Interferon-alpha, zidovudine, and granulocyte-macrophage colony-stimulating factor: a phase I AIDS Clinical Trials Group study in patients with Kaposi's sarcoma associated with AIDS.

1992 ◽  
Vol 10 (8) ◽  
pp. 1344-1351 ◽  
Author(s):  
S E Krown ◽  
J Paredes ◽  
D Bundow ◽  
B Polsky ◽  
J W Gold ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Neutrophil Count ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Ifn Alpha ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE To increase the hematologic tolerance of interferon-alpha (IFN alpha) and zidovudine combination therapy by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF), and to evaluate the safety, tolerance, and potential efficacy of the combination in patients with Kaposi's sarcoma and AIDS. PATIENTS AND METHODS Seventeen patients with Kaposi's sarcoma associated with AIDS received zidovudine 200 mg orally every 4 hours and GM-CSF 5 micrograms/kg/d subcutaneously. Successive cohorts received IFN-alpha 2b at a daily subcutaneous dose of 5, 10, or 20 million units. The dose of GM-CSF was titrated to maintain the neutrophil count between 1 and 5 x 10(9) cells/L. Doses of all three drugs were reduced, as required, for nonhematologic toxicities. RESULTS GM-CSF induced leukocytosis in all patients. On average, a dose of 1.25 micrograms/kg/d was sufficient to maintain the neutrophil count within the desired range. The combination of 20 million units of IFN-alpha with zidovudine and GM-CSF induced dose-limiting toxicity in four of six patients. The major side effects were constitutional symptoms, which included malaise, anorexia, fatigue, fever, and were dose-limiting in three patients. Severe anemia and/or thrombocytopenia developed in three patients. Seven patients (41%; 95% confidence interval [CI], 18% to 64%) showed objective tumor regression that persisted for a median of 51 weeks. A rapid decrease in free-serum p24 antigen levels was observed in seven patients who had measurable levels at baseline; the mean time required to isolate human immunodeficiency virus (HIV-1) from peripheral-blood cells was increased by 7 days. The number and percentage of CD4-positive lymphocytes showed no significant change. CONCLUSIONS GM-CSF prevents neutropenia induced by the IFN-alpha and zidovudine combination and induced no adverse effects on immune function or HIV activity. However, nonhematologic toxicity precluded a major increase in the maximum-tolerated doses of IFN-alpha and zidovudine.

scholarly journals Clinical and cytogenetic responses to granulocyte-macrophage colony- stimulating factor in therapy-related myelodysplasia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2463-2470
Author(s):  
WJ Gradishar ◽  
MM Le Beau ◽  
R O'Laughlin ◽  
JW Vardiman ◽  
RA Larson
Keyword(s):  
Neutrophil Count ◽  
Effective Control ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Transfusion Requirements ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Initial Starting ◽  
Stimulating Factor ◽  
Stimulation Of

We treated 10 patients with a therapy-related myelodysplastic syndrome with escalating doses of granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) in a phase II trial and used sequential cytogenetic analyses to determine whether there was stimulation of nonclonal hematopoiesis. The GM-CSF was administered by continuous intravenous infusion over 2 hours daily for 14 days, followed by a 14- day rest period. The initial starting dose was 60 micrograms/m2/d. The GM-CSF dose was escalated within individual patients to 125 micrograms/m2, 250 micrograms/m2, and then 500 micrograms/m2/d until the peripheral blood neutrophil count at least doubled and exceeded 1,000/microL. GM-CSF treatment then continued in monthly maintenance cycles. During 57 treatment courses, the neutrophil count increased in 52 but only doubled and exceeded 1,000/microL in 21. Mild eosinophilia was stimulated in five patients, but only two had greater than 1,000 eosinophils/microL. In only three patients was any stimulation of platelet or red blood cell production observed, and thus, little change in transfusion requirements occurred. The bone marrow karyotypes from individual patients either remained completely abnormal or became increasingly abnormal over the course of treatment. We found no evidence that GM-CSF preferentially stimulated normal marrow stem cells to proliferate or had the ability to eradicate the cytogenetically abnormal clone by inducing terminal differentiation. Although the effect on granulopoiesis was transient and dependent on continued GM- CSF treatment, the increase in the neutrophil count was clinically important in some patients, allowing more effective control of ongoing infections.

Granulocyte-Macrophage Colony-Stimulating Factor Treatment Before Doxorubicin and Cyclophosphamide Chemotherapy Priming in Women With Early-Stage Breast Cancer

1999 ◽  
Vol 17 (11) ◽  
pp. 3426-3430 ◽  
Author(s):  
Nathan L. Kobrinsky ◽  
Diane E. Sjolander ◽  
Mary S. Cheang ◽  
Ralph Levitt ◽  
Preston D. Steen
Keyword(s):  
Breast Cancer ◽  
Neutrophil Count ◽  
Early Stage ◽  
Early Stage Breast Cancer ◽  
Colony Stimulating Factor ◽  
Cytotoxic Effects ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 ± 2.5 days v 14.8 ± 1.5 days, respectively; P = .0001) and platelet nadir (mean ± SD, 10.1 ± 1.9 days v 11.1 ± 2.2 days, P < .05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean ± SD, 490 ± 310/μL v 550 ± 350/μL, respectively; P = .2); however, on day 16 the mean neutrophil count was higher (mean ± SD, 1030 ± 580/μL v 690 ± 370/μL, P = .004), and the proportion of patients with a neutrophil count less than 500/μL was lower after priming than before (six of 35 or 17.1% v 12 of 34 or 35.3%, respectively; P = .04). The platelet nadir was higher (mean ± SD, 166,000 ± 51,000/μL after priming v 151,000 ± 45,000/μL before priming, P = .007), and the duration of thrombocytopenia, ie, a platelet count less than 150,000/μL, was shorter (1.5 ± 2.1 days v 2.8 ± 2.9 days, P = .0025) after priming. Episodes of fever and neutropenia were not observed. CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (< 500/μL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy.

scholarly journals Clinical and cytogenetic responses to granulocyte-macrophage colony- stimulating factor in therapy-related myelodysplasia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2463-2470 ◽  
Author(s):  
WJ Gradishar ◽  
MM Le Beau ◽  
R O'Laughlin ◽  
JW Vardiman ◽  
RA Larson
Keyword(s):  
Neutrophil Count ◽  
Effective Control ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Transfusion Requirements ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Initial Starting ◽  
Stimulating Factor ◽  
Stimulation Of

Abstract We treated 10 patients with a therapy-related myelodysplastic syndrome with escalating doses of granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) in a phase II trial and used sequential cytogenetic analyses to determine whether there was stimulation of nonclonal hematopoiesis. The GM-CSF was administered by continuous intravenous infusion over 2 hours daily for 14 days, followed by a 14- day rest period. The initial starting dose was 60 micrograms/m2/d. The GM-CSF dose was escalated within individual patients to 125 micrograms/m2, 250 micrograms/m2, and then 500 micrograms/m2/d until the peripheral blood neutrophil count at least doubled and exceeded 1,000/microL. GM-CSF treatment then continued in monthly maintenance cycles. During 57 treatment courses, the neutrophil count increased in 52 but only doubled and exceeded 1,000/microL in 21. Mild eosinophilia was stimulated in five patients, but only two had greater than 1,000 eosinophils/microL. In only three patients was any stimulation of platelet or red blood cell production observed, and thus, little change in transfusion requirements occurred. The bone marrow karyotypes from individual patients either remained completely abnormal or became increasingly abnormal over the course of treatment. We found no evidence that GM-CSF preferentially stimulated normal marrow stem cells to proliferate or had the ability to eradicate the cytogenetically abnormal clone by inducing terminal differentiation. Although the effect on granulopoiesis was transient and dependent on continued GM- CSF treatment, the increase in the neutrophil count was clinically important in some patients, allowing more effective control of ongoing infections.

Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity.

1998 ◽  
Vol 16 (7) ◽  
pp. 2352-2358 ◽  
Author(s):  
H Gómez ◽  
L Mas ◽  
L Casanova ◽  
D L Pen ◽  
S Santillana ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Hematologic Toxicity ◽  
Colony Stimulating Factor ◽  
Chop Chemotherapy ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkin's lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.

scholarly journals A phase I/II study of sequential interleukin-3 and granulocyte- macrophage colony-stimulating factor in myelodysplastic syndromes

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 357-360 ◽  
Author(s):  
S Nand ◽  
J Sosman ◽  
JE Godwin ◽  
RI Fisher
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Neutrophil Count ◽  
Myelodysplastic Syndromes ◽  
Refractory Anemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract In this phase I/II study, 9 patients with myelodysplastic syndromes (MDS) were treated with interleukin-3 (IL-3) followed by granulocyte- macrophage colony-stimulating factor (GM-CSF). Each treatment cycle was 28 days long and administered as follows: 1 microgram/kg/d IL-3 on days 1 through 7 and 3 micrograms/kg/d GM-CSF for days 8 through 21, followed by a 7-day rest period. IL-3 dose escalations were planned, but the dose of GM-CSF was fixed. Three patients had refractory anemia, 4 had refractory anemia with ringed sideroblasts, and 2 had refractory anemia with excess blasts. Six patients were dependent on red blood cell transfusions, 1 on platelet transfusions, and 2 on both. The absolute neutrophil count improved in 7 (77%) patients and the platelet count improved in 3 (33%) patients during therapy. Hemoglobin levels were unchanged. A clinically relevant response was seen in only 1 patient with thrombocytopenia, and he received five cycles of therapy. The neutrophil count decreased in 2 patients and the platelet count decreased in 4 patients during treatment. The toxicity of the treatment was significant. In the first cohort of 3 patients, 1 patient developed supraventricular tachycardia and congestive heart failure. In the second group, 1 patient developed progressive granulocytopenia and died of gram-negative septicemia. Because of the disparate toxicity, 3 more patients were treated at the same dose level. One of these experienced a high fever and bone pain requiring hospitalization. Because of these adverse effects, the IL-3 dose was not escalated and all patients received 1 microgram/kg/d for 7 days. We believe that sequential therapy with IL-3 and GM-CSF at these dose levels causes unacceptable toxicity in patients with MDS. The major toxic events occurred during weeks 4 and 5 after starting treatment and may have been primarily caused by GM-CSF therapy. Although neutrophil counts improve in most patients, the effect on red blood cells and platelets is minimal. At present, this form of therapy remains problematic and appears to have a limited potential in the management of MDS.

scholarly journals A phase I/II study of sequential interleukin-3 and granulocyte- macrophage colony-stimulating factor in myelodysplastic syndromes

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 357-360 ◽  
Author(s):  
S Nand ◽  
J Sosman ◽  
JE Godwin ◽  
RI Fisher
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Neutrophil Count ◽  
Myelodysplastic Syndromes ◽  
Refractory Anemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

