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Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: a review of the evidence.

The prophylactic use of myeloid growth factors reduces the risk of chemotherapy-induced neutropenia and its complications, including febrile neutropenia and infection-related mortality. Perhaps most importantly, the prophylactic use of colony-stimulating factors (CSFs) has been shown to reduce the need for chemotherapy dose reductions and delays that may limit chemotherapy dose intensity, thereby increasing the potential for prolonged disease-free and overall survival in the curative setting. National surveys have shown that the majority of patients with potentially curable breast cancer or non-Hodgkin's lymphoma (NHL) do not receive prophylactic CSF support. In this issue, the National Comprehensive Cancer Network presents guidelines for the use of myeloid growth factors in patients with cancer. These guidelines recommend a balanced clinical evaluation of the potential benefits and harms associated with chemotherapy to define the treatment intention, followed by a careful assessment of the individual patient's risk for febrile neutropenia and its complications. The decision to use prophylactic CSFs is then based on the patient's risk and potential benefit from such treatment. The routine prophylactic use of CSFs in patients receiving systemic chemotherapy is recommended in patients at high risk (>20%) of developing febrile neutropenia or related complications that may compromise treatment. Where compelling clinical indications are absent, the potential for CSF prophylaxis to reduce or offset costs by preventing hospitalization for FN should be considered. The clinical, economic, and quality of life data in support of these recommendations are reviewed, and important areas of ongoing research are highlighted.

Antineoplastic Agents↗

Effect of granulocyte-colony stimulating factor on empiric therapy with flomoxef sodium and tobramycin in febrile neutropenic patients with hematological malignancies. Kan-etsu Hematological Disease and Infection Study Group.

The clinical effects of concomitant use of granulocyte-colony stimulating factor (G-CSF) on empiric antibiotic therapy in febrile neutropenic patients were evaluated in a randomized fashion. Two hundred and fourteen neutropenic febrile episodes (neutrophil counts < 1.0 x 10(9)/l) were treated with flomoxef sodium and tobramycin with or without G-CSF. The resolution of fever at day 4 (excellent response) or at day 7 (good response) was deemed effective. Among 157 evaluable episodes, the observed excellent responses were 31 (38.8%) and the good responses were 20 (25.0%) in the G-CSF group; those in the control group were 26 (33.8%) and 25 (32.5%), respectively. The overall efficacy rate was 63.8% (51/80) in the G-CSF group and 66.2% (51/77) in the control group (not significant). The initial neutrophil count was 0.186 +/- 0.249 x 10(9)/l in the G-CSF group and 0.235 +/- 0.290 x 10(9)/l in the control group, and rose to 2.889 +/- 4.198 x 10(9)/l and 0.522 +/- 0.844 x 10(9)/l, respectively, at day 7. These results indicate that G-CSF does not affect the rate of response to empiric antibiotic therapy in febrile neutropenic patients, although a significant effect of G-CSF was observed on neutrophil recovery.

Adolescent↗

Pretreatment with granulocyte colony-stimulating factor reduces myelopoiesis in irradiated mice.

The purpose of this study was to investigate effects of the treatment prior to irradiation with granulocyte colony-stimulating factor (G-CSF) on hematopoiesis in B10CBAF1 mice exposed to a sublethal dose of 6.5 Gy of 60Co gamma radiation. G-CSF was administered in a 4-day regimen (3 microg/day); irradiation followed 3 h after the last injection of G-CSF. Such a treatment was found to stimulate granulopoiesis, as shown by increased counts of granulocyte-macrophage progenitor cells (GM-CFC) and of granulocytic cells in the femoral marrow and spleen at the time of irradiation. However, postirradiation counts of GM-CFC and granulocytic cells in the marrow of mice pretreated with G-CSF were reduced up to day 18 after irradiation. Interestingly, the D0 values for marrow GM-CFC determined 1 h after in vivo irradiation were 1.98 Gy for controls and 2.47 Gy for mice pretreated with G-CSF, indicating a decreased radiosensitivity of these cells after drug treatment. The inhibitory effects of the pretreatment with G-CSF on the postirradiation granulopoiesis could be attributed to the phenomenon of "rebound quiescence" which can occur after cessation of the treatment with growth factors. Postirradiation recovery of erythropoiesis in the spleen of mice pretreated with G-CSF exhibited a dramatic increase and compensated for the decreased erythropoiesis in the marrow at the time of irradiation. This complexity of the hematopoietic response should be taken into account when administering G-CSF in preirradiation regimens.

Animals↗

Large-volume leukapheresis in pediatric patients: pre-apheresis peripheral blood CD34+ cell count predicts progenitor cell yield.

BACKGROUND AND OBJECTIVE: In children it is very important to optimize PBPC harvesting and to reduce the number of leukaphereses per patient. The value of pre-apheresis peripheral blood CD34+ cell concentration as a predictor of PBPC yield was studied in 23 pediatric patients with hematologic and non-hematologic malignancies in order to optimize duration of PBPC collection. DESIGN AND METHODS: The patients underwent 25 stem-cell mobilization episodes with G-CSF alone and 40 large-volume leukapheresis procedures. Peripheral blood and harvested CD34+ cell concentrations were analyzed by means of flow cytometry. RESULTS: Using linear regression analysis, a highly significant correlation was found between the peripheral blood CD34+ cell count and the CD34+ cells/kg patient body weight collected on the apheresis day (r = 0.826, p = 0.0001). The results indicate that at least 1 x 10(6)/kg CD34+ cells can be harvested during one leukapheresis procedure in all patients if the pre-apheresis blood CD34+ cell count is > or = 30/microL and a CD34+ cell target of > or = 5 x 10(6)/kg is achieved in at least 80% of patients if this value is > or = 50 CD34+ cells/microL processing a median blood volume of 438.7 mL/kg (range, 207-560) over a median time of 232.5 minutes (range, 182-376). INTERPRETATION AND CONCLUSIONS: Our results suggest that the number of CD34+ cells harvested in a single large-volume leukapheresis can be predicted from the measurement of peripheral blood CD34+ cell concentration on the collection day.

Adolescent↗

Neutrophil activation and hemostatic changes in healthy donors receiving granulocyte colony-stimulating factor.

Granulocyte colony-stimulating factor (G-CSF) enhances neutrophil functions in vitro and in vivo. It is known that neutrophil-derived products can alter the hemostatic balance. To understand whether polymorphonuclear leukocyte (PMN) activation, measured as PMN degranulation and phenotypical change, may be associated to hemostatic alterations in vivo, we have studied the effect of recombinant human G-CSF (rHuG-CSF) administration on leukocyte parameters and hemostatic variables in healthy donors of hematopoietic progenitor cells (HPCs). Twenty-six consecutive healthy donors receiving 10 micrograms/kg/d rHuG-CSF subcutaneously for 5 to 7 days to mobilize HPCs for allogeneic transplants were included in the study. All of them responded to rHuG-CSF with a significant white blood cell count increase. Blood samples were drawn before therapy on days 2 and 5 and 1 week after stopping rHuG-CSF treatment. The following parameters were evaluated: (1) PMN activation parameters, ie, surface CD11b/CD18 antigen expression, plasma elastase antigen levels and cellular elastase activity; (2) plasma markers of endothelium activation, ie, thrombomodulin (TM) and von Willebrand factor (vWF) antigens; (3) plasma markers of blood coagulation activation, ie, F1+2, TAT complex, D-dimer; and (4) mononuclear cell (MNC) procoagulant activity (PCA) expression. The results show that, after starting rHuG-CSF, an in vivo PMN activation occurred, as demonstrated by the significant increment of surface CD11b/CD18 and plasma elastase antigen levels. Moreover, PMN cellular elastase activity, which was significantly increased at 1 day of treatment, returned to baseline at day 5 to 6, in correspondence with the elastase antigen peak in the circulation. This change was accompanied by a parallel significant increase in plasma levels of the two endothelial and the three coagulation markers. The PCA generated in vitro by unstimulated MNC isolated from rHuG-CSF-treated subjects was not different from that of control cells from untreated subjects. However, endotoxin-stimulated MNC isolated from on-treatment individuals produced significantly more PCA compared with both baseline and control samples. All of the parameters were decreased or normal 1 week after stopping treatment. These data show that rHuG-CSF induces PMN activation and transiently affects some hemostatic variables in healthy HPC donor subjects. The clinical significance of these findings remains to be established.

