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PubMed1997

Mobilization of CD34+ cells by glycosylated and nonglycosylated G-CSF in healthy volunteers--a comparative study.

In vitro studies indicate that lenograstim (glycosylated G-CSF) is more potent than filgrastim (nonglycosylated G-CSF) on a weight for weight basis. However, such a difference has not yet been shown in vivo. The primary objective of this trial was to compare the efficacy of equivalent doses (microgram) of lenograstim and filgrastim in mobilizing CD34+ cells. Thirty-two healthy male volunteers, median age 27 yr (19-44 yr), were randomized to receive either lenograstim 10 micrograms/kg followed by filgrastim 10 micrograms/kg or vice versa with a washout period of a minimum 4 wk. Both drugs were administered as s.c. injections once daily for 5 d (d 1-5). CD34+ cells were mobilized with a similar kinetics, peaking at median d 6 (5-6) for both drugs. A significant difference in favour of lenograstim was shown for peak number of CD34+ cells/microliter blood (104 +/- 38 vs. 82 +/- 35, mean +/- 1 SD, p < 0.0001, paired t-test, n = 30) and number of CFU-GM/microliter blood at d 6 (14.6 +/- 8.4 vs. 10.2 +/- 4.6, p < 0.0001), respectively. There was no difference in the d 6 number of CD3+ cells. Both drugs were generally well tolerated and did not differ with respect to number of adverse events. In conclusion, lenograstim 10 micrograms/kg/d mobilizes PBPC more efficiently than the identical dose of filgrastim, indicating a difference in in vivo potency between the two G-CSFs.

Adjuvants, Immunologic↗

PubMed2006

Pegfilgrastim effectively mobilizes PBSC in a poor mobilizer multiple myeloma patient.

Studies performed on mice and healthy human volunteers have shown that a single dose of pegfilgrastim (Peg-GCSF) is effective in stimulating peripheral blood stem cells (PBSC) mobilization. This prompted us to try the stimulation with pegfilgrastim in a patient previously non-mobilizing with a combination of chemotherapy and filgrastim. In December 2003, a 65-yr-old man was diagnosed as having stage III A IgG/k multiple myeloma. He received three courses of polichemotherapy (DC-IE) obtaining a stable response. Afterwards, the patient was treated with high-dose cyclophosphamide (CPM; 7 g/sqm) plus daily 10 mcg/kg filgrastim in order to mobilize PBSC, without success. After 2 months off therapy, the disease progressed and the patient received alternate cycles VAD (vincristine, dexamethasone, adriblastine)/high-dose dexamethasone. A second attempt to mobilize PBSC, using daily 10 mcg/kg filgrastim after the second and third VAD cycle, failed. In a further attempt to mobilize PBSC, we administered a single dose of 12 mg pegfilgrastim on day 5 after a fourth VAD course. Daily evaluation of circulatory CD34+ cells was started from day 8 after the end of chemotherapy. On day +10 postchemotherapy the CD34+ cell count was 24/microL and two aphaeresis were performed, harvesting 1.6 x 10(6) and 0.89 x 10(6) CD34+ cells/kg respectively (total 2.49 x 10(6) cells/kg). The only side effect was moderate skeletal pain. The patient underwent successful transplantation. The median times necessary to recover 0.5 x 10(9) PMN/L and 20 x 10(9) platelets/L after PBSC reinfusion were 9 and 12 d respectively. The patient did not need red blood cell or platelet transfusions. He experienced a sustained engraftment and maintains complete remission 9 months after the reinfusion. In conclusion, a single dose of pegfilgrastim was able to mobilize a sufficient number of CD34+ in a multiple myeloma patient not responsive to two previous attempts with high or standard dose chemotherapy followed by filgrastim. This approach, if confirmed on larger series and other diseases, could open new opportunities in stem cell mobilization for poor or non-mobilizers.

Aged↗

PubMed1993

Treatment of clozapine- and molindone-induced agranulocytosis with granulocyte colony-stimulating factor.

