Use of granulocyte-macrophage colony-stimulating factor in patients with malignancy and bone marrow failure

1990 ◽  
Vol 8 (S1) ◽  
pp. 303-313 ◽  
Author(s):  
Richard K. Shadduck ◽  
Craig S. Rosenfeld ◽  
Matthew Sulecki ◽  
Nabil Phillips ◽  
Donna Przepiorka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Stimulation of hematopoiesis in patients with bone marrow failure and in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 134-141 ◽  
Author(s):  
S Vadhan-Raj ◽  
S Buescher ◽  
A LeMaistre ◽  
M Keating ◽  
R Walters ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Fixed Dose ◽  
Red Cell ◽  
Colony Stimulating Factor ◽  
Advanced Malignancy ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotential hematopoietin. To assess the toxicity and biological activity of recombinant human GM-CSF (rhGM-CSF) in vivo, 25 patients with malignancy or bone marrow failure were treated with rhGM-CSF (specific activity approximately 5 x 10(7) U/mg) as part of a phase 1 trial. The treatment was administered by continuous intravenous (IV) infusion daily for 2 weeks at fixed dose levels and repeated after a 2- week rest period. Over the entire dose range tested (15 to 500 micrograms/m2/d), rhGM-CSF treatment was associated with dramatic increases (two- to 70-fold) in total leukocyte counts, which consisted predominantly of neutrophils, bands, eosinophils, and monocytes. Furthermore, six of the 14 patients with one or more cytopenias that received at least two cycles of treatment had multilineage responses characterized by twofold or greater increases in platelet count to a level above 100,000, twofold or greater increases in corrected reticulocyte count, and a reduced requirement for red cell transfusions. Three of these patients became independent of both red cell and platelet transfusions for 17 to 37 weeks of follow-up. Treatment was associated also with an increase in bone marrow cellularity and frequency of cycling progenitor cells. The treatment was well tolerated; side effects included constitutional symptoms and bone pain. These results demonstrated that rhGM-CSF has a significant impact on hematopoiesis in patients with advanced malignancy and also in patients with bone marrow failure.

scholarly journals Stimulation of hematopoiesis in patients with bone marrow failure and in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 134-141 ◽  
Author(s):  
S Vadhan-Raj ◽  
S Buescher ◽  
A LeMaistre ◽  
M Keating ◽  
R Walters ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Fixed Dose ◽  
Red Cell ◽  
Colony Stimulating Factor ◽  
Advanced Malignancy ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotential hematopoietin. To assess the toxicity and biological activity of recombinant human GM-CSF (rhGM-CSF) in vivo, 25 patients with malignancy or bone marrow failure were treated with rhGM-CSF (specific activity approximately 5 x 10(7) U/mg) as part of a phase 1 trial. The treatment was administered by continuous intravenous (IV) infusion daily for 2 weeks at fixed dose levels and repeated after a 2- week rest period. Over the entire dose range tested (15 to 500 micrograms/m2/d), rhGM-CSF treatment was associated with dramatic increases (two- to 70-fold) in total leukocyte counts, which consisted predominantly of neutrophils, bands, eosinophils, and monocytes. Furthermore, six of the 14 patients with one or more cytopenias that received at least two cycles of treatment had multilineage responses characterized by twofold or greater increases in platelet count to a level above 100,000, twofold or greater increases in corrected reticulocyte count, and a reduced requirement for red cell transfusions. Three of these patients became independent of both red cell and platelet transfusions for 17 to 37 weeks of follow-up. Treatment was associated also with an increase in bone marrow cellularity and frequency of cycling progenitor cells. The treatment was well tolerated; side effects included constitutional symptoms and bone pain. These results demonstrated that rhGM-CSF has a significant impact on hematopoiesis in patients with advanced malignancy and also in patients with bone marrow failure.

Down-regulation of osteoprotegerin production in bone marrow macrophages by macrophage colony-stimulating factor

Cytokine ◽  
2005 ◽  
Vol 31 (4) ◽  
pp. 288-297 ◽  
Author(s):  
Naoko Yamada ◽  
Tohru Tsujimura ◽  
Haruyasu Ueda ◽  
Shin-Ichi Hayashi ◽  
Hideki Ohyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Colony Stimulating Factor ◽  
Down Regulation ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation

2008 ◽  
Vol 295 (1) ◽  
pp. L114-L122 ◽  
Author(s):  
Megan N. Ballinger ◽  
Leah L. N. Hubbard ◽  
Tracy R. McMillan ◽  
Galen B. Toews ◽  
Marc Peters-Golden ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Host Defense ◽  
Receptor Expression ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Bacterial Killing ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E2(PGE2) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF−/− donors (GM-CSF−/− BMT) with untransplanted mice. GM-CSF−/− BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF−/− BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF−/− BMT mice overproduced PGE2, but expression of the inhibitory EP2receptor was diminished. As a consequence of decreased EP2receptor expression, we found diminished accumulation of cAMP in response to PGE2stimulation in GM-CSF−/− BMT AMs compared with control BMT AMs. In addition, GM-CSF−/− BMT AMs retained cysteinyl leukotriene production and normal TNF-α response compared with AMs from control BMT mice. GM-CSF−/− BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF−/− recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT.

scholarly journals Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support

Blood ◽  
1993 ◽  
Vol 81 (9) ◽  
pp. 2452-2459 ◽  
Author(s):  
J Rabinowitz ◽  
WP Petros ◽  
AR Stuart ◽  
WP Peters
Keyword(s):  
Bone Marrow ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
Tnf Alpha ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Autologous Bone ◽  
Macrophage Colony ◽  
Stimulating Factor

Endogenous cytokines are thought to mediate numerous biologic processes and may account for some adverse effects experienced following the administration of recombinant proteins. This study describes the pattern of endogenous cytokine exposure following high-dose chemotherapy. Blood concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF), and erythropoietin (EPO) were measured by enzyme-linked immunosorbent assay (ELISA) methods in 68 patients receiving the same ablative chemotherapy regimen (cyclophosphamide, cisplatin, carmustine). Patients were grouped according to cellular support (autologous bone marrow [BM] CSF-primed peripheral blood progenitor cells [PBPCs]) and prescribed growth factor (recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor [rHuG- CSF or rHuGM-CSF]). Leukocyte reconstitution was most accelerated in the groups treated with PBPCs and rHuG-CSF. IL-6, M-CSF, and TNF-alpha concentrations were higher in the groups treated with rHuGM-CSF and without PBPCs. Maximal endogenous cytokine concentrations occurred approximately 12 days after BM reinfusion. High concentrations of EPO occurred in patients experiencing significant hypotension despite routine transfusions for hematocrit < 42%. High M-CSF and IL-6 levels were associated with increased platelet transfusion requirements. Concentrations of all four cytokines were significantly higher in patients experiencing renal or hepatic toxicity, with elevations occurring in a predictable sequence and M-CSF elevations occurring first. This report shows that endogenous cytokine concentrations may be influenced by either cellular or CSF support and are associated with differences in platelet reconstitution and organ toxicity.

scholarly journals Enhanced survival but reduced engraftment in murine recipients of recombinant granulocyte/macrophage colony-stimulating factor following transplantation of T-cell-depleted histoincompatible bone marrow

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1148-1154 ◽  
Author(s):  
BR Blazar ◽  
MB Widmer ◽  
CC Soderling ◽  
S Gillis ◽  
DA Vallera
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Hematological Parameters ◽  
Donor Cell ◽  
Colony Stimulating Factor ◽  
Murine Bone Marrow ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract In vivo administration of murine recombinant granulocyte/macrophage colony stimulating factor (rGM-CSF) was evaluated for effects on survival and engraftment in an allogeneic murine bone marrow transplantation (BMT) model involving T-cell depletion of donor marrow. The model provides a high incidence of graft failure/rejection. Recipients of continuous subcutaneous infusions of rGM-CSF had a significant survival advantage when compared with untreated controls. However, a significantly lower incidence of donor cell engraftment was noted. Hematological parameters were not substantially affected. When rGM-CSF was administered intraperitoneally (IP), twice daily injections closely approximated the effects of continuous infusion on survival. Single IP injections were without significant effects on survival or engraftment. These results demonstrate that prolonged frequent in vivo exposure to rGM-CSF can significantly improve survival but significantly decreases donor cell repopulation in recipients of T-cell- depleted histoincompatible marrow grafts.

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