Treatment of aplastic anemia in children with recombinant human granulocyte colony-stimulating factor

Twenty children (aged 1 to 17 years) with severe or moderate aplastic anemia were treated with recombinant human granulocyte colony- stimulating factor (rhG-CSF) at a dose of 400 micrograms/m2 per day administered as a 30-minute intravenous (IV) infusion daily for 2 weeks. This treatment increased the neutrophil counts (2.7- to 28.0- fold) in 12 of the 20 patients. Increasing doses (800 or 1,200 micrograms/m2 per day) were administered to five patients who had not responded to the initial dose, and three showed an increase in neutrophil count. Differential counts of bone marrow (BM) aspirates showed an increase in the myeloid/erythroid ratio. The response was transient, however, and the neutrophil count returned to baseline within 2 to 10 days of discontinuing treatment. No severe toxicity attributable to rhG-CSF was observed. The results suggest that this agent is effective in stimulating granulopoiesis in children with aplastic anemia. Our study also indicates that rhG-CSF will be particularly useful in managing patients with aplastic anemia complicated by bacterial or fungal infection.     

Stimulation of granulopoiesis by high-dose recombinant human granulocyte colony-stimulating factor in children with aplastic anemia and very severe neutropenia

We investigated the efficacy and safety of high-dose recombinant human granulocyte colony-stimulating factor (rhG-CSF) in treating 10 children with severe aplastic anemia and fewer than 0.05 x 10(9)/L neutrophils. Doses of rhG-CSF ranging from 400 to 2,000 micrograms/m2/d were administered as a 30-minute intravenous infusion daily for 4 weeks. In 6 of the 10 children, treatment increased the neutrophil count by 10- fold to greater than 60-fold (range, 0.21 to 1.8 x 10(9)/L). Bacterial or fungal infections that were present at study entry resolved in all 6 responders, who are still alive with a median survival of more than 27 months (range, 15 to 54 months) since the initiation of treatment. Three of 4 nonresponders died of infection, whereas 1 nonresponder received a bone marrow transplant and is alive. No serious toxicity was attributable to rhG-CSF. It was well tolerated at doses up to 2,000 micrograms/m2/d and effectively stimulated granulopoiesis. This agent thus offers promise as adjuvant treatment for severe infections in children with aplastic anemia and very severe neutropenia.     

Bilineage response in refractory aplastic anemia patients following long-term administration of recombinant human granulocyte colony-stimulating factor.

5 patients with refractory aplastic anemia (AA) received long-term administration (2-11 + months) of recombinant human G-CSF (rhG-CSF) in doses from 250-500 micrograms/body/day by intravenous infusion or 75-300 micrograms/body/d by subcutaneous injection. All 5 evaluable patients showed a substantial increase in absolute neutrophil count (ANC) with a recovery of myeloid components in the bone marrow after 1 to 2 months of treatment. Interestingly, 2 out of the 5 patients showed a dramatic improvement in severe anemia after 2 to 4 months of treatment accompanying a recovery of erythroid components in the bone marrow. In addition, there was no serious infection before or during therapy. Long-term administration of rhG-CSF was well tolerated because of its minimal toxicity. Clonal assay revealed a recovery of myeloid progenitors in all patients and a recovery of erythroid progenitors in 3 out of the 5 patients. These results suggest that long-term administration of rhG-CSF at least mobilizes residual myeloid as well as erythroid progenitor cells and induces a bilineage response in severe refractory AA.     

Very low doses of GM-CSF administered alone or with erythropoietin in aplastic anemia.

PURPOSE AND RATIONALE: There has been no previously published experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses less than 15 micrograms/m2/d in patients with aplastic anemia, and most observations have been made at doses of 100 to 500 micrograms/m2/d (2.5 to 12.5 micrograms/kg/d). The benefits of using considerably lower doses, if effective, should include a decrease in cost and in side effects. We have therefore used very low doses of GM-CSF to treat a group of patients with aplastic anemia. Additionally, since severe anemia is often a problem in these patients, we recently started administering erythropoietin along with the GM-CSF. Herein we report the results of very-low-dose GM-CSF therapy in patients with aplastic anemia and our preliminary findings in those individuals who received combination therapy. PATIENTS AND METHODS: We administered recombinant human GM-CSF subcutaneously at doses of 5 to 20 micrograms/m2/d ("very-low-dose GM-CSF") to 12 patients with aplastic anemia. In addition, a 13th patient received erythropoietin together with the GM-CSF regimen, and three of the 12 individuals who initially received 1 or more months of GM-CSF alone were later also given erythropoietin (4,000 U/d subcutaneously). RESULTS: In five of 12 patients (42%) treated with very-low-dose GM-CSF, an increase in neutrophil counts (2.0- to 6.7-fold) was noted, and one of these subjects attained a bilineage response (neutrophil counts, 0.3 to 1.75 x 10(9)/L; platelet counts, 8 to 169 x 10(9)/L). Moreover, a sixth patient showed a rise in platelet counts (19 to 80 x 10(9)/L) without a concomitant increase in neutrophils. Constitutional side effects were minimal. Combining erythropoietin and very-low-dose GM-CSF produced a bilineage response (neutrophils, 1.0 to 3.0 x 10(9)/L; hemoglobin, 7.4 to 9.4 g/dL) in the one patient who received erythropoietin together with the GM-CSF from the time that GM-CSF was initiated. In one of the other patients who were given combination therapy, the addition of erythropoietin appeared to enhance the response; this patient demonstrated a neutrophil response to GM-CSF alone and a trilineage response (neutrophils, 0.8 to 3.75 x 10(9)/L; hemoglobin, 7.0 to 13.1 g/dL; and platelets, 10 to 34 x 10(9)/L) to the combination. No toxicity was associated with the addition of erythropoietin. CONCLUSIONS: Our observations suggest that (1) very low doses of GM-CSF (5 to 20 micrograms/m2/d subcutaneously) may be used initially in neutropenic patients with aplastic anemia, and the dose subsequently increased only in patients who do not respond; and (2) the administration of erythropoietin together with GM-CSF is well tolerated, can augment responsiveness in some patients, and deserves further study.     

A phase I/II trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia

Nine pediatric patients (median age, 8 years; range, 0.7 to 19 years), eight with refractory aplastic anemia and one with newly diagnosed aplasia, were enrolled in a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administered via continuous intravenous infusion. Doses ranged from 8 to 32 micrograms/kg/d. Six of eight evaluable patients responded with a significant rise in neutrophil count (median fourfold increase; range, 2.5- to 31-fold) during the 28-day induction period. Five patients completed 2 further months of therapy (maintenance) with persistent or improved neutrophil responses. Three patients had bone marrow aspirates suggestive of increased erythropoiesis, although only one patient had improvement in peripheral hematocrit and platelet count. In the five patients completing maintenance, three experienced a rapid return to baseline counts after rhGM-CSF was discontinued, one maintained a neutrophil response for 2 months after drug discontinuation, and one has maintained a trilineage response for greater than 1 year off study. Drug therapy was well tolerated. Toxicity was minimal at doses from 8 to 16 micrograms/kg/d. Fever and rash were more commonly seen at 32 micrograms/kg/d. No patient developed an infection during the course of rhGM-CSF administration. These results demonstrate that rhGM-CSF increases peripheral neutrophil counts in children with refractory and newly diagnosed aplastic anemia and may be able to stimulate a multilineage response in a more limited number. Randomized, prospective trials are necessary to determine if rhGM-CSF administration will impact favorably on the morbidity and mortality of severe aplastic anemia.     

Treatment of refractory aplastic anemia with recombinant human granulocyte-macrophage-colony-stimulating factor

Fifteen patients with refractory aplastic anemia or agranulocytosis received treatment with recombinant human granulocyte-macrophage-colony-stimulating factor (rhGM-CSF) in doses from 4 to 64 micrograms/kg/d by continuous intravenous (IV) infusion. Ten of 11 evaluable patients with aplastic anemia had substantial increments in granulocytes, monocytes, and eosinophils associated with myeloid and eosinophilic hyperplasia in the bone marrow. Patients with pretreatment granulocytes greater than 0.3 x 10(9)/L had greater increments in circulating myeloid cells than patients with more severe granulocytopenia. Only one patient had improvement in erythrocytes and platelets. Blood counts fell to baseline after rhGM-CSF treatment was discontinued. Doses up to 16 micrograms/kg/d were relatively well tolerated in the absence of extreme leukocytosis. Fatigue and myalgia were common. Three patients developed pulmonary infiltrates that resolved with discontinuation of treatment. Patients tended to have recurrent inflammation in previously diseased tissues. These data indicate that rhGM-CSF will increase circulating granulocytes, monocytes, and eosinophils in patients with refractory aplastic anemia. Further studies are necessary to determine if rhGM-CSF treatment will reduce morbidity or improve survival.     