OBJECTIVE: To report a case of clozapine- and molindone-induced agranulocytosis and to discuss treatment using filgrastim, a granulocyte colony-stimulating factor. CASE SUMMARY: A 64-year-old woman who had been on long-term clozapine therapy for schizophrenia was hospitalized with presumed drug-induced agranulocytosis. She had also been on short-term molindone therapy. A bone marrow biopsy and the initial white blood cell (WBC) count were consistent with drug-induced agranulocytosis. Following seven days of treatment with subcutaneous filgrastim 300 micrograms/d, her absolute neutrophil count was above 500 x 10(6)/L. DISCUSSION: Reports in the literature discussing antipsychotic drug-induced agranulocytosis are reviewed. A relationship between treatment with filgrastim and WBC response is postulated. CONCLUSIONS: Filgrastim may be useful in ameliorating the effects of clozapine- and molindone-induced agranulocytosis.

Agranulocytosis↗

PubMed2004

Medical visits for chemotherapy and chemotherapy-induced neutropenia: a survey of the impact on patient time and activities.

BACKGROUND: Patients with cancer must make frequent visits to the clinic not only for chemotherapy but also for the management of treatment-related adverse effects. Neutropenia, the most common dose-limiting toxicity of myelosuppressive chemotherapy, has substantial clinical and economic consequences. Colony-stimulating factors such as filgrastim and pegfilgrastim can reduce the incidence of neutropenia, but the clinic visits for these treatments can disrupt patients' routines and activities. METHODS: We surveyed patients to assess how clinic visits for treatment with chemotherapy and the management of neutropenia affect their time and activities. RESULTS: The mean amounts of time affected by these visits ranged from approximately 109 hours (hospitalization for neutropenia) and 8 hours (physician and chemotherapy) to less than 3 hours (laboratory and treatment with filgrastim or pegfilgrastim). The visits for filgrastim or pegfilgrastim were comparable in length, but treatment with filgrastim requires several visits per chemotherapy cycle and treatment with pegfilgrastim requires only 1 visit. CONCLUSIONS: This study provides useful information for future modelling of additional factors such as disease status and chemotherapy schedule and provides information that should be considered in managing chemotherapy-induced neutropenia.

Activities of Daily Living↗

PubMed2003

Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.

PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.

Adolescent↗

PubMed2005

Pegfilgrastim: evidence in support of its use with cytotoxic chemotherapy.

The advent of granulocyte colony-stimulating factor, in particular filgrastim, in clinical use more than 10 years ago made a significant impact on the management of neutropenia and its complications. More recently, the application of pegylation technology has created a second-generation molecule, pegfilgrastim, with significantly altered pharmacokinetic properties. This has allowed for a once per chemotherapy cycle dosing in contrast to the requirement of daily subcutaneous administration for filgrastim. Several randomized trials in nonmyeloid malignancies have proven that a fixed dose of pegfilgrastim 6 mg is at least equivalent to daily filgrastim therapy. Emerging evidence also suggests that pegfilgrastim may be equally employed in the setting of chemotherapy for acute myeloid leukemia, dose-dense chemotherapy and peripheral stem cell mobilization. If confirmed in subsequent Phase III trials, it is likely that pegfilgrastim will eventually succeed filgrastim as the colony-stimulating factor of choice in clinical practice.

Acute Disease↗

PubMed2007

Recombinant granulocyte-colony stimulating factor as treatment for poor prognosis oligoblastic acute myeloid leukemia in elderly patients.

Twenty-five elderly patients with oligoblastic acute myeloid leukemia (AML) received subcutaneous granulocyte colony-stimulating factor (filgrastim) in addition to supportive care. Ninety-two percent of the patients had multilineage dysplasia, 17% hypoplasia, and 48% a high-risk karyotype. During filgrastim treatment neutrophil and platelet counts increased significantly (p<0.0001 and (p=0.042), respectively) and 3/13 patients (23%) no longer required transfusions. A complete peripheral hematologic response (CHR) was obtained in eight (32%) and marrow blast cell clearance (<5%) in five patients (20%), lasting 12 and 10 months, respectively. Filgrastim caused osteomyalgia and fever in 20% of cases. The median survival was 8 months overall, and 15 months in patients who achieved a CHR. Filgrastim may be a useful adjunct to supportive care in elderly patients with poor-risk AML.

