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), alternativ e approaches to deliver dose-intensive regimens without stem cell supp ort 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 p rogenitor cell mass. Priming may also render progenitor populations mi totically quiescent after growth factors are withdrawn, thereby making them less sensitive to the cytotoxic effects of chemotherapy. It is a lso possible, however, that growth factor priming may worsen aplasia w hen used with dose-intensive regimens by either depleting early progen itor pools or recruiting progenitor populations into cycle. To determi ne the safety and hematopoietic efficacy of growth factor priming, 13 patients with hematologic malignancy or breast cancer were treated wit h granulocyte-macrophage colony-stimulating factor (GM-CSF) (250 mu g/ m(2) twice daily subcutaneously) until the white blood cell (WBC) coun t reached either a plateau or 100,000 cells/mu L. Forty-eight hours af ter the last dose of GM-CSF, chemotherapy was begun using high-dose et oposide and cyclophosphamide. All patients received GM-CSF after chemo therapy. Two patients were withdrawn during GM-CSF priming because the y developed urticarial rashes.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 W BC of 100,000/mu L. The kinetics of leukocyte expansion were slow; a m edian of 13 days was needed to reach the maximum WBC. Furthermore, muc h 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 hematopoiet ic recovery after high-dose etoposide and cyclophosphamide, as there w as no significant difference in 1) recovery to an ANC > 500/mu L compa red to a historical control group that received no growth factor (medi an of 29 and 30 days, respectively; p = 0.4), 2) number of days with a n ANC < 500/mu L (median of 19 and 20 days, respectively; p = 0.11), a nd 3) number of days to an untransfused platelet count greater than or equal to 50,000/mu L (median 36 and 32 days, respectively; p = 0.23). The failure of GM-CSF priming may be a result of its modest stimulati on of hematopoiesis or the expansion of a committed progenitor cell po pulation that is exquisitely sensitive to this regimen.