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PubMed2000

The effect of short G-CSF administration on the numbers and clonogenic efficiency of hematopoietic progenitor cells in bone marrow and peripheral blood of normal donors.

We have analysed the cellularity, the number of clonogenic cells and their clonogenic efficiency (the number of clonogenic cells/2 x 10(5) MNC) in peripheral blood (PB) and bone marrow (BM) during and after filgrastim (rhG-CSF) mobilization of CD34+ cells in 12 healthy donors for allogeneic stem cell donation. G-CSF was administrated subcutaneously for 5 consecutive days at a dose of 10 micrograms/kg/day. WBC, MNC, CD34+ cell counts, CFU-GM and BFU-E assays in PB were performed at baseline and then daily 12 hours after each G-CSF dose. BM was assayed before start (day 1) and after the last dose (day 6) of G-CSF. Results are given as medians, with ranges in parentheses. In PB the total WBC and MNC increased 7.4-fold (6.0-12.3) and 3.3-fold (1.5-9.4), respectively, reaching a peak of 49.4 x 10(9)/l (32.5-66.6) on day 6 for WBC and 6.28 x 10(9)/l (4.7-13.3) for MNC on day 5. CD34+ cell number reached a peak value of 48.0 x 10(6)/l (45.6-285) on day 6 whereas CFU-GM and BFU-E reached their peaks on day 5, 0.95 x 10(4)/ml (0.05-6.08) and 1.04 x 10(4)/ml, respectively. CFU-MIX, not detectable at baseline, reached a peak of 0.95 x 10(4)/ml (0.006-0.51) on day 5 as well. This was accompanied by an increase in CFU-GM, BFU-E and CFU-MIX clonogenic efficiency: 23-fold (3-150), 9.75-fold (2.2-27.8) and 20-fold (2.5-210), respectively. In BM the total WBC number increased 2.5-fold (1.3-4.9) from the baseline value of 52.6 x 10(9)/l (7.9-137.0) whereas the MNC count increased 2.0-fold (0.81-3.7) from a baseline of 13.6 x 10(9)/l (3.5-54.8). This was, however, not significant. The number of CD34+ cells increased significantly 2.9-fold (0.8-8.3). In 8 donors CFU-MIX were detectable before but not after G-CSF treatment. A similar decrease in CFU-GM and BFU-E clonogenic efficiency occurred but was not significant. CFU-GM and BFU-E numbers did not change. We conclude that the total body numbers of lineage committed progenitors increased during G-CSF administration, which indicate their proliferation in addition to mobilization. The effect of G-CSF on the number of more primitive progenitors in BM is less clear and needs further investigation.

Adolescent↗
PubMed2004

Neoadjuvant therapy with gemcitabine in breast cancer.

Primary systemic therapy (ie, preoperative or neoadjuvant) increases the possibility for breast-conserving surgery in patients with primary breast cancer. Patients with pathologic complete response to primary systemic therapy have improved survival compared with those with persistent tumors. Several phase II trials have evaluated gemcitabine-containing doublet or triplet regimens as primary systemic therapy for breast cancer, results of which have shown promising clinical and pathologic response rates with manageable toxicity. Results of a phase I/II study of gemcitabine (Gemzar)/epirubicin (Ellence)/docetaxel (Taxotere), or GEDoc, with prophylactic filgrastim (Neupogen), as primary systemic therapy in 77 evaluable patients with primary breast cancer are reported herein. Dose-limiting toxicities were grade 3 febrile neutropenia (n = 1) and grade 3 diarrhea (n = 2) at the fourth dose level of GEDoc tested (gemcitabine at 800 mg/m2 days 1 and 8, epirubicin at 90 mg/m2 day 1, and docetaxel at 75 mg/m2 day 1). As assessed by ultrasound, 92% of patients responded overall (22% complete response), and 79% of patients could undergo breast-conserving surgery. The pathologic complete response rate in resected breast tissue was 26%.

Adult↗
PubMedDate not supplied

Therapeutic administration of pegfilgrastim instead of prophylactic use.

OBJECTIVES: Pegfilgrastim is a new growth factor which can be administered subcutaneously once (versus multiple doses for days) on the day neutropenia occurs after chemotherapy. Our aims were to determine: (a) the percentage of patients who needed growth factor (pegfilgrastim) supportive treatment, (b) the duration of neutropenia-leukopenia after pegfilgrastim administration, and (c) the safety in using pegfilgrastim as a treatment and not as a prophylactic agent. MATERIALS AND METHODS: Ninety-eight patients were evaluated. All patients were scheduled to undergo chemotherapy treatment, which was either first- or second-line, and some patients had previously received granulocyte colony-stimulating growth factor (G-CSF): filgrastim on a daily basis. Twenty-five/98 patients required G-CSF support and were treated with pegfilgrastim 6 mg; the first 12 patients were admitted to hospital and remained until recovery from grade 3-4 neutropenia; the other 13 patients were treated on an outpatient basis or at home. Pegfilgrastim was administered when neutropenia appeared (days 6-8 following chemotherapy treatment). RESULTS: Therapeutic administration of pegfilgrastim on the day serious neutropenia occurred was needed by 25/98 patients (25.51%). White blood cell recovery for both grade 3-4 neutropenia was observed within 1-3 days in 75% of the patients treated with pegfilgrastim and in the remaining 25%, within 5 days. CONCLUSION: Pegfilgrastim, an active hemopoietic growth factor with effective slow-absorption properties, can be used safely, not necessarily as a prophylactic agent but on an outpatient basis as a therapy for serious neutropenia.

Adult↗
PubMed2006

Dose and outcome: the hurdle of neutropenia (Review).

The development of chemotherapy in the early 1970s resulted in the availability of curative therapeutic strategies for hematological malignancies and several types of solid tumors. It is evident that drugs should be used at their optimal dose and schedule, and drug combinations should be given at consistent intervals. According to the mathematical models that suggested the direct dose-response relationship in the improvement of outcomes in cancer chemotherapy, the dose intensity and, more recently, the dose-dense approach was considered one of the most important tools in conventional chemotherapy. Anticancer drugs are often associated with myelotoxicity, and reducing the dose or increasing the time interval between each cycle of treatment is a frequent empiric approach. Unfortunately, a dose reduction of >or=20% causes a loss of 50% in the cure rate, particularly in chemosensitive tumors. To accelerate bone marrow recovery and prevent the onset of severe myelosuppression and its complications, the standard use of granulocyte colony-stimulating factors (G-CSF), such as filgrastim and the long-acting pegfilgrastim, is recommended. The aim of this review is to analyze how dose intensification concepts and dose-dense regimens are able to increase the cure rate of chemosensitive solid tumors and lymphomas.

Antineoplastic Agents↗
PubMed1994

Carboplatin and granulocyte colony-stimulating factor as first-line treatment for epithelial ovarian cancer: a phase I dose-intensity escalation study.

A phase I study of frequently administered carboplatin with recombinant human granulocyte colony-stimulating factor (filgrastim) has been performed in patients with newly diagnosed epithelial ovarian cancer. Recombinant human granulocyte colony-stimulating factor was administered at a dose of 5 micrograms/kg/d for days 1 through 12 after carboplatin treatment. Carboplatin doses were calculated using a pharmacokinetic formula on an area under the curve (AUC) basis. Four doses of carboplatin were planned for each patient. The first cohort of patients received an AUC of 5 mg/mL x min every 3 weeks. Subsequently four additional cohorts received AUCs of 5, 7, 9, and 8 every 2 weeks. Non-hematologic toxicities were mild and not significant. The dose-limiting toxicity was thrombocytopenia and occurred at an AUC of 9. Most patients could complete treatment at an AUC of 7. Results for AUC 8 are awaited. Complete and partial responses were seen in most patients at all dose levels.

Adenocarcinoma↗
PubMed1994

Granulocyte colony stimulating factor significantly influences neutrophil recovery and duration of hospitalisation in bone marrow transplantation.

Eighty-eight consecutive patients undergoing bone marrow transplantation (BMT) from July 1985 to June 1993 were retrospectively studied for their bone marrow engraftment characteristics with and without granulocyte colony stimulating factor (R-metHUG-CSF, Filgrastim). Seventy-seven patients (87.5%) achieved engraftment, 55 out of 65 patients (84.6%) without R-metHUG-CSF and 22 out of 23 patients (95.7%) with R-metHUG-CSF (P > 0.1). The mean duration of administration of R-metHUG-CSF was 15.1 days. The mean time to engraftment was significantly reduced by 7.1 days, from 20.5 days to 13.4 days (P < 0.0001). The mean duration of hospitalisation was also significantly reduced by 11.1 days, from 52.6 days to 41.5 days (P < 0.0001). There were no side effects directly attributable to R-metHUG-CSF encountered. We conclude that R-metHUG-CSF is very effective in shortening the duration of neutropenia in the immediate post-BMT period with lesser BMT morbidity, earlier discharge from hospital and lower cost of BMT. We recommend a routine 2-week course beginning on the day after marrow infusion.

Adult↗
PubMed1995

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation.

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady-state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.

Antigens, CD↗
PubMed1995

Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial.

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Adolescent↗
PubMed1995

Paclitaxel and ifosfamide: a multicenter phase I study in advanced non-small cell lung cancer.

Both paclitaxel and ifosfamide have significant single-agent activity in non-small cell lung cancer. We designed a phase I study combining escalating doses of paclitaxel, administered by 24-hour infusion, with ifosfamide given at a dose of 1.6 g/m2 daily x 3. Paclitaxel dose levels were 135, 170, 200, 250, and 300 mg/m2. The goal of the study was to determine the maximum tolerated dose and dose-limiting toxicities of paclitaxel when used in this combination. Dose escalation was possible because of the use of filgrastim, a granulocyte colony-stimulating factor. Twenty-five patients at three institutions were treated. The dose-limiting toxicity of the combination was granulocytopenia, with other toxicities being generally mild to moderate. The maximum tolerated dose of paclitaxel was 300 mg/m2, and the recommended phase II dose is 250 mg/m2. There was a suggestion of a dose-response curve with paclitaxel as all three partial responses were seen at the 250 mg/m2 dose level. An additional II patients had objective regression or stable disease lasting for 9 to 30 weeks. A phase II study of this combination is currently being planned by the Cancer and Leukemia Group B.

Adult↗
PubMed1993

A review of the efficacy and tolerability of recombinant haematopoietic growth factors in bone marrow transplantation.

The clinical benefits of the haematopoietic growth factors (HGFs) granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) in conjunction with bone marrow transplantation (BMT) have been established from numerous phase II/III clinical trials. Trials with filgrastim (recombinant G-CSF) have shown that it reduces the period of severe neutropenia by about one week, which leads to a reduction in infectious complications and earlier discharge from hospital. Similar clinical effects have been shown in placebo-controlled trials with recombinant GM-CSF. The effect of other HGFs on haematopoietic reconstitution has been investigated in animals and preliminary human studies, however, further data are required before their clinical efficacy can be determined. G-CSF is well tolerated in the BMT setting. GM-CSF also appears to be well tolerated at low doses, but increased toxicity may be seen at higher dosages. Clinical studies have also indicated that the HGFs do not stimulate the proliferation of leukaemic cells, furthermore, graft-versus-host disease (GVHD) is not enhanced by the use of growth factors. Pharmacological purging of the bone marrow may lead to a reduction in the granulocyte-macrophage colony-forming unit (CFU-GM) content of transplanted marrow. An alternative purging approach is the positive selection of CD34+ marrow stem cells. This technique may also be used to select stem cells from the peripheral blood for use in conjunction with or as an alternative to autologous or allogeneic BMT.

Adult↗
PubMed1995

The protein tyrosine kinase JAK2 is activated in neutrophils from patients with severe congenital neutropenia.

Severe congenital neutropenia (SCN; or Kostmann syndrome) is an autosomal recessive disorder characterized by a maturation arrest of myelopoiesis at the level of promyelocytes. Myeloid precursor cells from patients with SCN require pharmacological dosages of recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF; Filgrastim; Amgen, Thousand Oaks, CA) to differentiate to normal neutrophils. Thus, it is hypothesized that the underlying defect responsible for SCN is based on an abnormal G-CSF-induced signal transduction pathway. Because JAK2, a nonreceptor tyrosine kinase, is involved in the signaling pathway of G-CSF, we examined the expression and activity of JAK2 in neutrophils from SCN patients during r-metHuG-CSF treatment. The immunoprecipitated JAK2 protein showed increased tyrosine phosphorylation in neutrophils from SCN patients as compared with that in neutrophils from healthy donors, suggesting that this kinase is activated. In vitro kinase assays of immunoprecipitated JAK2 confirmed that neutrophils from SCN patients show an increased autophosphorylation of JAK2 in comparison with that of neutrophils from healthy volunteers. These findings suggest that JAK2 is activated in SCN patients.

Adolescent↗
PubMed1996

Transplantation of allogeneic CD34+ blood cells.

Pluripotent stem cells of hematopoiesis and lymphopoiesis are among the CD34+ cells in blood or bone marrow. After granulocyte-colony stimulating factor (G-CSF) treatment, 1% to 2% of the mononuclear cells in blood are CD34+ cells, which can be procured by leukapheresis. We investigated the potential of CD34+ blood cells for reconstituting hematopoiesis and lymphopoiesis after allogeneic transplantation. HLA-identical sibling donors of 10 patients with hematologic malignancies were treated with G-CSF (filgrastim), 5 microgram/kg subcutaneously twice daily for 5 to 7 days. CD34+ cells were selected from the apheresis concentrates by immunoadsorption, concomitantly the number of T cells was reduced 100- to 1,000-fold. After transplantation, five patients received cyclosporine A for graft-versus-host disease (GvHD) prophylaxis (group I); five patients additionally received methotrexate (group II). G-CSF and erythropoietin were given to all patients. Mean numbers of 7.45 x 10(6) CD34+ and 1.2 x 10(6) CD3+ cells per kilogram were transplanted. In group I, the median times of neutrophil recovery to 100, 500, and 1,000 per mm3 were 10, 10, and 11 days, respectively. Group II patients reached these neutrophil levels after 10, 14, and 15 days, respectively. Platelet transfusions were administered for a median of 18 days in group I and 30 days in group II, and red blood cells for 9 and 12 days, respectively. Between day 30 and 60, lymphocytes reached levels of 353 +/- 269 cells per mm3. The median grades of acute GvHD were III in group I and I in group II. Two patients in group I died from acute GvHD. Two leukemic relapses occurred in group II. Complete and stable donor hematopoiesis was shown in all patients with a median follow up of 370 (45 to 481) days. Allogeneic blood CD34+ cells can successfully reconstitute hematopoiesis and lymphopoiesis. Reduction of T cells by CD34+ blood cell enrichment and cyclosporine A alone might not be sufficient for prophylaxis of severe acute GvHD.

Acute Disease↗
PubMed1996

Role of granulocyte colony stimulating factor (G-CSF) in reversing neutropenia in renal allograft recipients.

Neutropenia in solid organ transplant recipients may be caused by immunosuppressive therapy, antimicrobial therapy, as well as bacterial and viral infections. Filgrastim, a human granulocyte colony stimulating factor (G-CSF) is used for the reversal of neutropenia. Although its influence is principally restricted to neutrophil progenitors, the safety of G-CSF in terms of percipitating or aggravating allograft rejection and its efficacy in reversing neutropenia in kidney and combined kidney and pancreas transplant patients has not been studied or reported. In this study we retrospectively analyzed the use of G-CSF between March 1992 and May 1994 at the University of Cincinnati Medical Center, in patients who received either a kidney or a combined kidney and pancreas transplant. A total of 25 patients developed 35 episodes of neutropenia and received an average of 2.9 doses of G-CSF per episode. The mean WBC nadir was 2.6 x 10(3)/cu mm with an average peak WBC count of 15.5 x 10(3)/cu mm following treatment (p = < 0.00001). The average number of days to peak WBC after initiation of treatment was 4.6 days. The mean pre-treatment serum creatinine level was 2.3 mg/dl and the peak serum creatinine in the week following treatment remained the same. We conclude that G-CSF is an effective treatment in reversing neutropenia in renal transplant recipients and does not precipitate or aggravate allograft rejection.