Adolescent↗

Recombinant human thrombopoietin in combination with granulocyte colony-stimulating factor enhances mobilization of peripheral blood progenitor cells, increases peripheral blood platelet concentration, and accelerates hematopoietic recovery following high-dose chemotherapy.

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 micrograms/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 micrograms/kg on days -3, -1, and 1, or 0.6 micrograms/kg on days -1 and 1. G-CSF, 5 micrograms/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34(+) cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 x 10(6)/kg (range, 1.3 to 17.6) versus 0.8 x 10(6)/ kg (range, 0.3 to 4.2), P =.0003. The targeted minimum yield of 3 x 10(6) CD34(+) cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF-mobilized group versus 10% of G-CSF-mobilized patients (P =.001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P =.0001) and platelet recovery (day 9 v 10, P =.07) were accelerated, and fewer erythrocyte (3 v 4, P =.02) and platelet (4 v 5, P =.02) transfusions were needed compared with G-CSF-mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P <.0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 microgram/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF-mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Adult↗

Results of a phase II trial of combined chemotherapy for patients with diffuse malignant mesothelioma of the pleura.

BACKGROUND: Malignant pleural mesothelioma is associated with a poor prognosis because of its resistance to treatment. The authors conducted a Phase II trial in which two drugs (etoposide and 5-fluorouracil) were added to the Cancer and Leukemia Group B cisplatin-mitomycin regimen in an effort to define a more effective chemotherapy. METHODS: Forty-five patients with confirmed Stage II malignant pleural mesothelioma were prospectively enrolled in the study. Thirty-one patients received cisplatin 60 mg/m2 on Day 1, 5-fluorouracil 600 mg on Days 1-4, folinic acid 100 mg/m2 on Days 1-4, mitomycin C 10 mg/m2 on Day 3, and etoposide 100 mg/m2 i.v. on Days 1-3, with prophylactic hematopoietic growth factors. Fourteen patients received cisplatin, 5-fluorouracil, folinic acid, and mitomycin C with the protocol unchanged, and oral etoposide 50 mg on Days 1-21 without growth factors (1 cycle every 28 days). Histology included epithelial (in 33 cases), sarcomatous (in 6), mixed (in 3), and unspecified type (in 3). RESULTS: Two hundred eleven cycles were administered. Treatment was well tolerated and the major toxicity was hematologic: anemia in 30% of cases, neutropenia in 24%, and 2 probable cases of mitomycin-induced pneumonitis. The objective response rate was 38% (17 of 45 were partial responses), and the median response duration was 12 months. The median survival time was 16 months. There were no differences in response or survival between the 31 patients treated with growth factors and the 14 patients treated without them. Survival was slightly better for responders than for nonresponders who had stable disease or progression (20 vs. 10 months, P < 0.05). CONCLUSIONS: This four-drug combination was effective, with a notably high response rate, acceptable toxicity, and good adherence to protocol doses. The impact on survival was limited.

Adult↗

Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34(+) cells and their transmigration through reconstituted basement membrane.

