Neutropenia, defined as an absolute neutrophil count (ANC) less than 1000 neutrophils/mcL, commonly occurs in patients receiving myelosuppressive chemotherapy regimens for lymphoma. NCI classifies the disorder in 5 grades ranging from 0 to 4, with 4 being the most severe grade (ANC less than 500 neutrophils/mcL).5

Neutropenic patients may develop fever, a major adverse effect of chemotherapy that can result in treatment delays and dose reductions, leading to overall poor outcomes. Today, G-CSFs can reduce the risk of neutropenic fever.6 Smith and colleagues identified the possible indications of therapeutic use of G-CSFs: patients at risk for sepsis syndrome; patients age 65 years or older; patients at risk for profound neutropenia (defined as less than or equal to 0.1); neutropenia that is expected to last more than 10 days; patients at risk for pneumonia, invasive fungal infections, or other infections; hospitalization with fever. G-CSF are indicated for patients with poor performance, extensive prior therapy, and poor nutritional status.7 Other indications for G-CSFs are primary prophylaxis in patients at high risk due to medical history, age, disease characteristics, or myelosuppressive regimens. Other uses include stem cell mobilization and support after stem cell transplantation.5

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Adverse Effects Associated with G-CSFs

Skin Reports of skin reactions with G-CSF use include rash, urticaria, and facial edema. Delayed hypersensitivity reactions have been reported with pegfilgrastim use. Most skin reactions are believed to be caused by neutrophilic infiltration into the epidermis and dermis, and are associated with macrophage accumulation in the skin resulting in a maculopapular rash, annular desquamative eruption, or granulomatous dermatitis.8

Respiratory Respiratory symptoms such as wheezing and dyspnea are believed to occur due to polymorphonuclear mediated lung damage from neutrophil accumulation in the lung. Bleomycin is believed to cause pulmonary effects; however, in combination with a G-CSF, the harm to the lung is intensified due to resultant pulmonary edema and fibrosis.8 Other possible respiratory adverse effects include acute respiratory distress syndrome, alveolar hemorrhage, and hemoptysis.

Cardiovascular Potential cardiovascular adverse effects include tachycardia, hypotension, anaphylaxis, and capillary leak syndrome.

Bone pain The most commonly reported adverse effect is bone pain. Lambertini and colleagues identified 4 main causes for bone pain in patients receiving G-CSFs9:

Differentiation, maturation, and functional stimulation of mature cells caused by qualitative and quantitative expansion of the bone marrow. This leads to secretion of cytokines that create a form of communication between cells, which creates an inflammatory cascade that recruits other cells to make colony-stimulating factors (CSFs).

CSF stimulation of CSF receptors located on primary afferent nerve produces peripheral nociceptor sensitization to nociceptive stimuli through the development of morphological and electrophysiological changes in nerve fibers.

CSFs stimulate and recruit inflammatory cells that can sensitize their own peripheral nerve fibers, contributing to nerve remodeling through the release of inflammatory cytokines.

The direct effect of G-CSFs on bone metabolism. These agents may activate osteoclasts and osteoblasts with the final effect being bone resorption.

Additional adverse effects Clinicians administering G-CSFs should be aware of these other adverse effects that have been reported, including splenic rupture, myelodysplastic syndrome and acute myeloid leukemia, leukocytosis, thrombocytopenia, and elevated LDH levels.

Imaging G-CSFs can also influence diagnostic studies such as nuclear imaging, specifically PET scans. Transient positive bone imaging changes have been reported due to increased activity of the bone marrow in response to growth factor therapy.