Hematopoietic Growth Factors

For years, chemotherapy-associated myelosuppression has represented a major limitation to a patient's tolerance of anticancer therapy. In addition, the clinical consequences of chemotherapy-induced myelosuppression (such as febrile neutropenia, dose reductions, or lengthy dose delays) may have had significant negative effects on quality of life or even response to treatment.

Before the widespread availability of agents to stimulate host hematopoiesis, administration of antibiotics, transfusion of blood products, and reductions or delays in chemotherapy dose have been the major means of combating the myelotoxicity of chemotherapy. It is now possible to stimulate clinically relevant production of several formed elements of the blood: neutrophils, erythrocytes, and platelets.

This chapter summarizes data supporting the clinical activity of several hematopoietic growth factors. A thorough knowledge of these data will help clinicians to make judicious, informed decisions about how to use these agents most responsibly.

Hematopoietic growth factors

Over the past several years, a great deal of progress has been made in understanding the process of hematopoiesis by which mature cellular elements of blood are formed. Hematopoietic growth factors are a family of regulatory molecules that play important roles in the growth, survival, and differentiation of blood progenitor cells, as well as in the functional activation of mature cells.

Table 1 lists the recombinant human hematopoietic growth factors (also known as hematopoietic cytokines) that have been approved by the US Food and Drug Administration (FDA) for clinical use: granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]); pegfilgrastim [Neulasta]; yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine, Prokine]); recombinant human erythropoietin (epoetin alfa, EPO [Epogen, Procrit]); darbepoetin alfa (Aranesp); and interleukin-11 (IL-11, oprelvekin [Neumega]). In addition, several other hematopoietic cytokines are under clinical development.

The commercial availability of these recombinant human hematopoietic growth factors has led to their wide clinical application in oncology practice. However, the substantial costs of colony-stimulating factor utilization as supportive care for patients receiving myelosup-pressive chemotherapy make it imperative to identify the optimal settings in which their use can make a significant difference in patient outcomes.

This chapter discusses the appropriate uses of only the FDA-approved hematopoietic growth factors/cytokines: G-CSF, GM-CSF, EPO, darbepoetin alfa, and IL-11. For a more detailed review of recommendations for the use of myeloid CSFs, readers are referred to the evidence-based, clinical practice guidelines developed in 1994 (last updated in 2006) by the American Society of Clinical Oncology (ASCO). The ASCO guidelines were formulated to encourage reasonable use of CSFs when their efficacy has been well documented but to discourage excess use when marginal benefit is anticipated. These clinical practice guidelines have been published and are most easily accessed at the official web site of ASCO (www.asco.org). In addition, the National Comprehensive Cancer Network (NCCN) (www.nccn.org) has published for the first time guidelines on the use of colony-stimulating factors.

Myeloid growth factors

Three myeloid growth factors are currently licensed for clinical use in the United States: G-CSF, pegfilgrastim, and GM-CSF.

G-CSF (filgrastim) is lineage-specific for the production of functionally active neutrophils. G-CSF has been extensively evaluated in several clinical scenarios. G-CSF was first approved in 1991 for clinical use to reduce the incidence of febrile neutropenia in cancer patients receiving myelosuppressive chemotherapy.

This broad initial indication has since been expanded even further, to include many other areas of oncologic practice, such as stimulation of neutrophil recovery following high-dose chemotherapy with stem-cell support. In addition, G-CSF is indicated to increase neutrophil production in endogenous myeloid disorders, such as congenital neutropenic states.

Pegylated G-CSF (pegfilgrastim) When polyethylene glycol was attached to the protein backbone of filgrastim, a new molecule (pegfilgrastim) with a longer half-life than the standard human G-CSF was created. Pegfilgrastim was approved in 2002 to reduce febrile neutropenia. It has been studied and shown to be equally efficacious to filgrastim, with the advantage of once-per-cycle dosing and self-regulating features of clearance of the drug during neutrophil recovery. Findings have suggested that pegfilgrastim is more effective than G-CSF in preventing febrile neutropenia, but further study is required. The use of pegfilgrastim in cycles < 3 weeks has not been approved; however, it has been studied in 2-week regimens and appears to be safe and effective. In addition, pegfilgrastim is not currently approved in bone marrow transplantation (BMT) or in pediatrics, but studies are under way.

GM-CSF (sargramostim), primarily a myeloid-lineage–specific growth factor, stimulates the production of neutrophils, monocytes, and eosinophils. It has been extensively evaluated and received a more narrow FDA approval in 1991 for clinical use in patients with nonmyeloid malignancies undergoing autologous BMT. Since that initial indication, GM-CSF has also been approved for an expanded range of conditions, such as mitigation of myelotoxicity in patients with leukemia who are undergoing induction chemotherapy.

To date, no large-scale randomized trials have directly compared the efficacy of these two CSFs in the same clinical setting. Future comparative trials may help to determine the optimal clinical utility of these CSFs in different clinical situations.