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).     

Hereditary cyclic neutropenia in the male members of a Chinese family with inverted Y chromosome

We describe four male members of a Chinese family, including the father and three sons, with hereditary cyclic neutropenia. These patients had all developed cyclic neutropenia in childhood with a cycle of around 21 d. Recurrent mucosa and skin infections with fever had occurred frequently, but gradually decreased in severity on reaching adulthood. Monocytosis was found during the neutrophil nadirs in all four patients. Mildly increased serum immunoglobulin (Ig)A and IgG levels, low levels of serum stem cell factor, as well as decreased sperm count and motility were demonstrated in the two elder sons. Chromosomal analysis showed a pericentric inversion of Y chromosome [46,X, inv(Y)(p11.2;q11.23)] in all of the men. These findings may suggest an association between cyclic neutropenia with oligospermia and inv(Y)(p11.2;q11.23) in this particular family.     

Successful treatment of chronic severe neutropenia with weekly recombinant granulcyte-colony stimulating factor

Daily treatment for symptomatic chronic neutropenia with recombinant granulocyte-colony stimulating factor (rhG-CSF) filgrastim is costly and sometimes causes neutrophillia. We report the use of weekly filgrastim in a 40-year-old man with life-long symptomatic neutropenia. Baseline neutrophil counts were <1×10⁹/l 60% of the time, and fell below 0.5×10⁹/l for 7 d periods every 22 d. Following 1 year of weekly filgrastim treatment, the absolute neutrophil count was maintained >1×10⁹/l (averaging 2×10⁹/l) and the frequency and severity of symptoms were reduced by 85%. Therefore the benefits of filgrastim for the treatment of at least one form of chronic severe neutropenia can be derived from weekly rather than daily doses.     

Model analysis of the contrasting effects of GM-CSF and G-CSF treatment on peripheral blood neutrophils observed in three patients with childhood-onset cyclic neutropenia

Human cyclic neutropenia (CN) is a rare haematological disorder characterized by regular fluctuation in the serial count of blood neutrophils. The oscillations occur at subnormal levels with a stable 3-week period. To reduce the risk of serious infections during the severe neutropenic nadir phases (<0.25 ×10⁹ neutrophils/l) patients are usually treated with recombinant growth factors. Compared with G-CSF, which has been shown to enhance the amplitudes substantially, the response to GM-CSF is poor: neutrophil numbers are not amplified, the cycles remain unchanged or are dampened. However, two cases with a modest neutrophil increase have been reported in the literature. In a recently published clinical study the different effects of GM-CSF and G-CSF application have been investigated in the same patients. Based on a mathematical model of CN we previously proposed, the detailed neutrophil data measured in this study are analysed by simulation. The contrasting clinical results can be quantitatively explained by the model concept of regulatory control together with possible individual feedback defects, i.e. abnormally reduced mitotic responsiveness of granulopoietic progenitor cells to GM-CSF and G-CSF.     

Alteration of colony-stimulating factor output, endotoxemia, and granulopoiesis in cyclic neutropenia.

Cellular and humoral factors involved in the regulation of granulopoiesis were evaluated in two patients with cyclic neutropenia by utilizing the agar-gel marrow culture technique to serially study marrow granulocytic colony-forming capacity (CFC) and the urinary output of colony-stimulating factor (CSF). CSF output varied inversely with peripheral neutrophil counts and directly with monocyte counts and evidence for infection (endotoxemia and/or staphylococcal abscesses). Following autologous infusion of one patient's plasma obtained during a period of neutropenia, increased urinary excretion of CSF occurred concomitant with increments in both marrow CFC and the proportion of granulocytic progenitor cells in DNA synthesis. Neutrophil periodicity was not altered by the administration of the neutropenic plasma. These findings are consistent with the hypothesis that cyclic neutropenia is caused by a quantitatively decreased entry of stem cells or granulocytic progenitor cells into granulopoiesis.     

Acquired factor VIII inhibitor treated with cyclophosphamide, vincristine, and prednisone

Life-threatening bleeding can occur in non-hemophiliacs with factor VIII inhibitor and is difficult to control. Various methods have been used to suppress the inhibitor. Since 1993 we treated 6 non-hemophilic patients with factor VIII inhibitor with cyclophosphamide, vincristine, and prednisone (CVP) every 3-4 weeks. Five had complete response with disappearance of factor VIII inhibitor and normalization of factor VIII after 1 to 7 cycles of CVP. One patient did not respond after 4 cycles of CVP; mitoxantrone was added to additional two cycles of CVP, and the inhibitor disappeared.     

Successful treatment of chronic idiopathic neutropenia using recombinant granulocyte colony-stimulating factor

Summary A patient with chronic idiopathic neutropenia, who had been suffering from repeated infections, was successfully treated with recombinant granulocyte stimulating factor (rhG-CSF). Subcutaneous injection of 30g/m² rhG-CSF every two days was sufficient to maintain the neutrophil count at approximately 1,000/l. The patient has lived without any evidence of infection for the last 10 months using that treatment. There were no side effect caused by rhG-CSF and antibodies against G-CSF were not detected in the patient's plasma.     

