A comparison of treatment of canine cyclic hematopoiesis with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF interleukin-3, and canine G-CSF.

Cyclic hematopoiesis in gray collie dogs is a stem cell disease in which abnormal regulation of cell production in the bone marrow causes cyclic fluctuations of blood cell counts. In vitro studies demonstrated that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and granulocyte colony stimulating factor (G-CSF) all stimulated increases in colony formation by canine bone marrow progenitor cells. Based on these results, gray collie dogs were then treated with recombinant human (rh) GM-CSF, IL-3, or G-CSF subcutaneously to test the hypothesis that pharmacologic doses of one of these hematopoietic growth factors could alter cyclic production of cells. When recombinant canine G-CSF became available, it was tested over a range of doses. In vivo rhIL-3 had no effect on the recurrent neutropenia but was associated with eosinophilia, rhGM-CSF caused neutrophilia and eosinophilia but cycling of hematopoiesis persisted. However, rhG-CSF caused neutrophilia, prevented the recurrent neutropenia and, in the two animals not developing antibodies to rhG-CSF, obliterated periodic fluctuation of monocyte, eosinophil, reticulocyte, and platelet counts. Recombinant canine G-CSF increased the nadir neutrophil counts and amplitude of fluctuations at low doses (1 micrograms/kg/d) and eliminated all cycling of cell counts at high doses (5 and 10 micrograms/kg/d). These data suggest significant differences in the actions of these growth factors and imply a critical role for G-CSF in the homeostatic regulation of hematopoiesis.     

Effects of recombinant granulocyte colony-stimulating factor treatment on hematopoietic cycles and cellular defects associated with canine cyclic hematopoiesis.

Canine cyclic hematopoiesis (CH) is an autosomal recessive disease of gray collie dogs that is characterized by 14-day cycles of neutropenia, monocytosis, thrombocytosis, and reticulocytosis. Platelets from CH dogs have decreased dense-granule serotonin pools and decreased aggregation responses to collagen, platelet-activating factor (PAF), and thrombin. Recombinant granulocyte colony-stimulating factor (rG-CSF) was administered (5 micrograms/kg, b.i.d.) to four CH and six normal dogs to determine if G-CSF therapy corrected qualitative platelet defects in CH dogs. Neutrophil counts increase to greater than 25,000 cells/microliters within 24 h after starting treatment in all dogs. Treatment with G-CSF blocked neutropenic episodes in the CH dogs. Platelet aggregation, and serotonin content and secretion were significantly (p less than 0.05) decreased in the CH dogs both before and during recombinant human (rh) G-CSF treatment compared to normal dogs. Neutrophil myeloperoxidase, a primary granule enzyme, was significantly (p less than 0.05) decreased in CH dogs and was not corrected by rhG-CSF treatment. Administration of rG-CSF to CH dogs eliminated cell cycles but apparently did not correct cellular defects in CH dogs. Identification of primary biochemical defects in cells from CH dogs may be crucial to investigating the biochemical basis for cyclic hematopoiesis.     

Granulocyte colony-stimulating factor dosing in pegylated interferon alpha-induced neutropenia and its impact on outcome of anti-HCV therapy

Many patients with chronic hepatitis C (HCV) infection undergoing treatment with pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin develop neutropenia requiring dose reduction or granulocyte colony-stimulating factor (G-CSF) supplement. We analysed the database of patients who completed treatment for chronic HCV infection between 2003 and 2006. Patients with absolute neutrophil counts below 1000 cells/microL were initiated on G-CSF (G-CSF group) while a matching group of patients who received anti-HCV treatment without developing neutropenia were used as a control group (non-G-CSF group). Patients on the G-CSF arm were divided into two subgroups based on the timing of G-CSF administration relative to PEG-IFN-alpha administration. Of the 163 patients with HCV infection, 30 patients received G-CSF, most of who were maintained on 300 microg of G-CSF once a week. Administration of G-CSF 2 days before or after each dose of PEG-IFN-alpha did not make a significant difference in the neutrophil counts. In the G-CSF arm, 23 of 30 patients (77%) had undetectable end-of-treatment viral response which was comparable with 27 of 30 in the control group (90%; P = 0.17). There was no statistically significant difference in the sustained viral response between the two groups (61%vs 76%, P = 0.18). In most patients PEG-IFN-alpha induced neutropenia improved with a once-a-week dose of G-CSF with a comparable virological outcome. Timing of G-CSF administration did not make any significant impact on the patient's neutrophil counts but was better tolerated when given 2 days apart from PEG-IFN-alpha.     

The effect of recombinant human granulocyte colony-stimulating factor (rG-CSF) on childhood neutropenias]

The clinical effect of recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was studied in 27 patients with childhood neutropenias. The sample consisted of 8 patients with congenital neutropenia (Kostmann type), 9 with neutropenia with miscellaneous causes (5 chronic benign, 2 associated with hypogammaglobulinemia, 1 drug-induced, and 1 hypoplastic type), 3 with cyclic neutropenia, and 7 with severe aplastic anemia. The rG-CSF was given subcutaneously (or in a few cases intravenously) at a dose of 2 micrograms/kg/day for 7 days and 5 micrograms/kg/day for additional 7 to 28 days in cases with poor response. The rG-CSF was effective in 18 of 27 cases (67%). Patients with congenital neutropenia and aplastic anemia responded less frequently and poorly. The mean level of absolute neutrophil counts of 8 congenital neutropenia cases increased from 88/microliters to 2,718/microliters. That of 9 miscellaneous cases changed from 189/microliters to 7,224/microliters at a dose of 2 micrograms/kg/day. In 7 aplastic anemia cases pretreatment level of 220/microliters rose to 851/microliters, usually after increasing the dose up to 5 micrograms/kg/day. The rG-CSF was apparently effective in 3 cases of cyclic neutropenia. In any type of neutropenia, the effect was largely transient; after the discontinuation of rG-CSF, the absolute neutrophil counts tended to decrease to pretreatment levels within 1 to 2 weeks. The G-CSF was well tolerated, and only one case with mild lumbago and another with minimal elevation of transaminases were observed. We conclude that the rG-CSF can be effective for treating various types of childhood neutropenia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hematological effect of 14 days treatment of recombinant human granulocyte colony-stimulating factor for neutropenia in myelodysplastic syndromes]

Nineteen patients with myelodysplastic syndromes (MDS) were treated with a glycosylated recombinant granulocyte colony-stimulating factor (rG-CSF) for improvement of neutropenia. rG-CSF was administrated intravenously at a dose of 5 micrograms/kg/day for 14 consecutive days. Most of patients responded to rG-CSF and an approximately 10 fold increase of the peak neutrophil counts was observed. The neutrophil counts were maintained at high level during the treatment period and returned to pretreatment levels several days after stopping rG-CSF. Consistent with the recovery of neutrophil, infectious complications improved in many cases. Effects of rG-CSF were confined to neutrophils, sparing blast cells and other blood cells. Eruption was observed in one patient as toxicity. We conclude that rG-CSF therapy is effective in improving neutropenia with MDS patients.     

Clinical evaluation of recombinant human G-CSF in children with cancer]

Recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was administered in 69 chemotherapy-induced neutropenic pediatric patients (pts) with malignant tumors. Each pt received two cycles of the same chemotherapy and had neutropenia with absolute neutrophil counts (ANC) less than 500/microliter in the first cycle. Initiating 72 hours after termination of chemotherapy in the second cycle, rG-CSF (2 micrograms/kg/day) was given subcutaneously or intravenously to each pt for 10 days. rG-CSF significantly increased ANC at nadir; 72 +/- 14 vs. 206 +/- 40/microliter (data in the first cycle vs. data in the second cycle, respectively), and reduced the period of neutropenia with ANC less than 500/microliter; 9.7 +/- 0.6 vs. 5.1 +/- 0.6 days, and the period for restoration to ANC greater than or equal to 1,000/microliter after initiation of chemotherapy; 25.5 +/- 0.6 vs 17.5 +/- 0.9 days. rG-CSF did not affect other components of peripheral blood. The number of days with fever greater than or equal to 38 degrees C was significantly reduced by rG-CSF treatment. Neck pain and lumbago were observed in one pt, pollakisuria in one pt, and elevation of the serum levels of LDH and uric acid in one pt, however these were mild to moderate, transient, and resolved without any specific treatment. We concluded that rG-CSF was effective in neutropenia induced by intensive chemotherapy for malignant tumors without any serious side effects.     

Granulocyte-colony stimulating factor-induced proliferation of primary adult T-cell leukaemia cells

Granulocyte-colony stimulating factor (G-CSF) is known to induce proliferation and differentiation of granulocyte progenitors, and is widely used to treat neutropenia induced by intensive chemotherapy for malignant lymphoma or adult T-cell leukaemia/lymphoma (ATL). G-CSF is thought not to stimulate malignant lymphoid cells. In the present study we examined the ability of G-CSF to induce in vitro growth of primary ATL cells from 14 patients (nine acute-type, two chronic-type and three lymphoma-type), and we analysed the in vivo counts of ATL cells in patients who received G-CSF for neutropenia. FACS analysis using phycoerythrin-labelled recombinant G-CSF demonstrated that ATL cells from 11/14 patients express some G-CSF receptor (G-CSFR), with a range between 5.4% and 87.3%. Cells expressing G-CSFR also expressed CD4. Reverse polymerase chain reaction (PCR) analysis demonstrated expression of G-CSFR messenger RNA in G-CSFR expressing cells. Leukaemic cells derived from seven (four acute-type, one chronic-type and two lymphoma-type) of the 14 patients proliferated in vitro in response to G-CSF, as measured by [³H]thymidine incorporation; maximum responses were at G-CSF concentrations of 10–100 ng/ml. Nine of 14 patients receiving rG-CSF for neutropenia were analysed retrospectively for ATL cell numbers. Four patients whose primary tumour cells proliferated in response to rG-CSF in vitro showed a significant increase in ATL cell count after administration of rG-CSF ( P  =0.038), whereas five patients whose leukaemic cells did not proliferate in vitro showed no significant increase in ATL cell count. G-CSF can stimulate proliferation of ATL cells which may complicate therapy for this disease.     

Adult-onset cyclic neutropenia responsive to cyclosporine therapy in a patient with ankylosing spondylitis

A 45-year-old female with a long history of HLA-B27-positive ankylosing spondylitis and ulcerative colitis developed cyclic neutropenia. She was hospitalized for high fever during each of three consecutive episodes of absolute neutropenia. On the third hospitalization, granulocyte-colony-stimulating factor (G-CSF), 5 μg/kg/day, was given by subcutaneous injection and resulted in an increase of absolute neutrophil count from 0 to 2.2 × 10⁹/liter and an associated decrease of platelet count and hemoglobin as well as severe bone and joint pain predominantly in the middle and lower back and purulent diarrhea. The back pain necessitated discontinuation of the drug. Oral cyclosporine therapy was begun, and although the neutrophil count continued to oscillate, both the peaks and the nadirs were higher than previously, and symptoms of neutropenia subsided. We conclude that cyclosporine can be an effective treatment for cyclic neutropenia associated with autoimmunity since G-CSF may cause exacerbations of autoimmune disorders.     

Chronic idiopathic neutropenia improved by recombinant granulocyte colony stimulating factor]

A 55-year-old man was admitted to our hospital for the evaluation of neutropenia. On physical examination, he had apthae and splenomegaly. CBC showed 1,000/microliter WBC with 5% neutrophils, and microcytic anemia consistent with iron deficiency. Bone marrow examination revealed a marked decrease of mature neutrophils, but normal percentage of immature myeloid cells. There was no morphological abnormality in the hemopoietic cells. He had no drug or family history responsible for the neutropenia. Anti-neutrophil auto-antibody was negative. Hence, a diagnosis of chronic idiopathic neutropenia (CIN) was made. He developed frequent episodes of infection such as balanitis, peri-anal infection, gingivitis, and pharyngitis. He was treated with steroid pulse therapy, anabolic hormone, and high dose gamma-globulin infusion, but no significant improvement occurred. Then, recombinant granulocyte-colony stimulating factor (rG-CSF) was started. The neutrophil count was normalized by the 7th day of 5 micrograms/kg/day rG-CSF administration. The administration of G-CSF was discontinued after a 14-day course. Thereafter, the neutrophil count remained at near normal level (approximately 1,500/microliter) and there have been no episodes of infection in the last 5 months. However this cannot be explained simply by the direct effect of rG-CSF on the myeloid precursors; rather, it suggests some unknown effect of G-CSF on the bone marrow microenvironment regulating myeloid hemopoiesis. We consider this to be a rare case of CIN with frequent episodes of infection, which was successfully treated with G-CSF.     

Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor

STUDY OBJECTIVE: To determine whether recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in increasing neutrophil counts in patients with hairy cell leukemia and neutropenia. DESIGN: Open label, phase I/II study of G-CSF, given by daily subcutaneous injection for up to 7 weeks. SETTING: Outpatient oncology clinic of a university medical center. PATIENTS: A consecutive sample of four patients with hairy cell leukemia complicated by severe neutropenia. Three patients completed the study; one patient was removed after 2 weeks of therapy. INTERVENTIONS: Granulocyte colony-stimulating factor was given by daily subcutaneous injection. Each patient began therapy with 1 microgram/kg body weight.d; after 1 week the dose was increased to 3 micrograms/kg.d, and 1 week later to 6 micrograms/kg.d. Therapy was continued for 5 to 6 weeks. Patients were taught self-injection, and administered treatment at home. MEASUREMENTS and MAIN RESULTS: In three patients, an increase in absolute neutrophil counts from less than 0.9 X 10(9)/L to greater than 4.0 X 10(9)/L was noted within 2 weeks of beginning G-CSF therapy. In two patients, infections resolved during therapy. One patient developed acute neutrophilic dermatosis (the Sweet syndrome) while receiving 3 micrograms/kg.d of G-CSF, and drug therapy was discontinued. CONCLUSIONS: Granulocyte colony-stimulating factor may increase neutrophil counts within 2 weeks in patients with hairy cell leukemia and neutropenia. This therapy may be a useful adjunct to definitive treatment of hairy cell leukemia with interferon or pentostatin.     

Treatment of severe neutropenia due to Felty's syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor.

OBJECTIVES: To examine the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for the treatment of severe neutropenia due to Felty's syndrome (FS) or systemic lupus erythematosus (SLE). METHODS: Eight patients with absolute neutrophil counts (ANC) below 1,000/microL attributable to FS (n = 4) or SLE (n = 4) were treated with rhG-CSF. The hematologic and clinical response as well as side effects were recorded. In addition, reports on the use of rhG-CSF/rhGM-CSF in FS and SLE retrieved from the English language literature were analyzed. RESULTS: RhG-CSF effectively corrected neutropenia due to FS and SLE in seven of the current eight patients. In 54 of 55 FS and SLE patients retrieved from the literature, G-CSF or GM-CSF, respectively, proved to be effective at elevating the neutrophil count, which was often associated with improvement of infectious complications. The neutrophil count often declined again when growth factor treatment was stopped but generally stabilized at a level that exceeded the pretreatment count. Side effects included rare cases of thrombocytopenia, arthralgias, and development of cutaneous leukocytoclastic vasculitis. Side effects were dose dependent and resolved when treatment was discontinued. One of our own patients and 17 previously reported patients continued to benefit from long-term administration of rhG-CSF over periods of more than 40 months. CONCLUSIONS: RhG-CSF is an effective and generally well-tolerated treatment for neutropenia due to FS or SLE. Exacerbation of the underlying rheumatic condition due to G-CSF appears to be rare if G-CSF is administered at the lowest dose effective at elevating the ANC above 1,000/microL.     

Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.     

Circulating granulocyte colony-stimulating factor (G-CSF) levels after allogeneic and autologous bone marrow transplantation: endogenous G-CSF production correlates with myeloid engraftment.

Myeloid engraftment after bone marrow transplantation (BMT) is influenced by a number of variables, including cytoreductive chemoradiotherapy, genetic disparity, number of reinfused committed myeloid progenitor cells, healthy microenvironment, and the presence of hematopoietic growth factors. Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation of myeloid progenitor cells and enhances myeloid engraftment after BMT. We investigated the temporal relationship between endogenous G-CSF production and myeloid engraftment in both children and adults after allogeneic (ALLO) and autologous (AUTO) BMT. Circulating endogenous G-CSF levels ranged between 0 and 2552 pg/mL. The correlation coefficient between circulating serum G-CSF levels and the peripheral absolute neutrophil count (ANC) was r = -.875 (P less than .001). The endogenous serum G-CSF level was highest during the first week after BMT, when the ANC was less than or equal to 200/microL (699 +/- 82.3 pg/mL) (P less than .001). Both children and adults demonstrated a similar inverse relationship between circulating G-CSF level and degree of neutropenia. One patient failed to engraft after AUTO BMT and also failed to generate any endogenous G-CSF production. Lastly, once the serum G-CSF level decreased to less than 200 pg/mL, a mean of 6.1 +/- 0.9 days elapsed before the ANC was greater than or equal to 500/microL for 2 consecutive days. This study demonstrates that endogenous G-CSF production is associated with myeloid engraftment in both children and adults after AUTO and ALLO BMT and that the rate of increase and decrease in endogenous G-CSF may be predictive of either failure to engraft or duration of neutropenia.     

The effect of continuous G-CSF application in human cyclic neutropenia: a model analysis

Human cyclic neutropenia (CN) is a rare haematological disorder characterized by oscillations of blood neutrophils at subnormal levels with a stable period of approximately 21 d. During the phase of severe neutropenia (neutrophils <250 cells/yul), which last 4–10 d, the patients are endangered by serious infections. Several authors report that continuous G-CSF application can elevate the blood neutrophils to such a level that the risk of infections is significantly reduced. Although the characteristic cycles are not eliminated by G-CSF, the period of the oscillations is shortened to 12–14 d. Based on a previously proposed computer-simulation model of human CN, the effects of continuous G-CSF application on CN are studied. It is shown how the known different cell-kinetic effects of G-CSF on granulopoiesis explain the clinical data in CN. The reduced length of the cycles emerges as a result of the transit time reduction of the post-mitotic granulopoietic cells by G-CSF. The measured increase of the neutrophil maxima is reproduced by the additional mitoses of the immature granulopoietic bone marrow cells induced by G-CSF. The slight elevation of the neutrophil nadirs can be attributed to a weak effect of G-CSF on the assumed underlying defect in CN (an abnormally small variance of the granulopoietic bone-marrow transit time).     

Effect of recombinant human GH on circulating granulocyte colony-stimulating factor and neutrophils in patients with adult GH deficiency

BACKGROUND: We previously reported that short-term continuous subcutaneous infusion (CSI) of recombinant human growth hormone (rhGH) increased plasma erythropoietin levels and hemoglobin concentrations in patients with adult GH deficiency. In the present study, we investigated the effect of rhGH on plasma granulocyte colony-stimulating factor (G-CSF) levels and neutrophil counts in patients with adult GH deficiency. METHODS: rhGH was administrated for 1 year in six patients with adult GH deficiency (age range, 24-69 years; mean +/- S.E.M., 51.7 +/- 5.8 years; two males and four females) by means of CSI at a rate of 0.25 U/kg per week. Blood samples were obtained in the morning after overnight fasting every month before and after the start of rhGH administration. Plasma GH, insulin-like growth factor I (IGF-I) and G-CSF levels, and neutrophil counts, were measured. RESULTS: Mean ( +/- S.E.M.) plasma GH levels increased from 0.26 +/- 0.14 to 2.28 +/- 0.20 microg/l 1 month after the start of rhGH administration. An increase of the plasma GH levels was accompanied by an increase in the plasma IGF-I levels from 64.7 +/- 8.5 to 293.3 +/- 80.6 microg/l. Plasma G-CSF levels increased at 2, 3, 8, 9 and 10 months after the start of rhGH administration compared with 28.6 +/- 11.0 ng/l at time 0. The neutrophil counts increased at 2, 3, 7, 8, 9, 11 and 12 months after the start of rhGH administration compared with 2822 +/- 377 neutrophils/microl at time 0. CONCLUSION: rhGH administration increased plasma G-CSF levels and neutrophil counts. GH and/or IGF-I might stimulate neutrophil production and/or release via G-CSF.     

Sustained G-CSF plasma levels following administration of pegfilgrastim fasten neutrophil reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation in patients with multiple myeloma

OBJECTIVE: Pegfilgrastim has shown to decrease the duration of severe neutropenia after conventional chemotherapy, but its use after high-dose chemotherapy and autologous blood stem cell transplantation has not been established yet. Therefore we studied the efficacy and the pharmacokinetic profile of pegfilgrastim in patients with multiple myeloma undergoing high-dose chemotherapy. METHOD: In total, 21 patients received a single subcutaneous injection of 6 mg pegfilgrastim on day +1 after transplantation and pegfilgrastim plasma levels were measured daily by enzyme-linked immunosorbent assay. Clinical outcome was compared with pegfilgrastim levels of 282 plasma samples and data of a historical control group of patients without granulocyte colony-stimulating factor (G-CSF) support. RESULTS: Pegfilgrastim levels showed an inverse correlation (r = -0.68, p < 0.01) with neutrophil counts. Peak levels were reached at day +4 (94 ng/mL; range: 37-205) and were maintained until day +7 (85 ng/mL; range: 35-186). Comparison with the control group without G-CSF support showed that time to neutrophil reconstitution was significantly shorter in the pegfilgrastim group with 10 vs 15 days, respectively (p < 0.001). There was no correlation of pegfilgrastim levels and the duration of neutropenia, although patients with a fivefold increase in neutrophil counts the day after pegfilgrastim administration had a significantly shorter median duration of neutropenia in comparison to patients who were less susceptible to G-CSF stimulation (5 vs 7 days, p < 0.01). CONCLUSION: Neutrophil reconstitution after high-dose chemotherapy could be accelerated by the use of pegfilgrastim in patients with myeloma. Responsiveness of neutrophils to pegfilgrastim before neutropenia was correlated with faster neutrophil reconstitution, whereas G-CSF levels had no impact on neutrophil recovery.     

G-CSF in Peg-IFN induced neutropenia in liver transplanted patients with HCV recurrence

AIM: To evaluate the efficacy of granulocyte colony stimulating factors (G-CSF) in liver transplanted patients with hepatitis C (HCV) recurrence and Pegylated-IFN α-2b induced neutropenia, and to evaluate the impact of G-CSF administration on virological response.METHODS: Sixty-eight patients undergoing antiviral treatment for post-liver transplantation (OLT) HCV recurrence were enrolled.All patients developing neutropenia received G-CSF.RESULTS: Twenty three (34%) received G-CSF.Mean neutrophil count at the onset of neutropenia was 700/mmc (range 400-750/mmc); after 1 mo of G-CSF it increased to 1210/mmc (range 300-5590/mmc) ( P < 0.0001).Three patients did not respond to G-CSF.Treatment duration was similar in neutropenic and non-neutropenic patients.No differences in the rate of discontinuation, infections or virological response were observed between the two groups.G-CSF was protective for the onset of de novo autoimmune hepatitis ( P < 0.003).CONCLUSION: G-CSF administration is effective in the case of Peg-IFN induced neutropenia increasing neutrophil count, prolonging treatment and leading to sustained virological response (SVR) rates comparable to non-neutropenic patients.It prevents the occurrence of de novo autoimmune hepatitis.     

Effects of recombinant human granulocyte colony-stimulating factor on the mice receiving bone marrow transplantation following lethal irradiation: acceleration of recovery of the peripheral blood neutrophils and potentiation of anti-Pseudomonas resistance.

