Forms of G-CSF

Two different polypeptides are synthesized from the gene for G-CSF by differential splicing of mRNA. The two polypeptides differ by the presence or absence of three amino acids. Expression studies indicate that both have authentic G-CSF activity.

G-CSF receptor

G-CSF binds to a single high-affinity receptor. This receptor is expressed early in neutrophil development, but reaches the greatest density on mature neutrophils.

The G-CSF receptor is a single polypeptide containing 813 amino acids. It transduces signals that regulate the proliferation, maturation, and survival of myeloid progenitor cells. The cytoplasmic region proximal to the membrane of the receptor transduces proliferative and survival signals, whereas the distal C-terminal region transduces maturation signals and suppresses the receptor's proliferative signals.

Biologic activities of G-CSF

G-CSF is a relatively specific stimulator of the growth and differentiation of hematopoietic progenitor cells committed to the neutrophil lineage. It also protects neutrophils from apoptosis and enhances their function (chemotaxis, phagocytosis, oxidative responses, and microbicidal activity). Finally, G-CSF moves mature neutrophils from the marrow into the circulation.

G-CSF in human illness

In healthy persons, mean ± SD G-CSF levels are 25± 19.7 pg/ml. G-CSF levels increase by 30-fold in infection and by 10,000-fold in septic shock.¹⁸ Some patients with solid tumors present with significantly increased leukocyte counts (leukemoid reaction). In several of these individuals, elevated serum levels of G-CSF (or GM-CSF) have been demonstrated and probably account for the rise in white blood cell count.¹⁰ Presumably, G-CSF (or GM-CSF) is produced by the tumor itself.

Point mutations in the gene for the G-CSF receptor have been described in patients with AML, which evolved from severe congenital neutropenia. These mutations truncate the C-terminal cytoplasmic region of the G-CSF receptor and hence are presumed to disrupt the maturation signal of the receptor.¹⁴

Clinical indications for G-CSF

G-CSF promotes a rapid increase in neutrophilic leukocytes, which lasts about 24 hours. Despite the multitude of patients who have received G-CSF, few toxicities have been reported. Even very long-term G-CSF administration appears fairly innocuous; the most common side effect is bone pain.

Studies of G-CSF as an adjunct to standard-dose cytotoxic chemotherapy for solid tumors and lymphomas demonstrate that the duration of neutropenia, the number of days of hospitalization, and the number of days of antibiotic treatment are reduced significantly during G-CSF cycles. Placebo-controlled studies in patients with small cell lung cancer showed a clinically significant protective effect of G-CSF against febrile neutropenia.¹⁵ Significantly more patients recovered from chemotherapy-induced neutropenia in time to receive their next chemotherapy dose while on G-CSF cycles, compared with non-G-CSF cycles. After high-dose chemotherapy (both myeloablative and nonmyeloablative), recovery from neutropenia and its associated complications is more rapid when patients receive G-CSF. These studies suggest that the dose intensity of nonmyeloablative chemotherapy (in terms of total dose per unit time) can be increased with G-CSF support, by allowing higher doses of cytotoxic agents to be administered, by compressing the duration of chemotherapy cycles, or both. The efficacy of adding G-CSF to broad spectrum antibiotics in patients with high risk neutropenia has recently also been demonstrated.¹⁸

In the transplantation setting, the administration of G-CSF results in reductions in neutropenia and infection.¹⁶ G-CSF also mobilizes autologous peripheral blood progenitor cells; these cells are used to accelerate hematopoietic recovery in patients who have received myeloablative or myelosuppressive chemotherapy.¹⁷

In patients with de novo AML, G-CSF administration is associated with reductions in the time to neutrophil recovery and the duration of fever.¹⁹ However, there are no statistically significant differences between the G-CSF-treated and the placebo-treated groups, in terms of treatment outcome parameters-complete remission or relapse-free survival.

More than 90% of patients with severe chronic neutropenias (congenital, cyclic, or idiopathic) show increases in absolute neutrophil count and reductions in the incidence of fevers, mouth ulcers, and other infection-related events after G-CSF treatment.^12,20 Finally, in patients with acquired immune deficiency syndrome (AIDS), G-CSF reverses and prevents zidovudine-induced neutropenia.²¹ Of interest, G-CSF may also be useful in enhancing the defenses of non-neutropenic patients with AIDS who have bacterial infections. Studies have, however, shown only modest benefit for G-CSF in the setting of non-neutropenic infection in normal individuals.¹³

A new form of G-CSF has recently been developed-a conjugate of G-CSF and monomethoxypolyethylene glycol. Pegylated G-CSF has a prolonged half-life because of its reduced renal clearance. Serum clearance is directly related to neutrophil number. As a result, only a single s.c. dose of pegylated G-CSF (Neulasta) is required after chemotherapy. Based on the results of randomized, blinded trials, this molecule is indicated to decrease the incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy with a significant incidence of febrile neutropenia.²¹