Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming of high-dose etoposide and cyclophosphamide: a pilot trial.
Given the limitations of bone marrow transplantation (BMT), alternative approaches to deliver dose-intensive regimens without stem cell support are needed. Administration of hematopoietic growth factors before high-dose chemotherapy (priming) may reduce myelosuppression directly, delaying the onset of neutropenia by expanding the mature neutrophil compartment, and shortening the duration of neutropenia by expanding progenitor cell mass. Priming may also render progenitor populations mitotically quiescent after growth factors are withdrawn, thereby making them less sensitive to the cytotoxic effects of chemotherapy. It is also possible, however, that growth factor priming may worsen aplasia when used with dose-intensive regimens by either depleting early progenitor pools or recruiting progenitor populations into cycle. To determine the safety and hematopoietic efficacy of growth factor priming, 13 patients with hematologic malignancy or breast cancer were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) (250 micrograms/m2 twice daily subcutaneously) until the white blood cell (WBC) count reached either a plateau or 100,000 cells/microL. Forty-eight hours after the last dose of GM-CSF, chemotherapy was begun using high-dose etoposide and cyclophosphamide. All patients received GM-CSF after chemotherapy. Two patients were withdrawn during GM-CSF priming because they developed urticarial rashes. The maximum median increases in WBC and absolute neutrophil count (ANC) during GM-CSF priming were 7.1- and 4.4-fold, respectively. Only one patient achieved the original target WBC of 100,000/microL. The kinetics of leukocyte expansion were slow; a median of 13 days was needed to reach the maximum WBC. Furthermore, much of the leukocyte expansion was caused by an increase in eosinophils, which would not be expected to accelerate hematopoietic recovery. GM-CSF priming did not appear to have a significant impact on hematopoietic recovery after high-dose etoposide and cyclophosphamide, as there was no significant difference in 1) recovery to an ANC > 500/microL compared to a historical control group that received no growth factor (median of 29 and 30 days, respectively; p = 0.4), 2) number of days with an ANC < 500/microL (median of 19 and 20 days, respectively; p = 0.11), and 3) number of days to an untransfused platelet count > or = 50,000/microL (median 36 and 32 days, respectively; p = 0.23). The failure of GM-CSF priming may be a result of its modest stimulation of hematopoiesis or the expansion of a committed progenitor cell population that is exquisitely sensitive to this regimen.
Department of Hematological Oncology, Roswell Park Cancer Institute, Buffalo, NY.
S H
SH
Bernstein
N P
NP
Christiansen
J P
JP
Fay
R
R
Brown
R
R
Herzig
S
S
Frankel
L
L
Blumenson
G P
GP
Herzig
D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000633:toxicity; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D007964:Leukocytosis / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013234:Stem Cells / Q000187:drug effects*; D019172:Transplantation Conditioning
D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide