Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1190-1197
Author(s):  
T Buchner ◽  
W Hiddemann ◽  
M Koenigsmann ◽  
M Zuhlsdorf ◽  
B Wormann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

To reduce critical neutropenia after chemotherapy (CT) for acute myeloid leukemia (AML) we administered recombinant human granulocyte- macrophage colony-stimulating factor (GM-CSF) to patients over the age of 65 years with newly diagnosed AML and to patients with early or second relapse. CT was 9-day 6-thioguanine, ara-C, and daunorubicin (TAD9) in newly diagnosed AML and sequential high-dose ara-C and mitoxantrone (S-HAM) for relapse. In patients whose bone marrow was free from blasts a continuous intravenous infusion of GM-CSF 250 micrograms/m2/d started on day 4 after CT. Thirty-six patients entered the study and 30 of them did receive GM-CSF. For comparison, a historical control group of 56 patients was used. Complete remission rate was 50% (18 of 36) versus 32% in controls (P = .09), and early death rate was 14% versus 39% (P = .009). Treatment with GM-CSF was not associated with major adverse events. Two patients showed a marked leukemic regrowth that was completely reversible in one patient and appeared to be GM-CSF independent in the other patient. Remission duration does not seem to be reduced after GM-CSF. Under GM-CSF the blood neutrophils recovered 6 and 9 days earlier in the TAD9 (P = .009) and S-HAM (P = .043) groups associated with a rapid clearance of infections in most patients. We conclude that GM-CSF was of therapeutic benefit to our patients and this provides a basis for larger controlled trials.

scholarly journals Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1190-1197 ◽  
Author(s):  
T Buchner ◽  
W Hiddemann ◽  
M Koenigsmann ◽  
M Zuhlsdorf ◽  
B Wormann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract To reduce critical neutropenia after chemotherapy (CT) for acute myeloid leukemia (AML) we administered recombinant human granulocyte- macrophage colony-stimulating factor (GM-CSF) to patients over the age of 65 years with newly diagnosed AML and to patients with early or second relapse. CT was 9-day 6-thioguanine, ara-C, and daunorubicin (TAD9) in newly diagnosed AML and sequential high-dose ara-C and mitoxantrone (S-HAM) for relapse. In patients whose bone marrow was free from blasts a continuous intravenous infusion of GM-CSF 250 micrograms/m2/d started on day 4 after CT. Thirty-six patients entered the study and 30 of them did receive GM-CSF. For comparison, a historical control group of 56 patients was used. Complete remission rate was 50% (18 of 36) versus 32% in controls (P = .09), and early death rate was 14% versus 39% (P = .009). Treatment with GM-CSF was not associated with major adverse events. Two patients showed a marked leukemic regrowth that was completely reversible in one patient and appeared to be GM-CSF independent in the other patient. Remission duration does not seem to be reduced after GM-CSF. Under GM-CSF the blood neutrophils recovered 6 and 9 days earlier in the TAD9 (P = .009) and S-HAM (P = .043) groups associated with a rapid clearance of infections in most patients. We conclude that GM-CSF was of therapeutic benefit to our patients and this provides a basis for larger controlled trials.

scholarly journals Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony- stimulating factor

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1766-1769
Author(s):  
EH Estey ◽  
D Dixon ◽  
HM Kantarjian ◽  
MJ Keating ◽  
K McCredie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Early Death ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

scholarly journals Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony- stimulating factor

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1766-1769 ◽  
Author(s):  
EH Estey ◽  
D Dixon ◽  
HM Kantarjian ◽  
MJ Keating ◽  
K McCredie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Early Death ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia.

1997 ◽  
Vol 15 (12) ◽  
pp. 3496-3506 ◽  
Author(s):  
B Löwenberg ◽  
M A Boogaerts ◽  
S M Daenen ◽  
G E Verhoef ◽  
A Hagenbeek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Outcome ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

PURPOSE The hematopoietic growth factors (HGFs) introduced into induction chemotherapy (CT) of acute myeloid leukemia (AML) might be of benefit to treatment outcome by at least two mechanisms. HGFs given on days simultaneously with CT might sensitize the leukemic cells and enhance their susceptibility to CT. HGFs applied after CT might hasten hematopoietic recovery and reduce morbidity or mortality. MATERIALS AND METHODS We set out to evaluate the use of granulocyte-macrophage colony-stimulating factor (GM-CSF; 5 microg/kg) in a prospective randomized study of factorial design (yes or no GM-CSF during CT, and yes or no GM-CSF after CT) in patients aged 15 to 60 years (mean, 42) with newly diagnosed AML. GM-CSF was applied as follows: during CT only (+/-, n = 64 assessable patients), GM-CSF during and following CT (+/+, n = 66), no GM-CSF (-/-, n = 63), or GM-CSF after CT only (-/+, n = 60). RESULTS The complete response (CR) rate was 77%. At a median follow-up time of 42 months, probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years were 38% and 37% in all patients. CR rates, OS, and DFS did not differ between the treatment groups (intention-to-treat analysis). Neutrophil recovery (1.0 x 10(9)/L) and monocyte recovery were significantly faster in patients who received GM-CSF after CT (26 days v 30 days; neutrophils, P < .001; monocytes, P < .005). Platelet regeneration, transfusion requirements, use of antibiotics, frequency of infections, and duration of hospitalization did not vary as a function of any of the therapeutic GM-CSF modalities. More frequent side effects (eg, fever and fluid retention) were noted in GM-CSF-treated patients predominantly related to the use of GM-CSF during CT. CONCLUSION Priming of AML cells to the cytotoxic effects of CT by the use of GM-CSF during CT or accelerating myeloid recovery by the use of GM-CSF after CT does not significantly improve treatment outcome of young and middle-aged adults with newly diagnosed AML.

