Congenital neutropenia: diagnosis, molecular bases and patient management

The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l. When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease. Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant. About half the forms of congenital neutropenia with no extra-hematopoetic manifestations and normal adaptive immunity are due to neutrophil elastase (ELANE) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia. Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman-Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified. Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF). G-CSF has considerably improved these patients' outlook. It is usually well tolerated, but potential adverse effects include thrombocytopenia, glomerulonephritis, vasculitis and osteoporosis. Long-term treatment with G-CSF, especially at high doses, augments the spontaneous risk of leukemia in patients with congenital neutropenia.     

Oral ezatiostat HCl (Telintra®, TLK199) and Idiopathic Chronic Neutropenia (ICN): a case report of complete response of a patient with G-CSF resistant ICN following treatment with ezatiostat, a glutathione S-transferase P1-1 (GSTP1-1) inhibitor

Idiopathic chronic neutropenia (ICN) describes a heterogeneous group of hematologic diseases characterized by low circulating neutrophil levels often associated with recurrent fevers, chronic mucosal inflammation, and severe systemic infections. The severity and risk of complications, including serious infections, are inversely proportional to the absolute neutrophil count (ANC), with the greatest problems occurring in patients with an ANC of less than 0.5 × 10⁹/L. This case report describes a 64-year-old female with longstanding rheumatoid arthritis who subsequently developed ICN with frequent episodes of sepsis requiring hospitalization and prolonged courses of antibiotics over a 4-year period. She was treated with granulocyte colony stimulating factors (G-CSF) but had a delayed, highly variable, and volatile response. She was enrolled in a clinical trial evaluating the oral investigational agent ezatiostat. Ezatiostat, a glutathione S-transferase P1-1 inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitor stem cells. She responded by the end of the first month of treatment with stabilization of her ANC (despite tapering and then stopping G-CSF), clearing of fever, and healing of areas of infection. This ANC response to ezatiostat treatment has now been sustained for over 8 months and continues. These results suggest potential roles for ezatiostat in the treatment of patients with ICN who are not responsive to G-CSF, as an oral therapy alternative, or as an adjunct to G-CSF, and further studies are warranted.     

Progenitor cell self-renewal and cyclic neutropenia

Objectives: Cyclic neutropenia (CN) is a rare genetic disorder where patients experience regular cycling of numbers of neutrophils and various other haematopoietic lineages. The nadir in neutrophil count is the main source of problems due to risk of life-threatening infections. Patients with CN benefit from granulocyte colony stimulating factor therapy, although cycling persists. Mutations in neutrophil elastase gene ( ELA2 ) have been found in more than half of patients with CN. However, neither connection between phenotypic expression of ELA2 and CN nor the mechanism of cycling is known.
Materials and methods:  Recently, a multicompartment model of haematopoiesis that couples stem cell replication with marrow output has been proposed. In the following, we couple this model of haematopoiesis with a linear feedback mechanism via G-CSF.
Results:  We propose that the phenotypic effect of ELA2 mutations leads to reduction in self-renewal of granulocytic progenitors. The body responds by overall relative increase of G-CSF and increasing progenitor cell self-renewal, leading to cell count cycling.
Conclusion:  The model is compatible with available experimental data and makes testable predictions.     

Hereditary neutropenia: dogs explain human neutrophil elastase mutations

Mutations in ELA2, the gene encoding neutrophil elastase (NE), cause the human diseases cyclic neutropenia (CN) and severe congenital neutropenia (SCN). Numerous mutations are known, but their lack of consistent biochemical effect has proven puzzling. The recent finding that mutation of AP3B1, which encodes the beta subunit of adaptor protein complex 3 (AP3), is the cause of canine CN suggests a model for the molecular basis of hereditary neutropenias, involving the mistrafficking of NE: AP3 recognizes NE as a cargo protein, and their interaction implies that NE is a transmembrane protein. Computerized algorithms predict two NE transmembrane domains. Most CN mutations fall within predicted transmembrane domains and lead to excessive deposition of NE in granules, whereas SCN mutations usually disrupt the AP3 recognition sequence, resulting in excessive transport to the plasma membrane.     

Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L)

The levels of hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders were investigated using a variety of approaches. Firstly, serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and Flt3-ligand (Flt3L) were examined in acute leukemia patients with treatment-induced cytopenia and complicating bacterial infections. Increased serum levels of both G-CSF and Flt3-ligand (Flt3L) were detected when these patients developed therapy-induced leukopenia, whereas GM-CSF levels were low or undetectable. Development of complicating bacterial infections then increased the serum levels of both G- and GM-CSF, and the Flt3L levels remained high during the infections. Secondly, release of growth factors was characterized for clonogenic T cells that remained in the circulation of acute leukemia patients with chemotherapy-induced cytopenia. CD4(+) and CD8(+) T cells from these patients released high levels of GM-CSF, relatively low levels of IL-3 secretion having been detected, and only a minority of the clones released detectable amounts of Flt3L. Thus, circulating T cells may contribute to the high systemic growth factor levels in cytopenic patients. Thirdly, plasma levels of GM-CSF and interleukin-3 (IL-3) were examined in patients with malignant disorders who received chemotherapy plus G-CSF for stem cell mobilization. Increased levels of GM-CSF and Flt3L were detected both in the patients' plasma and in the stem cell grafts. Despite the increased growth factor levels in neutropenic patients with complicating infections, the occurrence of febrile neutropenia did not have a major impact on normal hematopoietic reconstitution (i.e. duration of treatment-induced neutropenia) after intensive chemotherapy for acute myelogenous leukemia.     

Multistability in an age-structured model of hematopoiesis: Cyclical neutropenia

Cyclical neutropenia (CN) is a rare hematopoietic disorder in which the patient's neutrophil level drops to extremely low levels for a few days approximately every three weeks. CN is effectively treated with granulocyte colony stimulating factor (G-CSF), which is known to interfere with apoptosis in neutrophil precursors and to consequently increase the circulating neutrophil level. However, G-CSF treatment usually fails to eliminate the oscillation. In this study, we establish an age-structured model of hematopoiesis, which reduces to a set of four delay differential equations with specific forms of initial functions. We numerically investigate the possible stable solutions of the model equations with respect to changes in the parameters as well as the initial conditions. The results show that the hematopoietic system possesses multistability for parameters typical of the normal healthy state. From our numerical results, decreasing the proliferation rate of neutrophil precursors or increasing the stem cell death rate are two possible mechanisms to induce cyclical neutropenia, and the periods of the resulting oscillations are independent of the changing parameters. We also discuss the dependence of the model solution on the initial condition at normal parameter values corresponding to a healthy state. Using insight from our results we design a hybrid treatment method that is able to abolish the oscillations in CN.     

Nosocomial infections in acute leukemia: comparison between younger and elderly patients

The progressive decline in immune functions render elderly individuals more susceptible to infections than younger patients. To evaluate potential age-related differences in nosocomial infections between younger (<60 yr) and elderly (> or =60 yr) patients with acute leukemia, we retrospectively reviewed 161 consecutive febrile episodes. All neutropenic patients with an absolute neutrophil count (ANC) less than 500/microl were examined during the different phases of intensive chemotherapy and hospitalized until fever and neutropenia resolved. Fever was recorded in 66% of younger and in 64% of elderly patients and occurred respectively in 45% and in 51% during induction, in 32% and in 36% during consolidation, in 23% and in 13% during relapse/refractory treatment (P=0.01). A central venous catheter (CVC) was present in 68% and in 42% of patients (P=0.001). Febrile episodes during severe neutropenia with ANC <100/microl were recorded in 47% and in 22% respectively, during neutropenia with ANC >100/microl in 53% and in 78% respectively (P=0.002). No significant difference was documented in the overall incidence of infections, type of febrile episodes, nosocomial pattern, defervescence-time, median duration of antimicrobic therapy and in overall outcome. Elderly patients do not seem to be more susceptible to infections than younger ones, although the lower frequency of some risk factors must be taken into account.     

Granulopoeisis and leukemogenesis: lessons from congenital neutropenia

Congenital neutropenia are extremely rare diseases, defined by a permanent or cyclic decrease of blood neutrophils. Molecular basis of several congenital neutropenia has been recently determined, involving gene coding for the neutrophil elastase gene (ELA2), GFI1, WAS protein and mitochondrial HAX1 protein. These mutations, dominant (ELA2, GFI1), X-linked (WAS) and autosomal recessive (HAX1), result in instability of the contents of the granules- particularly the neutrophil elastase- or in abnormalities of the cytoskeleton, and possibly, in an increased apoptosis. ELA2 mutations resulting both in profound and permanent neutropenia, and in cyclic--pseudo sinusoidal--neutropenia lead to consider that time pattern is very close in the two apparently distinct phenotypes. This observation suggests that temporal variations of neutrophils could be represented by non linear functions. Congenital neutropenia, specifically ELA2 mutated, are also characterized by a high rate of leukemia (about 15% at 20 years of age). Leukemia risk does not appear to be related to an oncogenic effect of ELA2 mutations, but much likely to the deepness of the neutropenia, and the intensity of G-CSF therapy.     

Efficacy of moxifloxacin (Avelox) in prophylaxis of infection in patients with profound neutropenia]

Comparative efficacy of moxifloxacin and ciprofloxacin as prophylactics of infection in cancer patients with severe neutropenia after the chemotherapy was studied. The study included 40 patients with malignant lymphomas and solid tumore who received 52 courses of the aggressive chemotherapy. Twenty four patients (30 courses) received oral moxifloxacin in a dose of 400 mg once a day from the first day of the neutrophil count decrease below 1.0 x 10(9)/l until its recovery to > 1.0 x 10(9)/l or when the signs of infection appeared. In the control group 16 patients (22 courses) received oral ciprofloxacin in a dose of 500 mg twice a day. The patients in both the groups were compatible by the diagnosis, age and neutropenia duration. The median of the days of the febrile neutropenia duration in the patients prophylactically treated with moxifloxacin was statistically lower (2.1 vs 3.6 in the control group, p < 0.05). The incidence of febrile neutropenia in the moxifloxacin group was significantly lower than that in the control group (73 and 100% respectively, p = 0.01). The incidence of bacteriologically confirmed infection in the moxifloxacin group was also lower (6% vs 27.2%, p = 0.04). Therefore, moxifloxacin proved to be a more efficient agent vs ciprofloxacin (standard prophylactic) in prevention of febrile neutropenia and neutropenic infection in cancer patients, which is likely due to its higher activity against grampositive organisms.     

Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis

Osteopetrosis is a heterogeneous group of inherited disorders that includes a malignant autosomal recessive form, an intermediate autosomal recessive form and autosomal dominant forms of the disease. Most malignant osteopetroses have been ascribed to mutations in the OC116 gene encoding the human a3 subunit of vacuolar H(+)-ATPase. Few cases of autosomal recessive malignant osteopetrosis have been ascribed to mutations in the chloride channel 7 gene (CLCN7), which accounts for all autosomal dominant type II cases reported to date. Up until now, however, nothing has been known regarding the molecular basis of the intermediate form of osteopetrosis (IARO). Our study of two Portuguese IARO families shows that homozygosity for ClCN7 mutations also accounts for this form of osteopetrosis. The two patients presented with spontaneous fractures in the first years of life and generalised increase of bone density. Direct sequencing of the ClCN7 gene in both patients revealed homozygosity for two mutations (G203D and P470Q). We conclude therefore that ClCN7 mutations not only account for some dominant and malignant forms but also for intermediate forms of osteopetrosis.     