In this phase I/II study, 9 patients with myelodysplastic syndromes (MDS) were treated with interleukin-3 (IL-3) followed by granulocyte- macrophage colony-stimulating factor (GM-CSF). Each treatment cycle was 28 days long and administered as follows: 1 microgram/kg/d IL-3 on days 1 through 7 and 3 micrograms/kg/d GM-CSF for days 8 through 21, followed by a 7-day rest period. IL-3 dose escalations were planned, but the dose of GM-CSF was fixed. Three patients had refractory anemia, 4 had refractory anemia with ringed sideroblasts, and 2 had refractory anemia with excess blasts. Six patients were dependent on red blood cell transfusions, 1 on platelet transfusions, and 2 on both. The absolute neutrophil count improved in 7 (77%) patients and the platelet count improved in 3 (33%) patients during therapy. Hemoglobin levels were unchanged. A clinically relevant response was seen in only 1 patient with thrombocytopenia, and he received five cycles of therapy. The neutrophil count decreased in 2 patients and the platelet count decreased in 4 patients during treatment. The toxicity of the treatment was significant. In the first cohort of 3 patients, 1 patient developed supraventricular tachycardia and congestive heart failure. In the second group, 1 patient developed progressive granulocytopenia and died of gram-negative septicemia. Because of the disparate toxicity, 3 more patients were treated at the same dose level. One of these experienced a high fever and bone pain requiring hospitalization. Because of these adverse effects, the IL-3 dose was not escalated and all patients received 1 microgram/kg/d for 7 days. We believe that sequential therapy with IL-3 and GM-CSF at these dose levels causes unacceptable toxicity in patients with MDS. The major toxic events occurred during weeks 4 and 5 after starting treatment and may have been primarily caused by GM-CSF therapy. Although neutrophil counts improve in most patients, the effect on red blood cells and platelets is minimal. At present, this form of therapy remains problematic and appears to have a limited potential in the management of MDS.

scholarly journals Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jani Lappalainen ◽  
Nicolas Yeung ◽  
Su D. Nguyen ◽  
Matti Jauhiainen ◽  
Petri T. Kovanen ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Foam Cells ◽  
Colony Stimulating Factor ◽  
Human Macrophages ◽  
Gm Csf ◽  
Macrophage Subpopulations ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

AbstractIn atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte–macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.

The Truncated Splice Variant of the Granulocyte-Macrophage-Colony-Stimulating Factor Receptor β- Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns

Neonatology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Verena Schulte ◽  
Alexandra Sipol ◽  
Stefan Burdach ◽  
Esther Rieger-Fackeldey
Keyword(s):  
Respiratory Failure ◽  
Peripheral Blood ◽  
Colony Stimulating Factor ◽  
Term Infants ◽  
Respiratory Impairment ◽  
Gm Csf ◽  
A Subunit ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

<b><i>Background:</i></b> The granulocyte-macrophage-colony-stimulating factor (GM-CSF) plays an important role in surfactant homeostasis. β<sub>C</sub> is a subunit of the GM-CSF receptor (GM-CSF-R), and its activation mediates surfactant catabolism in the lung. β<sub>IT</sub> is a physiological, truncated isoform of β<sub>C</sub> and is known to act as physiological inhibitor of β<sub>C</sub>. <b><i>Objective:</i></b> The aim of this study was to determine the ratio of β<sub>IT</sub> and β<sub>C</sub> in the peripheral blood of newborns and its association with the degree of respiratory failure at birth. <b><i>Methods:</i></b> We conducted a prospective cohort study in newborns with various degrees of respiratory impairment at birth. Respiratory status was assessed by a score ranging from no respiratory impairment (0) to invasive respiratory support (3). β<sub>IT</sub> and β<sub>C</sub> expression were determined in peripheral blood cells by real-time PCR. β<sub>IT</sub> expression, defined as the ratio of β<sub>IT</sub> and β<sub>C</sub>, was correlated with the respiratory score. <b><i>Results:</i></b> β<sub>IT</sub> expression was found in all 59 recruited newborns with a trend toward higher β<sub>IT</sub> in respiratory ill (score 2, 3) newborns than respiratory healthy newborns ([score 0, 1]; <i>p</i> = 0.066). Seriously ill newborns (score 3) had significantly higher β<sub>IT</sub> than healthy newborns ([score 0], <i>p</i> = 0.010). Healthy preterm infants had significantly higher β<sub>IT</sub> expression than healthy term infants (<i>p</i> = 0.019). <b><i>Conclusions:</i></b> β<sub>IT</sub> is expressed in newborns with higher expression in respiratory ill than respiratory healthy newborns. We hypothesize that β<sub>IT</sub> may have a protective effect in postnatal pulmonary adaptation acting as a physiological inhibitor of β<sub>C</sub> and, therefore, maintaining surfactant in respiratory ill newborns.

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