scholarly journals Gene Immunotherapy in Murine Acute Myeloid Leukemia: Granulocyte-Macrophage Colony-Stimulating Factor Tumor Cell Vaccines Elicit More Potent Antitumor Immunity Compared With B7 Family and Other Cytokine Vaccines

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 222-230 ◽  
Author(s):  
Kyriaki Dunussi-Joannopoulos ◽  
Glenn Dranoff ◽  
Howard J. Weinstein ◽  
James L.M. Ferrara ◽  
Barbara E. Bierer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tumor Rejection ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract In an attempt to explore novel treatment modalities in acute myeloid leukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mice can be cured with CD80 transfected leukemic cells (B7.1-AML vaccine) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosuppression induced by tumor growth. CD8+ T cells, which are necessary for tumor rejection, are activated rather than suppressed during the first half of the leukemic course in nonvaccinated mice. In this report, we question whether CD86 (B7.2) or the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-α (TNF-α) can improve the vaccination potential of AML cells. The choice of cytokines was based on their combined and alone as well ability to direct the differentiation of CD34+ cells into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-α (GM-, IL-4–, TNF-α–AML) do not develop leukemia; (2) GM-AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T-cell–dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL-4–, or TNF-α–AML cells, can elicit leukemia-specific protective and therapeutic immunity; and (4) in head-to-head comparison experiments, vaccination with irradiated GM-AML is more potent than B7.1-AML, curing 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines. These preclinical data emphasize that GM-CSF gene immunotherapy deserves clinical evaluation in AML.

scholarly journals Gene Immunotherapy in Murine Acute Myeloid Leukemia: Granulocyte-Macrophage Colony-Stimulating Factor Tumor Cell Vaccines Elicit More Potent Antitumor Immunity Compared With B7 Family and Other Cytokine Vaccines

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 222-230 ◽  
Author(s):  
Kyriaki Dunussi-Joannopoulos ◽  
Glenn Dranoff ◽  
Howard J. Weinstein ◽  
James L.M. Ferrara ◽  
Barbara E. Bierer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tumor Rejection ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

In an attempt to explore novel treatment modalities in acute myeloid leukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mice can be cured with CD80 transfected leukemic cells (B7.1-AML vaccine) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosuppression induced by tumor growth. CD8+ T cells, which are necessary for tumor rejection, are activated rather than suppressed during the first half of the leukemic course in nonvaccinated mice. In this report, we question whether CD86 (B7.2) or the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-α (TNF-α) can improve the vaccination potential of AML cells. The choice of cytokines was based on their combined and alone as well ability to direct the differentiation of CD34+ cells into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-α (GM-, IL-4–, TNF-α–AML) do not develop leukemia; (2) GM-AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T-cell–dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL-4–, or TNF-α–AML cells, can elicit leukemia-specific protective and therapeutic immunity; and (4) in head-to-head comparison experiments, vaccination with irradiated GM-AML is more potent than B7.1-AML, curing 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines. These preclinical data emphasize that GM-CSF gene immunotherapy deserves clinical evaluation in AML.

scholarly journals Common binding structure for granulocyte macrophage colony-stimulating factor and interleukin-3 on human acute myeloid leukemia cells and monocytes

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1439-1445 ◽  
Author(s):  
LM Budel ◽  
O Elbaz ◽  
H Hoogerbrugge ◽  
R Delwel ◽  
LA Mahmoud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
High Affinity ◽  
Human Acute Myeloid Leukemia ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) control the proliferation of human acute myeloid leukemia (AML) cells in vitro. Previously, we have shown that receptors for GM-CSF and IL-3 are often coexpressed on AML cells. Here we present experiments with purified AML blasts, normal monocytes, and granulocytes that were conducted to analyze the properties of GM-CSF and IL-3 binding proteins in more detail. On AML cells from eight cases we demonstrate two types of GM-CSF receptors: one with low affinity (dissociation constant [kd] 5.1 to 24.8 nmol/L) and one with a high affinity (kd 31 to 104 pmol/L). These AML cells also expressed high affinity receptors for IL-3 (kd 24 to 104 pmol/L). Cross-competition experiments showed that an excess concentration of nonlabeled IL-3 completely prevented the high affinity binding of radiolabled GM-CSF. This competition occurred at 37 degrees C as well as 4 degrees C. Low affinity GM-CSF binding was not affected by IL-3. Binding of radiolabeled IL-3 could be prevented by nonlabeled GM-CSF. In certain cases, this competition was complete, whereas in others only partial (49% to 77%) reduction of the radiolabeled IL-3 binding was seen. On the basis of these ligand binding features, we propose the existence of three receptor types on AML cells: (1) low affinity GM-CSF receptors that do not bind IL-3, (2) dual high affinity GM-CSF/IL-3 receptors, and (3) high affinity IL-3 receptors that do not bind GM-CSF. We could also demonstrate these receptor types on normal monocytes. In addition, a fourth type of receptor was apparent on normal granulocytes (4), incapable of binding IL-3 and with an intermediate affinity for GM-CSF (approximately 400 pmol/L). Chemical crosslinking showed that GM-CSF and IL-3 both bind to proteins with molecular weight values of 130, 105, and 75, which provides additional evidence for the existence of a common GM-CSF/IL-3 receptor complex.