Assessment of the value of prednisone test in differential diagnosis of neutropenic state.

The prednisone test revealed normal bone marrow reserve of neutrophils (BMR) in subjects with innocent neutropenias e.g. neutropenias not associated with any other disturbances in haemopoiesis or with increased incidence of infections, assumed to be an individual anomaly of the subject. On the other hand, diminution or absence of MBR in chronic hypoplastic neutropenias, transient post-chemotherapeutic neutropenias and neutropenias with increased destruction of neutrophils were observed. The magnitude of that diminution was not dependent of the cause of neutropenia. It is suggested, that the prednisone test (and probably tests with other BMR mobilizing agents) may serve as screening tests for exclusion (or confirmation) of relative granulopoietic insufficiency as the cause of neutropenia. Only after confirmation of reduced BMR another explanations of neutropenia should be sought using other method as muramidase level, adrenaline test or granulocyte kinetics with DF32P, 3HDFP, or 51Cr.     

Intermediate-dose CY and G-CSF more efficiently mobilize adequate numbers of PBSC for tandem autologous PBSC transplantation compared with low-dose CY in patients with multiple myeloma

BACKGROUND: Autologous PBSC transplantation is the standard care for patients with multiple myeloma. The most common regimen used to mobilize PBSC consists of CY and G-CSF. METHODS: We retrospectively analyzed the efficacy and toxicity of two regimens of CY for PBSC mobilization: low-dose CY (1-2 g/m(2), LD-CY, n=61) plus G-CSF, and intermediate-dose CY (3-4 g/m(2), ID-CY, n=26) plus G-CSF. RESULTS: In the LD-CY group, 5.17 (0.23-17.3)x10(6) CD34(+) cells/kg, and in the ID-CY group 7.71 (0.08-26.4)x10(6) CD34(+) cells/kg (P=0.018), were collected. Although >/=2x10(6)/kg CD34(+) cells were collected in 89% of the LD-CY group and 92% of the ID-CY group, this was achieved after a single leukapheresis in 54% of the LD-CY group and 92% of the ID-CY group (P=0.0001). Patients who are to have tandem autologous PBSC transplants require >/=4x10(6)/kg CD34(+) cells. This was achieved in only 65% patients in the LD-CY group but 88% in the ID-CY group (P=0.05). Among patients who had not had prior melphalan and/or >12 months of prior treatment, 74% in the LD-CY group and 100% in ID-CY group mobilized >/=4x10(6)/kg CD34(+) cells. Febrile neutropenia was more frequent in the ID-CY group (38% vs. 13%). DISCUSSION: In conclusion, compared with LD-CY, patients receiving ID-CY were more likely to collect a total CD34(+) cell number adequate for tandem autologous PBSC transplantation. The increased toxicity was manageable and considered acceptable.     

Granulocyte colony-stimulating factor and its receptor in normal hematopoietic cell development and myeloid disease

Hematopoiesis, the process of blood cell formation, is orchestrated by cytokines and growth factors that stimulate the expansion of different progenitor cell subsets and regulate their survival and differentiation into mature blood cells. Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic growth factor involved in the control of neutrophil development. G-CSF is now applied on a routine basis in the clinic for treatment of congenital and acquired neutropenias. G-CSF activates a receptor of the hematopoietin receptor superfamily, the G-CSF receptor (G-CSF-R), which subsequently triggers multiple signaling mechanisms. Here we review how these mechanisms contribute to the specific responses of hematopoietic cells to G-CSF and how perturbations in the function of the G-CSF-R are implicated in various types of myeloid disease.     

The Role of Apoptosis in the Pathophysiology of Chronic Neutropenias Associated with Bone Marrow Failure

Chronic neutropenia syndromes associated with bone marrow (BM) failure comprise distinct congenital and acquired hematologic disorders with varying degree of neutropenia due to decreased or ineffective BM neutrophil production. Recent evidence suggests that defective granulocytopoiesis in these neutropenia states is a consequence of accelerated apoptotic cell death of BM myeloid progenitor cells and/or their differentiated progeny. Inherited or spontaneously appearing mutations in the ELA2 gene encoding for neutrophil elastase have been implicated in the accelerated apoptotic process of the BM myeloid cells in patients with cyclic and severe congenital neutropenia. A disturbed balance between pro-apoptotic and anti-apoptotic intracellular or membrane molecules such as down-regulation of the bcl-2 family members or up-regulation of the death receptor Fas, have been implicated in neutropenia associated with myelokathexis, Shwachman-Diamond syndrome and acquired chronic idiopathic neutropenia of adult. In this review we summarize the available evidence suggesting that abnormally increased apoptosis and impaired proliferative and differentiating properties of neutrophil progenitor and precursor cells represent a common pathogenetic mechanism for impaired granulocytopoiesis in both acquired idiopathic and congenital neutropenia states. The underlying distinct cellular and molecular abnormalities and the role of the BM microenvironment are extensively analysed.     

Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome

WHIM syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the syndrome.     

The role of apoptosis in the pathophysiology of chronic neutropenias associated with bone marrow failure

Chronic neutropenia syndromes associated with bone marrow (BM) failure comprise distinct congenital and acquired hematologic disorders with varying degree of neutropenia due to decreased or ineffective BM neutrophil production. Recent evidence suggests that defective granulocytopoiesis in these neutropenia states is a consequence of accelerated apoptotic cell death of BM myeloid progenitor cells and/or their differentiated progeny. Inherited or spontaneously appearing mutations in the ELA2 gene encoding for neutrophil elastase have been implicated in the accelerated apoptotic process of the BM myeloid cells in patients with cyclic and severe congenital neutropenia. A disturbed balance between pro-apoptotic and anti-apoptotic intracellular or membrane molecules such as downregulation of the bcl-2 family members or upregulation of the death receptor Fas, have been implicated in neutropenia associated with myelokathexis, Shwachman-Diamond syndrome and acquired chronic idiopathic neutropenia of adult. In this review we summarize the available evidence suggesting that abnormally increased apoptosis and impaired proliferative and differentiating properties of neutrophil progenitor and precursor cells represent a common pathogenetic mechanism for impaired granulocytopoiesis in both acquired idiopathic and congenital neutropenia states. The underlying distinct cellular and molecular abnormalities and the role of the BM microenvironment are extensively analysed.     

Prophylaxis of fungal infection in patients with hematologic neoplasms and severe neutropenia after high-dose chemotherapy]

Infection is one of the main causes of death in patients with hemoblastoses. Within the last years there was observed an increase in the ratio of fungal infections in the structure of mortality among hematologic patients with neutropenia. The present study was aimed at comparative estimation of the efficacy of the prophylactic use of various azole antifungal agents in patients with hematologic neoplasms and severe neutropenia. The trial enrolled 88 patients comparable by the diagnosis and chemotherapy characteristics, in whom severe neutropenia developed after intensive therapy. Antifungal drugs were used prophylactically when the neutrophil count lowered below 1.0 x 10(9)/l until its increasing above 1.0 x 10(9)/l or when the signs of fungal infection were evident. Itraconazole was used in cyclodextrin solution in 30 patients in a dose of 0.2 g orally twice a day and fluconazole was used in capsules in 24 patients in a dose of 0.2 g orally once a day. The results were compared with those of the ketoconazole use in a dose of 0.2 g orally twice a day (n = 34). The frequency of fungal infection proved by the clinical documentation was 20.5% in the ketoconazole group (k) (7 out of 34 patients), 8.3% in the fluconazole group (f) (2 out of 24 patients) and 6.6% in the itraconazole group (i) (2 out of 30 patients), p (k-f) = 0.21, p (k-i) = 0.11 and p (f-i) = 0.74. The frequency of fungal infection proved by the microbiological documentation was statistically much higher in the ketoconazole group (38.2%) vs. the fluconazole group (8.3%) (p = 0.013) and the itraconazole group (6.6%) (p = 0.004). The prophylactic use of itraconazole and fluconazole was efficient in preventing development of invasive mycoses in the patients with hemoblastoses and severe neutropenia. Their efficacy was much higher than that of ketoconazole.     