The mechanism(s) underlying the release of stem/progenitor cells from bone marrow into the circulation is poorly understood. We hypothesized that matrix metalloproteinases (MMPs), especially gelatinases, which are believed to participate in the proteolysis of basement membranes and in the migration of leukocytes, may facilitate this process. First, we investigated whether CD34(+) stem/progenitor cells express gelatinases A (MMP-2) and/or B (MMP-9) and whether growth factors and cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], stem cell factor [SCF], macrophage colony-stimulating factor [M-CSF], interleukin-3 [IL-3], IL-6, IL-8, and tumor necrosis factor-alpha [TNF-alpha]) are able to modulate their expression. Next, we examined the transmigration of these stem/progenitor cells through reconstituted basement membrane (Matrigel) and its modulation by growth factors and cytokines. CD34(+) cells were obtained from steady-state bone marrow and peripheral blood (from leukapheresis products collected either in steady-state hematopoiesis or after mobilization with G-CSF plus chemotherapy or G-CSF alone). We found that peripheral blood CD34(+) cells, regardless of whether they were mobilized or not, strongly expressed both gelatinases (MMP-2 and MMP-9) in contrast to steady-state bone marrow CD34(+) cells, which did not. However, all the growth factors and cytokines tested could induce MMP-2 and MMP-9 secretion by the latter cells. Moreover, the stimulatory effects of G-CSF and SCF on both MMP-2 and MMP-9 secretion were found to be significantly higher in CD34(+) cells isolated from bone marrow than in those from peripheral blood. In addition TNF-alpha, GM-CSF, and IL-6 increased the secretion of a partially active form of MMP-2. Basal transmigration of bone marrow CD34(+) cells through Matrigel was lower than that of peripheral blood CD34(+) cells (P <.0001), but growth factors and cytokines increased it by 50% to 150%. Positive correlations were established between expression of gelatinases and CD34(+) cell migration (r >.9). The stimulatory effect of G-CSF was significantly greater on the migration of CD34(+) cells from bone marrow than on those from peripheral blood (P =.004). Moreover, CD34(+) cell migration was reduced to approximately 50% by antibodies to MMP-2 and MMP-9, tissue inhibitors of metalloproteinases (rhTIMP-1 and -2), and o-phenanthroline. TNF-alpha-induced gelatinase secretion and migration of CD34(+) cells and of clonogenic progenitors (colony-forming unit-granulocyte-macrophage [CFU-GM], burst-forming unit-erythroid [BFU-E], colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM], and colony-forming unit-megakaryocyte [CFU-MK]) were dose-dependent. Therefore, this study demonstrated that CD34(+) cells that are circulating in peripheral blood express both MMP-2 and MMP-9 and transmigrate through Matrigel. In contrast, CD34(+) cells from steady-state bone marrow acquire similar properties after exposure to growth factors and cytokines, which upregulate expression of gelatinases and transmigration of these cells when they enter the bloodstream. Hence, we suggest that growth factors and cytokines induce release of stem/progenitor cells from bone marrow into peripheral blood during mobilization, as well as during steady-state hematopoiesis, by signaling through gelatinase pathways.

Antigens, CD34↗

[Local application of G-CSF, GM-CSF and EGF in treatment of wounds].

G-CSF, GM-CSF and EGF play an important role in wound healing as components of the cytokine network which regulates cooperation of cells in the repair processes. The first two cytokines have been registered as hematopoietic drugs under the names Neupogen (Roche) and Leucomax (Sandoz). Both G-CSF and GM-CSF stimulate phagocytosis in maturated leucocytes and enhance proliferation of endothelial cells. G-CSF, GM-CSF and EGF which is known as mitogenic agent were applied as topical drugs for wound care; the application resulted in acceleration of wound healing. Preliminary suggestions as to the topical dosage of the cytokines in the treatment of wounds are put forward.

Administration, Topical↗

Neutrophil recovery time and adverse side effects in acute leukemia patients treated with intensive chemotherapy and concomitant G or GM-CSF.

