Biologic and clinical effects of granulocyte colony-stimulating factor in normal individuals.

RANULOCYTE colony-stimulating factor (G-CSF) is G a hematopoietic cytokine produced by monocytes, fibroblasts, and endothelial cells.’” G-CSF is known to have multiple functions in normal, steady-state hematopoiesis such as the regulation of neutrophil production and release from the bone marrow, neutrophil progenitor proliferation and differentiation, and the state of functional activation of neutrophils. Genetically engineered recombinant human G-CSF, now available both in a nonglycosylated (filgrastim) and glycosylated (lenograstim) form, was introduced in phase I clinical trials about 8 years ago! At pharmacologic doses ranging from 1 to 70 pgkg/d, it was found to have reproducible biologic and clinical activity in various settings, such as chronic idiopathic neutropenia, chemotherapy-induced myelosuppression, recovery from aplasia after allogeneic or autologous marrow transplantation and mobilization of CD34’ progenitor cells in the peripheral circulation with or without prior chemotherapy.’ Its expanding use since then, occasionally for indications not clearly supported by available evidence, led recently to the formulation of recommendations on the use of hematopoietic colony-stimulating factors (G-CSF and granulocyte-macrophage colony-stimulating factor [GM-CSF]) by the American Society for Clinical Oncology.6 G-CSF at low doses (3.5 to 6 pglkgld) has been successfully administered with minimal toxicity to normal subjects to improve the yield of granulocyte collections by leukaphere~is.’.~ Similarly, G-CSF was well tolerated when administered to normal subjects to mobilize (and collect) peripheral blood progenitor cells (PBPCs) for syngeneic transplantation.” Based on such initial experience, over the past 2 years, the use of G-CSF in normal individuals has undergone a substantial increase, with the focus on mobilizing and collecting by leukapheresis PBPCs for allografting in HLAidentical and, to a lesser extent, HLA-nonidentical patients with hematologic malignancies.”-” Although preliminary reports seem to indicate an acceptable short-term toxicity profile despite doses up to 16 ,~g/kg/d,”-’~ the number of normal donors treated so far has been relatively small (particularly at the higher dose levels) and legitimate concerns remain about the short-term and particularly long-term safety of GCSF. On the other hand, collecting granulocytes from GCSF-mobilized normal donors is now a recognized blood banking pr~cedure .~ .~ As allografting with G-CSF-mobilized PBPCs is gaining considerable momentum in transplant centers worldwide,”-’6 the time seems appropriate to review available information on the biologic and clinical effects of G-CSF administration in normal subjects. Because most of the currently available literature on G-CSF refers to filgrastim, in the remainder of this review the terms G-CSF and filgrastim will be used interchangeably, unless otherwise specified.