G-CSF Control of Neutrophils Dynamics in the Blood

White blood cell neutrophil is a key component in the fast initial immune response against bacterial and fungal infections. Granulocyte colony stimulating factor (G-CSF) which is naturally produced in the body, is known to control the neutrophils production in the bone marrow and the neutrophils delivery into the blood. In oncological practice, G-CSF injections are widely used to treat neutropenia (dangerously low levels of neutrophils in the blood) and to prevent the infectious complications that often follow chemotherapy. However, the accurate dynamics of G-CSF neutrophil interaction has not been fully determined and no general scheme exists for an optimal G-CSF application in neutropenia. Here we develop a two-dimensional ordinary differential equation model for the G-CSF—neutrophil dynamics in the blood. The model is built axiomatically by first formally defining from the biology the expected properties of the model, and then deducing the dynamic behavior of the resulting system. The resulting model is structurally stable, and its dynamical features are independent of the precise form of the various rate functions. Choosing a specific form for these functions, three complementary parameter estimation procedures for one clinical (training) data set are utilized. The fully parameterized model (6 parameters) provides adequate predictions for several additional clinical data sets on time scales of several days. We briefly discuss the utility of this relatively simple and robust model in several clinical conditions. Dedicated to Lee Segel who guided us to apply mathematics for the benefit of mankind—a teacher, a colleague, a friend. L.A. Segel passed away on 31 January 2005.     

Clinical effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on various types of neutropenia including cyclic neutropenia

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was investigated for its clinical efficacy in the treatment of various types of neutropenia (3 cases with idiopathic neutropenia of suspected drug induction, 5 cases with idiopathic neutropenia of other origin, and 2 cases with cyclic neutropenia). Treatment with glycosylated rhG-CSF produced in the Chinese Hamster Ovary cells at dose levels of 2–5g/kg/day caused rapid increases of neutrophil counts associated with an improvement of the infection. In cyclic neutropenia patients, marked reduction in the duration of the neutropenic period was observed with rhG-CSF administration started before the period. Intercurrent stomatitis, which occurred in 1 patient, was markedly milder as compared to a previous episode which occurred during an untreated neutropenic period.The treatment of rhG-CSF was well tolerated and no adverse events were observed, nor was there any detectable anti-rhG-CSF antibody in any patients studied; hence the clinical use of rhG-CSF is considered to be safe.These results suggest beneficial effects of rhG-CSF on the recovery of neutrophil counts in cyclic and other types of idiopathic neutropenias, as well as for the treatment of neutropenia-associated infection.     

Clinical applications of recombinant human colony-stimulating factors.

The differentiation and maturation of hematopoietic progenitor cells are regulated by certain growth factors. Several of these glycoproteins have been characterized, and their amino acid sequences have been delineated. Modern DNA technology provides sufficient quantities of these hormones for testing in clinical trials. Erythropoietin (EPO) has been shown to increase the hemoglobin level and hematocrit in patients with end-stage renal disease. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) can increase the numbers of neutrophils and monocytes, in a dose-dependent fashion. The function of granulocytes and monocytes is also enhanced. Clinical studies of the toxicity and activity of G-CSF and GM-CSF have been conducted in patients with acquired immune deficiency syndrome, aplastic anemia, myelodysplastic syndromes, and neutropenia due to cancer and chemotherapy. In almost all patients the neutrophil count increased within 24 hours after the start of treatment. Side effects of G-CSF and GM-CSF are infrequent and usually mild. Combinations of CSFs may be even more effective.