The effects of recombinant human granulocyte colony-stimulating factor (rG-CSF) on the recovery of peripheral blood neutrophil counts and resistance to i.p. infection by Pseudomonas aeruginosa were studied using a mouse bone marrow transplantation (BMT) model. A severe neutropenic period continued in the BMT mice for greater than 9 days following BMT. In contrast, the number of peripheral blood neutrophils in the BMT mice that received a daily administration of 2.5 micrograms of rG-CSF following BMT returned to normal by day 9. Thus, rG-CSF accelerated the recovery of the peripheral blood neutrophil counts in BMT mice. Anti-Pseudomonas resistance of the control BMT mice examined on days 7, 9, and 11 following BMT was one fifteenth to one fiftieth of normal mice, as indicated by the LD50 value. The anti-Pseudomonas resistance was elevated six- to sevenfold by the rG-CSF treatment. A marked increase in the neutrophils exudating into the peritoneal cavity in response to casein injection was observed in the rG-CSF-treated BMT mice. In addition, the reduced superoxide generative and phagocytic activity of the peritoneal neutrophils of the BMT mice were restored to normal by the rG-CSF treatment. It is suggested that rG-CSF potentiated anti-Pseudomonas resistance of the BMT mice by increasing neutrophils migrating to the infection site and restoring their functions; this may result from a prompt recovery of the peripheral blood neutrophil level together with the effect on neutrophil functions. These results indicate the clinical usefulness of rG-CSF in applications for BMT.     

Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C

Interferon therapy of hepatitis C causes a decrease in neutrophil counts, and neutropenia is a common reason for dose adjustment or early discontinuation. However, it is unclear whether neutropenia caused by interferon is associated with an increased rate of infection. In this study, we assessed factors associated and clinical consequences of neutropenia before and during interferon therapy of chronic hepatitis C. A total of 119 patients with chronic hepatitis C treated with the combination of interferon alfa and ribavirin were analyzed. In these studies, neutropenia was not used as an exclusion or dose modification criterion. In multivariate analysis, only black race was associated with baseline neutropenia. During treatment, neutrophil counts decreased by an average of 34%. Among 3 blacks with baseline neutropenia without cirrhosis or splenomegaly, there was little or no decrease in neutrophil counts (despite typical decreases in platelet and lymphocyte counts). Documented or suspected bacterial infections developed in 22 patients (18%), but in no patient with neutropenia. United States population estimates suggest that 76,000 blacks with hepatitis C have neutrophil counts below 1,500 cells/microL and might be denied therapy if this exclusion criterion was generally applied. In conclusion, neutropenia is frequent during treatment of hepatitis C with interferon and ribavirin, but it is not usually associated with infection. Constitutional neutropenia, which is common among blacks, should not exclude patients from therapy with interferon as these patients usually have minimal further decreases in neutrophil counts on therapy and are not excessively prone to bacterial infections.     

Clinical significance of recombinant human granulocyte colony-stimulating factor (rG-CSF) in the chemotherapy of patients with malignant lymphoma]

We examined the effects of recombinant human granulocyte colony-stimulating factor (rG-CSF) on neutropenia induced by chemotherapy in 10 patients with non-Hodgkin's lymphoma (NHL). The numbers of peripheral blood hematopoietic progenitors were also evaluated before and after administration of rG-CSF. Six patients received an administration of 2 micrograms/kg/body weight of rG-CSF subcutaneously for 14 days after 2nd chemotherapy. Four patients received intravenous infusion of rG-CSF (300 micrograms/body/day) for 4 days from nadir state after chemotherapy. Administration of rG-CSF from the termination of chemotherapy, markedly shortend the period of bone marrow hypoplasia induced by chemotherapy. On the other hand, administration of rhG-CSF from nadir state after chemotherapy have accelerated the recovery of neutrophil counts. In addition, this type of therapy induced 26 to 60 folds increase of peripheral blood hematopoietic progenitors. These results demonstrate the validity of administration of rhG-CSF not only in the chemotherapy of NHL, but also in peripheral blood stem cell transplantation (PBSCT).