Creatinine↗
PubMed1996

Increase of mobilized CD34-positive peripheral blood progenitor cells in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and cancer of the testis.

G-CSF (filgrastim) can effectively mobilize peripheral blood progenitor cells (PBPC) when administered during steady-state hematopoiesis. In this single center study, we compared the effectiveness of two different doses of G-CSF on the mobilization of peripheral blood stem cells in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and cancer of the testis. A first group including 33 patients received 10 micrograms G-CSF/kg BW per day (group A), whereas a second group comprising 34 patients was treated with 24 (2 x 12) micrograms G-CSF/kg body weight (BW) per day (group B) prior to the leukapheresis. A significant difference (P = 0.015) in the total number of CD34+ cells between group A: 11.32 x 10(7) (range 0.34-110.2) and group B: 48.25 x 10(7) (range 1.33-447.4) has been observed in the first leukapheresis product. Moreover, the total number of CFU-GM increased significantly from 34.79 x 10(4) (range 1.07-300.9) to 147.69 x 10(4) (range 1.03- 1204.0) (P < 0.005), and the number of MNC increased from 1.35 x 10(10) (range 0.41-3.09) group A) to 2.93 x 10(10) (range 0.66-9.7) (group B) (P < 0.001). Comparable results were obtained in the second leukapheresis. Our data indicate, that the application of higher doses of G-CSF can significantly improve the effectiveness of mobilizing PBPC during steady-state conditions, and thereby considerably contribute to a safe and fast engraftment as well as a reduced number of leukapheresis procedures to achieve sufficient number of PBPC.

Adolescent↗
PubMed1995

Haematopoietic growth factors as supportive therapy in HIV-infected patients.

BACKGROUND: Neutropenia and anaemia are common problems in patients with HIV infection. Neutropenia can lead to a reduction in drug doses or to withdrawal of important myelosuppressive agents such as ganciclovir, zidovudine, cotrimoxazole and pyrimethamine, while anaemia may require the administration of blood transfusions. SUPPORTIVE THERAPY WITH HAEMATOPOIETIC GROWTH FACTORS: Haematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are effective in the treatment of AIDS-related neutropenia. G-CSF appears to be better tolerated than GM-CSF. Moreover, GM-CSF can stimulate HIV replication in the absence of antiretroviral treatment. Thus G-CSF may offer a better treatment option in some patients. Doses of up to 300 micrograms G-CSF (filgrastim) per day rapidly reverse neutropenia in most HIV-infected patients. Subsequently, normal neutrophil counts can be maintained with intermittent doses (1-7 days a week). This allows greater use of myelosuppressive agents. Recombinant human erythropoietin is well tolerated and effective in the treatment of anaemia due to zidovudine when endogenous erythropoietin levels are < or = 500 IU/l. Recombinant human erythropoietin combined with CSF also appears to be well tolerated and effective in the treatment of combined cytopenias. Other haematopoietic growth factor combinations are currently being explored. CONCLUSIONS: CSF and recombinant human erythropoietin, used alone or in combination, appear to be well tolerated and effective in the treatment of neutropenia and anaemia, respectively, in patients with HIV infection. G-CSF may be preferable to GM-CSF in some patients. However, the advantages of therapy with haematopoietic growth factors have to be balanced against the disadvantages of cost, inconvenience and discomfort associated with repeated subcutaneous injections. At present there is no clear evidence that CSF prolongs the survival of AIDS patients.

Anemia↗
PubMed1996

Allogeneic peripheral blood progenitor cell (PBPC) transplantation in children.

The use of peripheral blood as a source of hematopoietic precursors is an alternative to the bone marrow in allogeneic transplantation. Although pediatric allogeneic PBPC experience is limited, there is no reason to believe that the outcome and benefit with PBPC should be different than adults. We describe our initial experience in two children who received PBPC allogeneic transplantation in whom the donors were mobilized with filgrastim. Hematopoietic recovery was achieved on days 14 and 16, and the patients did not develop severe GVHD.

Adolescent↗