Hematopoietic recovery following high-dose combined alkylating-agent chemotherapy and autologous bone marrow support in patients in phase-I clinical trials of colony-stimulating factors: G-CSF, GM-CSF, IL-1, IL-2, M-CSF.
Hematopoietic recovery in 115 patients with metastatic breast cancer or metastatic melanoma, enrolled in phase-I studies of recombinant growth factors while undergoing treatment with high-dose chemotherapy with autologous bone marrow support, was examined with assays of bone marrow progenitor cells and peripheral blood progenitor cells, and by evaluation of peripheral blood counts. Groups of patients receiving hematopoietic cytokine support [with interleukin-1 (IL-1), interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or monocyte CSF (M-CSF)] post marrow infusion were compared with contemporaneous control patients not receiving growth factor support. Patients receiving GM-CSF demonstrated statistically significant increases in the growth of granulocyte/macrophage colony-forming units (CFU-GM) in the bone marrow and peripheral blood compared with control patients. The effect of GM-CSF was dose dependent in the early period post marrow infusion (day +6) with bone marrow CFU-GM colonies at doses 8-16 micrograms/kg/day 34 times those measured in controls. Significant increases in bone marrow multipotential progenitor cells (CFU-GEMM) were seen in patients receiving GM-CSF day +21 post marrow infusion. Patients receiving IL-1 demonstrated significant increases in bone marrow CFU-GM at day +21, maximal at dosages of 24-32 ng/kg/day. There were no significant increases in burst forming unit-erythroid (BFU-E) among any study group. Patients receiving G-CSF had significantly increased absolute neutrophil counts (ANC) and total white blood cell counts (WBC) by day +11 post transplant compared with control patients. Patients receiving GM-CSF demonstrated significantly increased WBC (greater than 2000/mm3) at day +11 and ANC greater than 500/mm3 at day +16. Optimal dose of G-CSF and GM-CSF to stimulate neutrophil recovery post transplant was 4-8 micrograms/kg/day and 8-16 micrograms/kg/day, respectively. Platelet recovery did not differ among the six study groups. These data demonstrate accelerated myeloid recovery after high-dose chemotherapy and autologous bone marrow support in patients receiving either G-CSF or GM-CSF. Moreover, GM-CSF and IL-1 stimulate myelopoiesis at the level of bone marrow CFU-GM, while G-CSF causes earlier neutrophil recovery peripherally.
Laughlin
M J
MJ
Duke University Bone Marrow Transplant Program, Duke University Medical Center, Durham, NC.
Kirkpatrick
G
G
Sabiston
N
N
Peters
W
W
Kurtzberg
J
J
D000477:Alkylating Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000188:drug therapy*; D003114:Colony-Forming Units Assay; D003115:Colony-Stimulating Factors / Q000627:therapeutic use* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count / Q000187:drug effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use / Q000633:toxicity; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use / Q000633:toxicity; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000627:therapeutic use / Q000633:toxicity; D007376:Interleukin-2 / Q000627:therapeutic use / Q000633:toxicity; D007958:Leukocyte Count / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000627:therapeutic use / Q000633:toxicity*; D008545:Melanoma / Q000188:drug therapy*; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D013997:Time Factors; D014182:Transplantation, Autologous
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D003115:Colony-Stimulating Factors; D007375:Interleukin-1; D007376:Interleukin-2; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor