Colony-stimulating factors (CSFs)
Colony-stimulating factors (CSFs) are glycoproteins that play a crucial role in stimulating the production of blood cells, particularly during supportive care for patients undergoing chemotherapy or radiation therapy. These factors are primarily used to increase red blood cell, white blood cell, and hematopoietic stem cell counts, which can be depleted as a result of cancer treatments. CSFs are not directly used to treat cancer but serve to mitigate side effects, such as febrile neutropenia, and enhance the overall effectiveness of chemotherapy regimens.
Recombinant forms of CSFs, like filgrastim and pegfilgrastim, have been widely adopted in clinical practice, while others remain unapproved by regulatory agencies. These factors are typically administered through intravenous infusions or subcutaneous injections, as they are proteins that would be degraded in the digestive system. The process of hematopoiesis, or blood cell formation, is regulated by CSFs, which influence stem cell differentiation into various blood cell lineages.
While CSFs are generally well-tolerated, they do come with potential side effects, including bone pain and flu-like symptoms. Patients are advised to communicate with their healthcare professionals about any concerns and to weigh the benefits and risks associated with their use. CSFs have shown to improve bone marrow function and may even reduce the need for bone marrow transplants in certain cases, demonstrating their significant role in the management of cancer-related complications.
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Colony-stimulating factors (CSFs)
ATC CODE: B03XA01, erythropoietin; B03XA02, darbepoetin alfa; L03AA02, filgrastim; L03AA03, molgramostim; L03AA09, sargramostim; L03AA10, lenograstim; L03AA12, ancestim; L03AA13, pegfilgrastim; L03AA14, lipegfilgrastim
ALSO KNOWN AS: Hematopoietic growth factors
DEFINITION: Colony-stimulating factors (CSFs) are glycoproteins that stimulate the production of blood cells. Several recombinant CSFs have achieved widespread clinical use. Others have been identified but have not been assessed in clinical trials or have not been approved for use by the Food and Drug Administration (FDA).
Cancers treated: Colony-stimulating factors are not used to treat cancers per se. Rather, they are used as supportive care to increase red blood cell, white blood cell, and hematopoietic stem cell counts that are depleted during some forms of chemotherapy or radiation therapy. CSFs are generally administered only to patients with non-myeloid malignancies and usually as primary prophylaxis to prevent febrile neutropenia or to allow dose intensity with specific chemotherapy regimens. CSFs are administered after chemotherapy or radiation therapy. They also may be used before bone marrow or stem cell transplantation to increase the number of cells available for transplant or after transplantation to assist in bone marrow recovery.
Delivery routes: Because colony-stimulating factors are proteins and are subject to digestion and degradation in the stomach, they are administered either as intravenous (IV) infusions or subcutaneous injections, depending on the specific formulation used. Some CSFs are presented in prefilled syringes, allowing patients to inject themselves at home without the need to go to a hospital or doctor’s office.
How these drugs work: Hematopoiesis, or blood cell formation, is the process by which early hematopoietic stem cells in the bone marrow with potential for renewal, proliferation, and differentiation give rise to large numbers of mature cells through a series of intermediate cells. As the stem cells mature, they lose their ability to self-renew and become specialized. Stem cells produce cells that belong to one of three lineageserythroid cells (red blood cells), lymphoid cells (white blood cells, including T cells and B cells), and myeloid cells (white blood cells such as granulocytes and macrophages, and platelets or thrombocytes). The process of proliferation, differentiation, and maturation is complex, with many interacting steps, and is controlled by CSFs, alone or in combination. To date, more than twenty CSFs have been identified. They are active in very small amounts. The CSF family includes granulocyte–colony-stimulating factor (G-CSF or CSF 3), granulocyte-macrophage–colony-stimulating factor (GM-CSF), multiple-colony-stimulating factor, or interleukin 3 (IL-3), and macrophage–colony-stimulating factor (M-CSF).
Once CSFs were discovered in experimental models, the genes for them were identified and cloned. Many of the endogenous CSFs have been produced as recombinant human forms and have received marketing approval from the FDA. The recombinant human forms of CSFs can be used to replace or supplement endogenous proteins after chemotherapy or radiation therapy or in the case of anemia caused by kidney failure or the anemia of chronic disease, which includes cancer.
Erythropoietin or epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) increase the number of red blood cells by causing committed erythroid progenitor cells to proliferate and differentiate. According to the American Society of Clinical Oncology, serious side effects of these drugs include blood clots and an increased risk of death, making it vital for patients and doctors to carefully weigh the advantages and risks of taking them.
Filgrastim (Neupogen) and pegfilgrastim (Neulasta) are granulocyte CSFs that increase the number of neutrophils, white blood cells specific to fighting infection. Another white cell factor, lenograstim (Granocyte), is available in Europe and other countries. The granulocyte CSFs increase the circulating half-life of neutrophils and enhance their ability to attack bacteria. The granulocyte CSF pegfilgrastim (Lonquex) was approved for use in the European Union, Norway, Iceland, and Liechtenstein in the early 2010s.
Sargramostim (Leukine) is a granulocyte-macrophage CSF used to increase several types of white blood cells. Molgramostim (Leucomax) is another version that is available in Europe. Granulocyte-macrophage CSFs are locally active and remain at the site of infection to recruit and activate neutrophils. In 2008, a liquid formulation of Leukine was taken off the market voluntarily due to increased reports of syncope and other adverse reactions. The freeze-dried form of Leukine was unaffected. The US Food and Drug Administration (FDA) also recalled certain lots of Leukine in May 2012. Ancestim (Stemgen) is a CSF that promotes the development of stem cells, which can differentiate into other types of blood cells. Interleukin-11 (oprelvekin, Neumega; L03AC02) is not a CSF but is used to increase platelet counts in patients with cancer who are receiving myelosuppressive chemotherapy. In 2018, the FDA approved Mylan N. V.'s G-CSF drug Fulphila (pegfilgrastim-jmdb), which was the first Neulasta (pegfilgrastim) similar product intended to reduce infection of individuals undergoing myelosuppressive chemotherapy. Other biosimilars include filgrastim-sndz (Zarxio), filgrastim-aafi (Nivestym), and tbo-filgrastim (Granix).
When C-CSF is used in the early stages of breast carcinoma and non-Hodgkin’s lymphoma, patients experience about 50 percent less neutropenia and infection and a 40 percent survival rate increase. Pegylated G-CSF is retained in the body for a longer period, requiring fewer treatments with positive results. Some healthcare professionals recommend this treatment for every patient with a 20 percent or higher chance of febrile neutropenia. Additionally, other studies found CSF use improves bone marrow function and helps prevent the need for bone marrow transplant in patients with chemotherapy-induced aplastic anemia.
Side effects: All drugs and biologic products that are effective have side effects, and each type of CSF has side effects specific to it. Patients who are receiving CSFs should consult their healthcare professionals and the package inserts for specific information concerning side effects. In general, however, the side effects from the use of CSFs are much less intense than those from chemotherapy or radiation therapy. Common side effects are bone pain, extremity pain, flu-like symptoms, fever, fatigue, and loss of appetite.
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