OBJECTIVE: Compare the speed of neutrophil recovery and the unwanted secondary effects in two groups of acute leukemia patients treated with intensive chemotherapy and G or GM-CSF. PATIENTS AND METHODS: Patients were randomly assigned to receive subcutaneous G-CSF at a daily dose of 300 micrograms for adults and 150 micrograms for children or GM-CSF at 400 and 200 micrograms respectively, starting With chemotherapy and stopping when the absolute neutrophil count (ANC) reached 500/microL. Secondary effects were attributed to growth factors only when not coincidental with infection, chemotherapy or hemoderivative transfusion. RESULTS: 34 patients were included in the G-CSF arm and 37 in the GM-CSF arm. Distribution by sex, age, type of acute leukemia, induction or post-induction therapy, as well as initial neutrophil count were comparable among the two groups. Mean time for ANC > 500/microL was 19 days for G-CSF group and 16 days for GM-CSF group (p = 0.08). There were no statistically significant differences in secondary unwanted side effects between the two groups. There were two cases of growth factor-related-fever in the G-CSF group and five in the GM-CSF group (p = 0.25). There was a case of systemic reaction in the G-CSF group. Twenty-nine patients in each group presented febrile neutropenia episodes (p = 0.45). The only factor that showed significance on neutrophil recovery speed was type of leukemia (p = 0.04). CONCLUSIONS: We found no clear advantage of one growth factor over the other for this indication.

Acute Disease↗

HIV disease-related neutropenia: an independent risk factor for severe infections.

An increasing number of clinical studies have been reported in which neutropenia has been identified as an important independent risk factor in the development of infectious complications in patients with HIV and AIDS. Information on the clinical significance of infecting pathogens and the causes of neutropenia within different patient groups will be discussed, and may have clinical implications in subsequent disease management in these groups. Although the use of highly active antiretroviral therapy has shown some promise in the treatment of HIV-associated hematologic disturbances and immune dysfunction, the rate of virological failure with this treatment over time suggests that these disturbances could reappear in the near future, as well as their associated infectious complications.

Acquired Immunodeficiency Syndrome↗

Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma.

In a double-blind, placebo-controlled, randomized study, 10 healthy men received either a single dose of 480 microg granulocyte colony-stimulating factor (G-CSF) or saline. Blood taken from the volunteers was stimulated with 10 microg/mL endotoxin and released cytokines were measured by enzyme-linked immunosorbent assay. Expression of G-CSF receptors on leukocytes was examined by flow cytometry and reverse transcriptase-polymerase chain reaction. Functional activity of these receptors was tested by challenging isolated leukocyte populations to release cytokines with endotoxin in the presence of G-CSF. The G-CSF treatment attenuated the release of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1beta, and interferon (IFN)-gamma in ex vivo lipopolysaccharide (LPS)-stimulated whole blood. In blood from untreated volunteers the presence of G-CSF in vitro also attenuated the LPS-stimulated release of these cytokines. G-CSF in vitro also attenuated TNF-alpha release from elutriation-purified monocytes. In the presence of 10 ng/mL recombinant TNF-alpha, the attenuation of LPS-inducible IFN-gamma release by G-CSF was blunted in whole blood. However, G-CSF had no such effect on IFN-gamma release from isolated lymphocytes stimulated with anti-CD3 or a combination of TNF-alpha and IL-12. G-CSF receptor expression was detected in human neutrophils and monocytes but not in lymphocytes by means of RT-PCR as well as flow cytometry. These results indicate that G-CSF receptors expressed on monocytes are functional in modulating monokine release. We conclude that the attenuation of IFN-gamma release from lymphocytes is not a direct effect of G-CSF on these cells but is rather due to the inhibition of monocytic IL-12 and TNF-alpha release by G-CSF. (Blood. 2000;95:270-276)

Adult↗

Clonal hematopoiesis in acquired aplastic anemia revealed by rearrangement of the immunoglobulin heavy chain gene-JH region.

We report on a female patient with acquired aplastic anemia whose bone marrow cells showed DNA rearrangement of the immunoglobulin-JH region that disappeared after 1 month with recovery of hematopoiesis through treatment with granulocyte colony-stimulating factor (G-CSF) and immunosuppressive drugs. The patient is now 2 years and 6 months from onset, and her hematopoiesis is almost within normal limits without medication. This finding provides new data supporting clonal hematopoiesis in acquired aplastic anemia but does not imply that the disease is resistant to immunosuppressive therapy.

Anemia, Aplastic↗