scholarly journals Common binding structure for granulocyte macrophage colony-stimulating factor and interleukin-3 on human acute myeloid leukemia cells and monocytes

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1439-1445 ◽  
Author(s):  
LM Budel ◽  
O Elbaz ◽  
H Hoogerbrugge ◽  
R Delwel ◽  
LA Mahmoud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
High Affinity ◽  
Human Acute Myeloid Leukemia ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) control the proliferation of human acute myeloid leukemia (AML) cells in vitro. Previously, we have shown that receptors for GM-CSF and IL-3 are often coexpressed on AML cells. Here we present experiments with purified AML blasts, normal monocytes, and granulocytes that were conducted to analyze the properties of GM-CSF and IL-3 binding proteins in more detail. On AML cells from eight cases we demonstrate two types of GM-CSF receptors: one with low affinity (dissociation constant [kd] 5.1 to 24.8 nmol/L) and one with a high affinity (kd 31 to 104 pmol/L). These AML cells also expressed high affinity receptors for IL-3 (kd 24 to 104 pmol/L). Cross-competition experiments showed that an excess concentration of nonlabeled IL-3 completely prevented the high affinity binding of radiolabled GM-CSF. This competition occurred at 37 degrees C as well as 4 degrees C. Low affinity GM-CSF binding was not affected by IL-3. Binding of radiolabeled IL-3 could be prevented by nonlabeled GM-CSF. In certain cases, this competition was complete, whereas in others only partial (49% to 77%) reduction of the radiolabeled IL-3 binding was seen. On the basis of these ligand binding features, we propose the existence of three receptor types on AML cells: (1) low affinity GM-CSF receptors that do not bind IL-3, (2) dual high affinity GM-CSF/IL-3 receptors, and (3) high affinity IL-3 receptors that do not bind GM-CSF. We could also demonstrate these receptor types on normal monocytes. In addition, a fourth type of receptor was apparent on normal granulocytes (4), incapable of binding IL-3 and with an intermediate affinity for GM-CSF (approximately 400 pmol/L). Chemical crosslinking showed that GM-CSF and IL-3 both bind to proteins with molecular weight values of 130, 105, and 75, which provides additional evidence for the existence of a common GM-CSF/IL-3 receptor complex.

A urokinase-activated recombinant diphtheria toxin targeting the granulocyte-macrophage colony-stimulating factor receptor is selectively cytotoxic to human acute myeloid leukemia blasts

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2143-2148 ◽  
Author(s):  
Ralph J. Abi-Habib ◽  
Shihui Liu ◽  
Thomas H. Bugge ◽  
Stephen H. Leppla ◽  
Arthur E. Frankel
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Diphtheria Toxin ◽  
Myeloid Leukemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Novel agents to treat acute myeloid leukemia (AML) are needed with increased efficacy and specificity. We have synthesized a dual-specificity fusion toxin DTU2GMCSF composed of the catalytic and translocation domains of diphtheria toxin (DT) fused to the granulocyte-macrophage colony-stimulating factor (GM-CSF) in which the DT furin cleavage site 163RVRRSV170 is modified to a urokinase plasminogen activator (uPA) cleavage site 163GSGRSA170, termed U2. DTU2GMCSF was highly toxic to the TF1-vRaf AML cell line (proliferation inhibition assay; IC50 = 3.14 pM), and this toxicity was greatly inhibited following pretreatment with anti-uPA and anti-GM-CSF antibodies. The activity of this toxin was then tested on a larger group of 13 human AML cell lines; 5 of the 13 cell lines were sensitive to DTU2GMCSF. An additional 5 of the 13 cell lines became sensitive when exogenous pro-uPA was added. Sensitivity to DTU2GMCSF strongly correlated with the expression levels of uPA receptors (uPARs) and GM-CSF receptors (GM-CSFRs) as well as with total uPA levels. DTU2GMCSF was less toxic to normal cells expressing uPAR or GMCSFR alone, that is, human umbilical vein endothelial cells and peripheral macrophages, respectively. These results indicate that DTU2GMCSF may be a selective and potent agent for the treatment of patients with AML. (Blood. 2004;104:2143-2148)

Sign in / Sign up

Export Citation Format

Share Document