell types is not worked out, but is the subject of considerable interest. Most critically, the reported presence of functional EPO receptors on tumor cells has generated considerable concern about the safety of erythropoietic stimulating agents (ESAs) being used to correct the anemia of patients receiving chemotherapy.

Early Clinical Trials a Success

Adamson turned his attention to the first uses of EPO as a therapeutic agent. The first clinical application — correction of anemia in end-stage renal disease — involved patients who were severely anemic (5-7 g/dL hemoglobin levels). These patients required multiple transfusions that were often complicated by iron overload. Patient characteristics also included marked left ventricular hypertrophy and dilatation as well as a high incidence of cardiovascular disease.

Patient outcomes in early trials were positive. With EPO, red cell transfusion could be avoided, with a reversal of any iron overload. Cardiovascular disease was reduced and the quality of life was improved. Complications occurred, however, and included exacerbated hypertension, clotted vascular access and relative iron deficiency. 

Impact on the Blood Supply

Adamson asked the audience to consider the large number (approximately 400,000) of patients in the U.S. who are on dialysis and are anemic. Studies have shown that without EPO, the mean number of Red Blood Cell (RBC) units transfused per patient per month would be 0.5. If each of these patients receives EPO instead of RBC transfusions, the impact would be 0.5 x 12 x 400,000 or 2.4 million RBC units saved per year. He noted that even if the calculations are off by 50%, the amount of RBC transfusions saved would amount to 8% to 9% of the nation’s blood supply.

With the success of early clinical trials, a second “chapter” in the EPO story unfolded. Clinical indications broadened to include cancer patients with chemotherapy-induced anemia. The patients in registration studies were receiving chemotherapy for treatment of a variety of tumor types, and the primary endpoint was avoidance of transfusion, rather than improvement in quality of life. As new indications are considered and the use of EPO becomes widespread, the blood supply will be affected.

New Indications and New Drugs

In addition to four approved indications for EPO (dialysis and predialysis for chronic kidney disease, AIDS, cancer chemotherapy and perioperative use in selected orthopedic surgeries), potential settings for the use of EPO have been suggested.

·                      Stem cell transplantation.

·                      Extreme prematurity.

·                      Chronic inflammatory anemias, such as seen with rheumatoid arthritis.

·                      Hemoglobinopathies.

·                      Myelodysplasia.

·                      Anemia of aging.

Concurrent with the investigations into possible applications, research into new compounds has already produced one novel preparation — darbepoetin alfa. This EPO analogue has five rather than three N-linked carbohydrate chains, contains eight additional sialic acid residues and has a carbohydrate mass of approximately 52%. Its advantage is that it has a half-life in circulation of three or four times that of EPO and, thus, can be given less frequently — a convenience for patients.

However, although EPO has much potential, there has been concern recently about complications in patients with chemotherapy-induced anemia who were receiving EPO instead of red cell transfusion. Indications and guidelines for use have changed.

Adverse Effects Come to Light

Bennett continued the session with clinical observations focused on adverse effects of ESAs. He first noted that there have been barriers to identifying adverse effects, including the limited size of clinical trials, undetected toxicities at the time of approval by the Food and Drug Administration (FDA) and the fact that many adverse events are not identified until several years after the ESA has been on the market.

Reported adverse outcomes of ESA use in oncology trials include blood clots, loco-regional progression of disease, shortened disease-free or overall survival and mortality. Bennett emphasized that reports in the literature on ESA use must be analyzed cautiously. Studies affiliated with ESA manufacturers are much less likely to identify downstream effects of ESAs on solid cancer cell lines or to describe tumor stimulatory effects (cytoreduction, mitogenic, invasive).

Reassessing the Indications

The adverse effects of ESAs in chemotherapy-related anemia patients prompted a reassessment of the manufacturers’ claims of a quality of life benefit. As a result, such claims have been removed from package inserts for ESA use by patient with chronic kidney disease and cancer.

Other changes to the package inserts include:

·                      ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

·                      Therapy should not be initiated when hemoglobin levels are 10 g/dL or more.

·                      Dosing should be withheld if the hemoglobin level exceeds that needed to avoid transfusion.

Bennett briefly reviewed updated guidelines for chemotherapy-related anemia from the National Comprehensive Cancer Network and jointly issued guidelines from the American Society of Clinical Oncology and the American Society of Hematology. He also noted the changes to national coverage decisions for reimbursement by the Centers for Medicare and Medicaid Services.

Bennett concluded his remarks by noting that the FDA has taken steps to apply the lessons learned from ESAs to increase the agency’s pharmacovigilance with regard to other drugs. A question-and-answer session followed the presentations.

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