Aged↗

PubMedDate not supplied

Role of carbohydrate moiety in granulocyte colony stimulating factor.

Biological activities of two granulocyte-colony stimulating factor (G-CSF) preparations with (Lenograstim) or without (Filgrastim) sugar moiety were compared. Both G-CSF preparations similarly enhanced the N-Formyl-Met-Leu-Phe-induced-migration of human peripheral blood polymorphonuclear cells, but did not significantly affect the proliferation of human oral tumor cell lines (HSC-2, HSG). However, Lenograstim induced cytotoxicity (accompanied by the production of cytoplasmic vacuoles and large DNA fragments) in human promyelocytic leukemic cells HL-60, more potently than Filgrastim. Lenograstim, but not Filgrastim, enhanced the cytotoxic activity of sodium ascorbate. In contrast to Lenograstim, Filgrastim was degraded gradually, but too slowly to explain its lower biological activity. These data suggest that the carbohydrate moiety in G-CSF might confer unique biological activities.

Ascorbic Acid↗

PubMed2006

Granulocytic growth factors and cancer-related neutropenia: limited effects.

(1) Cancer chemotherapy often causes haematological complications, in particular neutropenia, which can have grave consequences in terms of the risk of infections (increasing with the degree and duration of neutropenia) and the need for modifications in chemotherapy protocols (longer intervals between cycles or dose reductions). (2) In France, three haematopoietic growth factors are licensed to stimulate leukocyte production: filgrastim (unglycosylated granulocyte colony-stimulating factor (G-CSF)), pegfilgrastim (pegylated filgrastim), and lenograstim (glycosylated G-CSF). (3) The main adverse effects of these three growth factors are joint and bone pain, a flu-like syndrome, and reactions at the injection site. (4) G-CSF has provided disappointing results in primary prevention, and its use is only justified for patients receiving chemotherapy that causes febrile neutropenia in at least 40% of cases: patients with acute leukaemia, elderly patients, and patients with cancer-related neutropenia or poor general status, etc. In these patients, G-CSF reduces the incidence of febrile neutropenia and, possibly, the risk of hospitalisation. A meta-analysis of 11 comparative trials involving about 1500 patients with non Hodgkin's lymphoma showed only a reduction in the incidence of febrile neutropenia and infections. (5) In the prevention of recurrences of neutropenia on continuing chemotherapy, only one trial, involving patients aged over 60 with high-grade non Hodgkin's lymphoma, showed an improvement in survival time with filgrastim (survival rate: 64.3% with filgrastim versus 49% with placebo, after a median follow-up of 40 months). Until these results are confirmed in other clinical trials, reduction in the intensity of chemotherapy (dosage, frequency) is generally recommended. (6) Curative treatment of neutropenia with G-CSF is only warranted for febrile patients with a high risk of severe infections requiring lengthy hospitalisation. Two meta-analyses, one including 8 trials and the other including 13 trials, involving a total of about 1500 patients, only showed a reduction in the length of hospitalisation.

Antineoplastic Agents↗

PubMed1994

A cancer and neutropenia database study.

The economic cost of treating febrile neutropenic cancer patients in Canada has not been defined. Amgen Canada Inc., the distributor of filgrastim (Neupogen Amgen Canada Inc.) was interested in determining this cost in order to evaluate the potential economic impact of filgrastim in the Canadian healthcare setting. Filgrastim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies who receive myelosuppressive antineoplastic drugs. In addition, the company sought to determine which demographic factors influenced the cost. This was done to characterize which patients could derive clinical benefit from filgrastim while at the same time producing cost offsets through anticipated reductions in hospitalizations. In order to address these issues a study was commissioned to collect demographic data on patients diagnosed with both cancer and neutropenia in Canadian acute care hospitals. This cancer/neutropenia database was created from patient discharge abstracts contained in the 1990/91 Hospital Medical Records Institute national acute-care hospital database. The data presented in the HMRI report are consistent with the concept that subgroups of cancer patients exist in whom clinical benefits and cost off-sets may be realized from the use of growth factors.

Adolescent↗

PubMedDate not supplied

The effect of granulocyte colony-stimulating factor (G-CSF) on bacterial translocation in the splenectomized rat.

BACKGROUND/AIMS: We created a study group in order to investigate the effects of splenectomy and filgrastim. Filgrastim is an immunomodulator granulocyte colony-stimulating factor (G-CSF), that affects bacterial translocation. MATERIALS AND METHODS: We created 3 study groups with 30 male Sprague-Dawley rats; the first group included sham splenectomy, the second group was splenectomy, and the third group was splenectomy+ filgrastim group. RESULTS: The mean bacterial colony count of the cecum were 2.5 x 10(9) in group 1, 1.2 x 10(10) in group 2 and 3.5 x 10(9) in group 3. The differences between these groups were accepted as statistically significant. The mean counts of the terminal ileum were 1.1 x 10(9) in group 1, 5.5 x 10(10) in group 2 and 2.5 x 10(10) in group 3. The p values of group 1-2 were 0.036 (statistically significant) and 0.123 in groups 2-3) were not statistically significant. The mean counts of the liver were 0.2 x 10(4), 1 x 10(10) and 3.4 x 10(5), respectively. In comparison of the groups the p values of the first and last 2 groups were found to be 0.047 (statistically significant). The mean counts of the mesenteric lymph node were 0.7 x 10(3), 1 x 10(10) and 0.9 x 10(6) respectively. The p values were 0.343 for the first and the last 2 groups both. As they were above 0.05, they were not statistically significant. The degrees of liver Kupffer cell hyperplasia were (+) 40%, (+2) 50% and (+3) 10% (group 1), (+) 10%, (+2) 40% and (+3) 50% (group 2), (+2) 60% and (+3) 40% (group 3) (p = 0.0039). The rates of the absence of pathology in mesenteric lymph nodes were 70% (group 1), 90% (group 2) and 100% (group 3) (p = 0.049). These findings were statistically significant. CONCLUSIONS: We found that splenectomy has activated the whole predisposing factors of bacterial translocation and created the latter itself. In addition, we showed that filgrastim, a recently widespread used G-CSF, decreases bacterial translocation significantly.

Adjuvants, Immunologic↗

PubMed1998

A phase I study of a daily x3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer.

PURPOSE: To determine the toxicity and activity of intravenous vinorelbine given daily for 3 consecutive days every 3 weeks in patients with platinum-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Between September 1994 and October 1995, 23 women with refractory epithelial ovarian cancer were entered onto this phase I study. All patients had measurable disease and platinum-resistant tumor, and prior therapy was limited to a maximum of two prior regimens. Nineteen (83%) were assessable for toxicity and 20 (87%) were assessable for response. Vinorelbine was administered intravenously daily for 3 consecutive days; this was repeated every 21 days. The starting dose was 20 mg/m2 daily x3, with dose escalation by 5 mg/m2 daily x3. Dose-limiting toxicity (DLT) was defined as grade 4 granulocytopenia for >3 days, grade 4 thrombocytopenia, neutropenic fever, or grade 3 or greater nonhematologic toxicity. The maximal tolerated dose (MTD) was defined as the highest dose level at which <50% of patients developed a DLT. Once the MTD of vinorelbine without granulocyte colony-stimulating factor (filgrastim) support was defined, dosing was begun at the MTD level and administration of 5 microg/kg filgrastim was initiated on day 4 and continued until WBC counts reached >10,000/microL. Clinical response, progression-free survival, and survival were also determined. RESULTS: Nineteen patients evaluable for toxicity received a total of 135 cycles of vinorelbine. The major DLT was neutropenia. The MTD of vinorelbine without filgrastim support was established as 20 mg/m2 daily x3. The MTD of vinorelbine with filgrastim support was established as 25 mg/m2 daily x3. Of 20 patients evaluable for response, 2 patients (10%) had a complete response and 4 (20%) had a partial response, for an overall response rate of 30%. CONCLUSION: These results warrant further study of vinorelbine in patients with platinum-resistant epithelial ovarian cancer. However, further study of the daily x3 schedule may not be warranted because of failure to achieve higher weekly dose intensity and because of nonhematologic toxicity in the form of intense bone pain.

Adult↗

PubMed1996

Pathophysiology and treatment of severe chronic neutropenia.

Severe chronic neutropenia (SCN) include a heterogeneous group of diseases characterized by blood neutrophil counts chronically less than 0.5 x 10(9)/ L. In phase I-III studies in SCN patients, treatment with recombinant human granulocyte colony stimulating factor (r-metHuG-CSF; Filgrastim) resulted in a rise in the absolute neutrophil counts (ANC) to above 1.0 x 10(9)/L associated with a reduction in bacterial infections. Long-term treatment with filgrastim up to 8 years demonstrate a sustained ANC response, a significant reduction of the need for intravenous antibiotics and a dramatic improvement in the quality of life. In 1994 an international registry for severe chronic neutropenia (SCNIR) was established to improve care for chronic neutropenia and for further understanding the pathophysiology of this rare disease. Three-hundred and ten patients have been enrolled to this registry so far. Worldwide phase I-III studies with filgrastim and SCNIR provide information on 424 patients with severe chronic neutropenia. Adverse events include the development of acute myeloid leukemia in approximately 7% of the patients within the cohort of patients with congenital neutropenia (Kostmann's syndrome) suggesting that congenital neutropenia is a preleukemic syndrome. None of the patients with cyclic of idiopathic neutropenia developed leukemia suggesting that filgrastim is not involved in the development of leukemia.

Chronic Disease↗

PubMed1999

Neutrophil deficiency and dysfunction in HIV-infected patients.

This paper describes abnormal neutrophil function in HIV-infected patients, as well as the in vitro effect of filgrastim (granulocyte colony stimulating factor) on neutrophil function in HIV infection. Research shows that HIV-infected patients have a variety of defects in neutrophil function, including abnormalities in chemotaxis, phagocytosis, and bacterial killing. Activation of neutrophils may also contribute to neutrophil dysfunction in HIV infection; it appears that neutrophils are activated at all stages of HIV disease, and this activation may result in a decreased ability to respond to a second stimulus in patients with CD4+ counts less than 200/cu mm. Accelerated neutrophil apoptosis (programmed cell death) may also contribute to impaired neutrophil function. Administration of filgrastim 300 microg s.c. daily or every other day for eight days to HIV-infected patients with CD4+ cell counts less than 200/cu mm resulted in a marked decrease in the rate of apoptosis compared with baseline. Since neutrophil activation, accelerated apoptosis, and functional defects appear to be reversible with administration of filgrastim, filgrastim may potentially be useful in preventing and treating secondary infections in HIV-infected patients.

HIV Infections↗

PubMed1999

Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Peripheral blood progenitor cell transplantation in lymphoma and leukemia using a single apheresis.

