Hematopoietic Growth Factors

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Hematopoietic Growth Factors
By Food and Drug Administration (FDA)
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Hematopoieticfl refers to blood cell formation. Hematopoietic growth factors are cytokines that stimulate blood cells to proliferate. Three have been licensed. Like most cytokines, they have long names and short acronyms. Erythropoietin (EPO), normally made by the kidneys in tiny amounts, accelerates red blood cell production.

Epoetin alfa, the genetically engineered form of EPO, was licensed in 1989 under the brand name Epogen to treat severe anemia in patients with chronic kidney failure. These patients may have as little as half the normal count of red blood cells and require frequent blood transfusions. But repeated transfusions put patients at risk of developing antibodies that would make it more difficult to match them with a donor for eventual kidney transplantation, or even for more transfusions. Patients might also develop a potentially harmful iron buildup. And, although blood is screened for viral contamination, repeated transfusions increase the risk of infection.

Studies in the United States and Europe of 1,200 patients with chronic renal disease treated with epoetin alfa showed that more than 95 percent had increased red blood cell counts. In patients who required them, the need for transfusions was reduced tenfold within three months, and most patients no longer required them at all.

EPO was licensed for a second use in 1991 — to treat patients with AIDS who develop severe anemia as a side effect of treatment with Retrovir (zidovudine, or AZT). In a study of 118 such patients, there was a 40 percent reduction in transfusions during a three-month period of treatment with Epogen, with very few adverse reactions — mostly fever, headaches and fatigue.

Two white-cell stimulating growth factors are also licensed: Granulocyte-colony stimulating factor, or G-CSF (marketed as Neupogen) and granulocyte-macrophage-colony stimulating factor, or GM-CSF (sold under the names Leukine and Prokine). Licensed within a month of each other in 1991, both are used to boost white cell counts depleted by cancer treatments.

GM-CSF is approved only for autologous bone marrow transplants in people with non-Hodgkin's lymphoma, Hodgkin's disease, and acute lymphoblastic leukemia. G-CSF, originally licensed for use in conjunction with chemotherapy for solid tumors, was recently licensed for use with bone marrow transplants also. The products are for use only with treatment regimens that cause a significant loss of white cells.

Bone marrow transplantation is such a treatment, done in patients with little or no hope of recovery using conventional chemotherapy alone. The patient's marrow is removed and checked for cancer cells. If malignant cells are found, the marrow is "purged"- -treated with chemotherapy to kill the cancer cells.

The patients also receive very high doses of chemotherapy, leaving them with virtually no white cells, red cells, or platelets. Their marrow is then returned, and they again begin to manufacture their own blood cells. It is a slow process, however, and until white cell counts rise sufficiently, the patients are at significant risk of death from infection. Normally, it takes three to four weeks after transplantation for marrow to begin producing white cells.

G-CSF and GM-CSF speed up this production. Although the body makes its own cytokines, they are produced in very small quantities. "By adding more cytokines, you're hurrying Mother Nature along," Gerrard says, "reducing the window of vulnerability by one-half to two-thirds."

Studies supporting licensing of both these cytokines showed that treated patients had significantly fewer infections, less need for intravenous antibiotics, and, in some cases, a shortened hospital stay, all contributing to improved quality of life.

GM-CSF causes relatively mild side effects, including fever, diarrhea, skin rash, and weakness. The most common adverse reaction of G-CSF is mild to moderate bone pain, usually controlled with acetaminophen.

Progress, But No Miracles

Many cytokine researchers are excited about future prospects for these versatile substances, but they temper their optimism with caution.

Donald Price, M.D., a neurologist-neurobiologist at Johns Hopkins University School of Medicine in Baltimore, is looking at neurotrophic factors that may be helpful in certain neurological diseases. He is enthusiastic about their potential for treatment, but cautious about applying them to humans prematurely.

"I think in the future, cytokines have enormous promise, but there needs to be more basic science work and work with animal models before taking these things into the clinic," he says.

Price is testing in animals the effectiveness of nerve growth factor (NGF) for Alzheimer's disease and brain-derived neurotrophic factor (BDNF) for amyotrophic lateral sclerosis (ALS). In ALS, motor neurons (nerve cells) degenerate, causing paralysis. In Alzheimer's disease, patients suffer dementia because the neurons governing cognition and memory are lost. Because neurons can't regenerate, the hope for cytokine treatment is that growth factors might act on these cells to prolong their function and viability.


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