Clinical study of rhG-CSF (KRN8601) in patients with myelodysplastic syndrome]

A clinical study of rhG-CSF (KRN8601) in patients with myelodysplastic syndrome (MDS) was performed to investigate the hematopoietic effects and the increase of neutrophils. The rhG-CSF was administered daily by intravenous infusion over 30 min. to 21 patients with MDS (PARA = 11, RAEB = 4, RAEB in T = 6). The dose was escalated stepwise from 50 to 400 microgram/m2 every week. Within one week to 26 days after commencement of rhG-CSF administration, the increases of absolute neutrophil counts in peripheral blood were observed in all patients. Treatment with rhG-CSF enhanced normal marrow myeloid cell differentiation and maturation in 3 of 9 PARA patients and in 3 of 4 RAEB patients. None of patients changed to acute leukemia attributable to rhG-CSF, but one of RAEB patient and two of RAEB in T patients progressed to leukemic phase in 21 days or two months after treatment. Minor side effects or abnormal laboratory findings were observed in 3 patients (14.3%). These results suggested that treatment with rhG-CSF was well tolerated and effective for improving the neutropenia between 50 to 400 micrograms/m2 in patients with MDS.     

Clinical evaluation of effects of KRN8601 (rhG-CSF) on neutropenia]

Clinical effects of KRN8601 (recombinant human granulocyte colony-stimulating factor:rhG-CSF) were studied in 26 patients with chronic neutropenia including 4 Kostmann's disease, 1 Shwachman's syndrome, 1 Lonsdale's syndrome, 1 glycogen storage disease Ib-associated, 6 chronic benign, 5 chronic hypoplastic, 2 cyclic, 4 autoimmune and 2 miscellaneous neutropenia. The patients were given rhG-CSF intravenously at doses of 20-540 micrograms/m2 or subcutaneously at doses 20-400 micrograms/m2, over the periods of 2-32 weeks. Increases in neutrophil counts occurred after rhG-CSF administration in 23 of the 26 patients. Patients with Kostmann's disease, Shwachman's syndrome and chronic hypoplastic neutropenia responded poorly compared to patients with other types of neutropenia. There were no serious side effects which caused interruption of the study. These results indicated a beneficial effect of KRN8601 in various types of chronic neutropenia.     

A phase II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes

We conducted a phase II study of the intravenous administration of a glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF) for 7-14 d in 41 patients with the myelodysplastic syndromes (MDS). Administration of rhG-CSF elicited striking rises in both leucocyte and neutrophil counts in the majority of the patients irrespective of the FAB subtypes of MDS. The rises in neutrophil counts were dose dependent and 5 micrograms/kg/d of rhG-CSF yielded approximately an 8-fold increase in neutrophil counts. Leucocytes and neutrophil counts started to increase shortly after the first injection of 5 micrograms/kg, was maintained at significantly elevated levels during 14 d of treatment, and returned to the pretreatment levels within several days following discontinuation of rhG-CSF. The action of rhG-CSF was specific for neutrophils since leucocytosis was due exclusively to neutrophilic increase associated with an increased marrow myeloid maturation. There were no consistent changes in the monocyte, eosinophil, lymphocyte, platelet or reticulocyte counts. After treatment, the percentage of marrow blast cells was reduced in eight of 13 evaluable patients with refractory anaemia with an excess of blasts (RAEB) or RAEB in transformation (RAEB-t). No patients developed acute leukaemia during the treatment or in the immediate follow-up period. The treatment was well tolerated with only minimal toxicity. The results suggest that rhG-CSF is a safe and effective way to promptly improve neutropenia in MDS patients.     

Clinical effect of recombinant human granulocyte colony-stimulating factor on aplastic anemia]

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutropenia was studied in 30 patients with aplastic anemia (AA). RhG-CSF was administered intravenously daily at a dose of 2, 5, 10, or 20 micrograms/kg/day for more than 7 days. In the patients whose absolute neutrophil counts (ANC) were more than 0.1 X 10(9)/l, the rhG-CSF injections at greater than or equal to 5 micrograms/kg/day caused rapid and selective elevation of ANC which maintained during the injection period. Most of the patients were well tolerated, and minor side effects were observed in only 3 patients. These findings suggest that daily injections of rhG-CSF at a dose of greater than or equal to 5 micrograms/kg/day may be an effective strategy for the treatment of bacterial and/or fungal infections in AA patients.     

Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia secondary to a maturational arrest at the level of promyelocytes. We treated five patients with SCN with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 42 days and subsequently, between 1 and 3 months later, with rhG-CSF for 142 days. The objective was to evaluate the safety and ability of these factors to elicit a neutrophil response. rhGM-CSF was administered at a dose of 3 to 30 micrograms/kg/d (30 to 60 minutes, intravenously). In all patients, a specific, dose-dependent increase in the absolute granulocyte counts was observed. However, in four patients this increase was due to an increase in eosinophils, and in only one patient it was due to an increase in the absolute neutrophil counts (ANC). Subsequently, all patients received rhG-CSF at a dose of 3 to 15 micrograms/kg/d subcutaneously. In contrast to rhGM-CSF treatment, all five patients responded to rhG-CSF during the first 6 weeks of treatment with an increase in the ANC to above 1,000/microL. The level of ANC could be maintained during maintenance treatment. In one patient, the increase in ANC was associated with an improvement of a severe pneumonitis caused by Peptostreptococcus and resistant to antibiotic treatment. No severe bacterial infections occurred in any of the patients during CSF treatment. All patients tolerated rhGM-CSF and rhG-CSF treatment without severe side effects. These results demonstrate the beneficial effect of rhG-CSF in SCN patients.     

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).     

Phase I/II study of recombinant human granulocyte-macrophage colony- stimulating factor in aplastic anemia and myelodysplastic syndrome

We performed a phase I/II study of the administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with aplastic anemia or myelodysplastic syndrome. Doses ranging from 15 to 480 micrograms/m2 were administered as a one-hour or four-hour intravenous infusion daily for 7 days or as a 12-hour infusion for 14 days. Temporary improvements were seen in granulocyte counts, monocyte counts, and reticulocyte counts in six of eight patients with aplastic anemia and five of seven patients with myelodysplastic syndromes. The patients with myelodysplastic syndromes had larger increases in granulocyte, monocyte, and reticulocyte counts than did those with aplastic anemia, and they also had increases in the numbers of eosinophils (two of seven), immature myeloid cells (two of seven), and myeloblasts (two of seven) that were not observed in patients with aplastic anemia. There was no reduction in erythrocyte transfusion requirements, and no effect was observed on platelet counts. There was only minimal toxicity consisting of transient low- back discomfort, anorexia, myalgias/arthralgias, and low-grade fever. Our data suggest that GM-CSF is well tolerated and is more likely to result in elevations of blood counts in patients with myelodysplasia than in patients with aplastic anemia, but the role of GM-CSF therapy in these disorders remains to be determined.     

Changes in neutrophil counts and functions after the administration of recombinant human granulocyte colony-stimulating factor in a patient with chronic idiopathic neutropenia]

The cause of chronic idiopathic neutropenia (CIN) is unknown. Recently recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been purified. Many studies of effects of rhG-CSF on the patients with neutropenia have been undertaken. We examined changes in neutrophil counts and functions after the administration of rhG-CSF in a patient with CIN. Six hours after the intravenous administration of 40 micrograms of rhG-CSF, neutrophil counts were raised from 90 to 1570/microliters, and the increased neutrophils functioned normally; chemotaxis, phagocytosis and O2(-) generation. It is suggested that rhG-CSF is beneficial for the treatment of infection in patients with CIN.     

Combination Therapy With Recombinant Human Granulocyte Colony-Stimulating Factor and Erythropoietin in Aplastic Anemia

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) and erythropoietin (rhEPO) were used to treat patients with aplastic anemia (AA). In terms of effects on erythrocyte recovery, the combined use of rhG-CSF and rhEPO showed a favorable response in 6 of 14 (42.9%) patients with moderate AA following 10 weeks treatment and in 3 of 14 (21.4%) patients thereafter. However, the response was poor in patients with severe AA (3/13). A favorable response in severe AA was observed in 1 of 13 (7.7%) patients following 10 weeks treatment and in 2 of 13 (15.4%) patients thereafter. The overall effect on erythrocytes was observed in 44.4% patients. A dose of 400 μ/m² G-CSF was sufficient to cause an increase in neutrophil count and 100 IU/kg rhEPO appeared to be sufficient to cause an increase in erythrocyte count. In 6 of 27 (22.2%) patients, a trilineage response was observed. Interestingly, a delayed and long-lasting effect was obtained in 5 of 27 (18.5%) patients. These results suggest that rhG-CSF can synergize with rhEPO in erythrocyte response, especially in patients with moderate AA.     

A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia

Host defenses in the human neonate are limited by immaturity in phagocytic immunity. Such limitations seem to predispose infected newborns to neutropenia from an exhaustion of the neutrophil reserve. Among the critical defects thus far identified in neonatal phagocytic immunity is a specific reduction in the capacity of mononuclear cells to express granulocyte colony-stimulating factor (G-CSF) after stimulation. However, the safety, pharmacokinetics, and biological efficacy of administration of recombinant human (rh)G-CSF to infected human newborns to compensate for this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of age) with presumed bacterial sepsis within the first 3 days of life were randomized to receive either placebo or varying doses of rhG-CSF (1.0, 5.0 or 10.0 micrograms/kg every 24 hours [36 patients] or 5.0 or 10.0 micrograms/kg every 12 hours [6 patients]) on days 1, 2, and 3. Complete blood counts with differential and platelet counts were obtained at hours 0, 2, 6, 24, 48, 72, and 96. Circulating G-CSF concentrations were determined at hours 0, 2, 6, 12, 14, 16, 18, 24, and 36. Tibial bone marrow aspirates were obtained after 72 hours for quantification of the bone marrow neutrophil storage pool (NSP), neutrophil proliferative pool, granulocyte progenitors, and pluripotent progenitors. Functional activation of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or placebo administration. Intravenous rhG-CSF was not associated with any recognized acute toxicity. RhG-CSF induced a significant increase in the blood neutrophil concentration 24 hours after the 5 and 10 micrograms/kg doses every 12 and 24 hours and it was sustained as long as 96 hours. A dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil C3bi expression was significantly increased at 24 hours after 10 micrograms/kg every 24-hour dose of rhG- CSF. The half-life of rhG-CSF was 4.4 +/- 0.4 hours. The rhG-CSF was well tolerated at all gestational ages treated. The rhG-CSF induced a significant increase in the peripheral blood and bone marrow absolute neutrophil concentration and in C3bi expression. Future clinical trials aimed at improving the outcome of overwhelming bacterial sepsis and neutropenia in newborn infants might include the use of rhG-CSF.     

Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

The effects of recombinant canine stem cell factor (rcSCF) on hematopoiesis were studied in normal dogs and in dogs given otherwise lethal total body irradiation (TBI) without marrow transplant. Results were compared with previous and concurrent data with recombinant granulocyte colony-stimulating factor (rG-CSF). Four normal dogs received 200 micrograms rcSCF per kilogram body weight daily either by continuous intravenous infusion for 28 days (n = 2) or by subcutaneous (SC) injection in two divided doses for 20 days (n = 2). All dogs showed at least a twofold increase in peripheral blood neutrophil counts starting approximately 7 days after the initiation of treatment. Hematocrit level and monocyte, lymphocyte, eosinophil, reticulocyte, and platelet counts were not elevated. Marrow sections after rcSCF treatment showed panhyperplasia. The only toxicity was facial edema during the first few days of rcSCF administration, presumably caused by mast cell stimulation. Ten dogs were given 400 cGy TBI at 10 cGy/min from two opposing 60Co sources. They were given no marrow infusion and received 200 micrograms/kg/d rcSCF SC in two divided doses for 21 days starting within 2 hours of TBI. Five of the 10 dogs showed complete and sustained hematopoietic recovery and survived as compared with 1 of 28 control dogs not receiving growth factor (P < .005). RcSCF treatment allowed for hematopoietic recovery in two of seven dogs administered 500 cGy of TBI but in none of five dogs given 600 cGy of TBI. Results with rcSCF are similar to those obtained with rG-CSF. The rate of neutrophil recovery in rcSCF-treated dogs after 400 cGy TBI was not different from that of rG-CSF-treated dogs (P = .65), but the rate of platelet recovery was faster (P = .06) in the rcSCF-treated animals. Combined treatment with rcSCF and rcG-CSF after 500 cGy TBI did not result in strongly improved survival as compared with results obtained with either factor alone.     