Myeloablative treatment and peripheral blood progenitor cell (PBPC) transplantation are increasingly used for lymphomas and leukemias. We have sought to optimize conditions for priming, collection, and engraftment of the leukapheresis product. Fifty-four consecutive adult patients were eligible, 31 with high-grade non-Hodgkin's lymphoma of poor prognosis, 12 with Hodgkin's disease in chemosensitive relapse, and 11 with poor prognosis acute lymphoblastic leukemia. Filgrastim was administered after routine chemotherapy with VAPEC-B or HiCCOM to mobilize PBPC. A rapidly increasing white blood cell count was used to predict the time of peak PBPC release and plan leukapheresis. Forty-five patients underwent leukapheresis. A median of 14 L of blood was processed at a single apheresis. A median of 2.4 x 10(8)/kg mononuclear cells (MNCs), 1.04 x 10(6)/kg granulocyte-macrophage colony-forming cells (GM-CFCs), and 10.6 x 10(6)/kg CD34+ cells were obtained. Slightly fewer MNCs were obtained from the heavily pretreated Hodgkin's disease group. There were no other significant differences in the size or composition of the leukapheresis harvest in the three patient groups. Forty patients underwent high-dose therapy and PBPC transplantation. Filgrastim was administered by daily subcutaneous injection until the absolute neutrophil count was > or = 1 x 10(9)/L for 2 consecutive days. Rapid and sustained hematopoietic engraftment occurred in all patients. The median time to achieve a neutrophil count > or = 0.5 x 10(9)/L was 9 days (range, 8 to 16 days); to achieve a platelet count > or = 20 x 10(9)/L was 10 days (range, 6 to 88 days); and to achieve a platelet count > or = 50 x 10(9)/L was 15.5 days (range, 10 to 100 days). Neutrophil recovery was faster than that of a historical control group treated with autologous bone marrow transplantation and filgrastim, but platelet recovery times were halved in the PBPC group. There was no secondary engraftment failure. Requirements for blood and platelet transfusions, antibiotic use, and parenteral nutrition were similar in the three patient groups. The median number of days in the hospital was 13 (range, 10 to 55) in the PBPC patients, compared with 19 (range, 14 to 51) in the historical controls. Leukapheresis yields (MNC, GM-CFC, and CD34+ cell numbers) were not useful for predicting the times to engraftment. We have shown that sufficient PBPC for transplantation can be obtained at a single leukapheresis after mobilization with routine chemotherapy and filgrastim in patients with non-Hodgkin's lymphoma, Hodgkin's disease, and acute lymphoblastic leukemia, even those heavily pretreated.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1997

Three types of recombinant human granulocyte colony-stimulating factor have equivalent biological activities in monkeys.

Three types of rhG-CSF are commercially available (non-glycosylated: filgrastim, glycosylated: lenograstim and N-terminal mutated: nartograstim). It has been reported that higher in vitro or in vivo efficacy was found in glycosylated or N-terminal mutated rhG-CSF than in non-glycosylated rhG-CSF. We reported that glycosylated or N-terminal mutated rhG-CSF showed equal efficacy to non-glycosylated rhG-CSF in vivo. In this study, we carried out a direct comparison of pharmacokinetics and pharmacological effects of three rhG-CSFs. We used commercially obtained rhG-CSF products whose activities are guaranteed by the manufacturers. Monkeys have been selected as the experimental animals because of their close relationship to humans concerning drug disposition and daily doses were in accordance with the clinical use of rhG-CSFs. Normal cynomolgus monkeys were given 1.5 or 5 micrograms/kg of rhG-CSF either intravenously or subcutaneously for 5 consecutive days. After intravenous injection, the serum concentration-time profiles of nartograstim were almost identical to those of filgrastim at both doses but the concentrations after lenograstim administration decreased faster. Following subcutaneous administration, no marked differences were observed between the three rhG-CSFs, although lenograstim showed lower serum concentrations than both filgrastim and nartograstim. In spite of some small differences in the pharmacokinetics of the three rhG-CSFs, the pharmacodynamics were identical.

Animals↗

PubMed2001

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part one: rationale and hypothesis.

GENERAL DESIGN: Presentation of a novel study protocol to evalue the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). OBJECTIVE: Part one of this protocol describes the concepts of three major sections of the study: Definition of optimum and sub-optimal recovery after operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i. e. death, complications and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patient and the surgeon (true endpoint). Its conventional early assessment within 14-28 days is artificial: longer periods (such as 6 months) are needed for the patient to state: "I am now as well as I was before". Identification of suitable target patients: the use of biological response modifiers (immune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropriate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cancer will be studied to prove this hypothesis. Choice of biological response modifier: Filgrastim has been chosen as an example of a biological response modifier because it was effective in a new study type, clinic-modelling randomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced host defence and has been anti-inflammatory in basic research. CONCLUSION: The following hypothesis will be tested in patients with operations for colorectal cancer and increased preoperative risk (ASA 3 and 4): is the outcome as evaluated by the hermeneutic endpoint (quality of life expressed by the patient) and mechanistic endpoints (mortality rate, complication rate, relative hospital stay, assessed by the doctor) improved in the group receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, statistical testing of confirmatory analysis.

Bacterial Infections↗