Clinical effects of recombinant human granulocyte colony-stimulating factor in leukemia patients: a phase I/II study

A phase I/II study of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in 24 leukemia patients was conducted at our institute. Recombinant human G-CSF (50-200 micrograms/m2/day) was administered i.v. In seven allogeneic bone marrow transplantation (BMT) recipients, treatment with rhG-CSF was started 5 days after BMT. Neutrophils began to increase within 3 days after the start of rhG-CSF administration in five of seven patients. The mean duration necessary for recovery of neutrophils to greater than 500/microliters was 11.3 days after BMT with rhG-CSF; 26.8 days is the figure for recovery without rhG-CSF from Japanese historical data. In seven out of eight patients who received rhG-CSF administration after the first remission-induction chemotherapy, the neutrophil counts increased from less than 300/microliters to greater than 4000/microliters within 10 days. Blasts did not increase in all patients including four acute nonlymphocytic leukemia (ANLL) patients. Severe infections such as septicemia and pneumonia, which were unable to be controlled by antibiotics only, were successfully treated with rhG-CSF and antibiotics. rhG-CSF either stimulated or inhibited myeloid leukemic cells in some refractory cases. Mild bone pain occurred in one patient while receiving rhG-CSF i.v. rhG-CSF seems to have the ability to shorten the period of neutropenia, prevent infections after allogeneic BMT and remission-induction chemotherapy for acute leukemia, and support therapy for infections.     

Efficacy of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with AIDS.

The efficacy of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutropenia was evaluated in 14 patients with AIDS and AIDS-related complex (ARC). In all patients, including 11 neutropenic patients, 100 or 200 micrograms/m2 of rhG-CSF significantly increased the neutrophil counts. The response was greater in patients with higher neutrophil counts before the treatment, and was also dose-dependent. Although the effect seemed to be less potent, the agent also increased the neutrophil counts even when zidovudine (azidothymidine, AZT) and other myelosuppressive antiviral agents were administered simultaneously. These observations indicate that rhG-CSF may be beneficial in preventing and treating some secondary infections, and will make it easier to continue therapy with antiviral agents in patients with AIDS or ARC.     

In vivo activation of human neutrophil functions by administration of recombinant human granulocyte colony-stimulating factor in patients with malignant lymphoma

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered (50 to 800 micrograms/m2) once daily as a half-hour intravenous (IV) infusion for 14 days to seven patients with malignant lymphoma. In all patients, administration of rhG-CSF not only ameliorated the decrease in absolute neutrophil count after the cytotoxic chemotherapy but also enhanced superoxide (O2-) release in neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP). The priming effect of rhG-CSF on neutrophil O2- release was rapid (evident within 6.5 hours) and sustained at least for 24 hours after a single IV administration of rhG-CSF. The responsiveness to further in vitro challenge of rhG-CSF was lost or reduced in neutrophils isolated after rhG-CSF treatment, indicating that neutrophils already primed in vivo by rhG-CSF are desensitized to this factor. In contrast to the results obtained with FMLP, when phorbol myristate acetate (PMA) was used as stimulus, no consistent enhancement of O2- release was observed, suggesting that rhG-CSF modulates the signal transduction pathways linked to FMLP receptors rather than increases the components of the O2- producing enzyme complexes. Administration of rhG-CSF also rapidly (evident within 15 minutes) caused an increase in expression of neutrophil C3bi-receptors that was sustained for at least 24 hours after a single IV administration of rhG- CSF. Pharmacokinetic study of rhG-CSF showed a half-life (t1/2) of 114 min. These findings show that rhG-CSF is a potent activator for neutrophil functions both in vivo and in vitro.