Successful treatment of autoimmune neutropenia with recombinant human granulocyte-colony stimulating factor (R-metHuG-CSF)

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG-CSF at 5–8 μg/kg body weight (300–480 μg) daily; the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0×10⁹/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can be maintained on a low dose administered twice or thrice weekly.     

How I manage children with neutropenia

Neutropenia, usually defined as a blood neutrophil count <1·5 × 10⁹/l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony‐stimulating factor to treat childhood neutropenia.     

Congenital neutropenia

Congenital neutropenia is strictly defined as neutropenia present at birth. However, it is more generally used to describe neutropenia secondary to inherited genetic mutations. This review will discuss the presentation of such children and the various causes of congenital neutropenia. In particular, it will focus on severe congenital neutropenia (SCN) and the recent discovery of mutations in the gene encoding neutrophil elastase in the majority of cases of SCN. The potential mechanisms of pathogenesis and of transformation to leukaemia will be discussed. Shwachman-Diamond Syndrome and other less common causes of congenital neutropenia will also be reviewed. Finally, an approach to the child with potential congenital neutropenia will be presented.     

Pathophysiology and treatment of severe chronic neutropenia

 Severe chronic neutropenia (SCN) include a heterogeneous group of diseases characterized by blood neutrophil counts chronically less than 0.5×10⁹/L. In phase I–III studies in SCN patients, treatment with recombinant human granulocyte colony stimulating factor (r-metHuG-CSF; Filgrastim) resulted in a rise in the absolute neutrophil counts (ANC) to above 1.0×10⁹/L associated with a reduction in bacterial infections. Long-term treatment with filgrastim up to 8 years demonstrate a sustained ANC response, a significant reduction of the need for intravenous antibiotics and a dramatic improvement in the quality of life. In 1994 an international registry for severe chronic neutropenia (SCNIR) was established to improve care for chronic neutropenia and for further understanding the pathophysiology of this rare disease. Three-hundred and ten patients have been enrolled to this registry so far. Worldwide phase I–III studies with filgrastim and SCNIR provide information on 424 patients with severe chronic neutropenia. Adverse events include the development of acute myeloid leukemia in approximately 7% of the patients within the cohort of patients with congenital neutropenia (Kostmann's syndrome) suggesting that congenital neutropenia is a preleukemic syndrome. None of the patients with cyclic of idiopathic neutropenia developed leukemia suggesting that filgrastim is not involved in the development of leukemia. Received: 19 December 1995 / Accepted: 21 December 1995     

Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias

Summary . Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44, cyclic n = 10) treated for 4–6 years. A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients. Two patients required an increase of > 25% in dose to maintain a clinical response; one patient became refractory to therapy. A significant decrease in the incidence of severe infections and the need for intravenous antibiotics was noted. Significant adverse events noted which may or may not be related to therapy included: osteopenia ( n = 15), splenomegaly ( n = 12), hypersplenism ( n = 1), vasculitis ( n = 2), glomerulonephritis ( n = 1), BM fibrosis ( n = 2), MDS/leukaemia ( n = 3), and transient inverted chromosome 5q with excess blasts ( n = 1). R-metHuG-CSF has been well tolerated in the majority of patients and resulted in a longterm improvement in their clinical status.     

Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry

Severe chronic neutropenia (SCN) is defined as an absolute neutrophil (ANC) of less than 0.5 x 10(9)/L, lasting for months or years. Congenital, cyclic, and idiopathic neutropenia are principal categories of SCN. Since 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has collected data to monitor the clinical course, treatments, and disease outcomes for SCN patients. This report summarizes data for 853 patients, almost all treated with daily or alternate-day recombinant human granulocyte colony-stimulating factor (G-CSF or Filgrastim). G-CSF treatment increased the ANC overall from 0.34 x 10(9)/L +/- 0.018 pre-treatment to 3.70 x 10(9)/L +/- 0.18 during the first year of treatment. For most patients, the responses were durable with patients remaining on the same dose of G-CSF for many years. Long-term hematological observations showed stable mean leukocyte and neutrophil counts and gradually increasing hemoglobin levels. Thrombocytopenia developed in 4% of patients. As of January 1, 2000, myelodysplasia (MDS) or acute myelogenous leukemia (AML) has occurred in 35 of 387 patients with congenital neutropenia with a cumulative risk of 13% after 8 years of G-CSF treatment. This event occurred without a predictable relationship to the duration or dose of G-CSF treatment. No patients with cyclic or idiopathic neutropenia developed MDS or AML. Other important adverse events included hepatomegaly, osteoporosis, vasculitis, glomerulonephritis, and deaths in 4 of 14 cases requiring splenectomy. Growth and development and the outcome of pregnancy appeared to be unaffected by G-CSF treatment. These data indicate that congenital, cyclic, and idiopathic neutropenia can be effectively treated with long-term G-CSF. The risk of leukemia, osteoporosis, other potentially adverse events, and pregnancy outcome need to be further evaluated with continuing long-term observations.     

Late listeriosis after fludarabine plus prednisone treatment

SUMMARY. Fludarabine plus prednisome treatment in patients with chronic lymphocytic leukaemia has recently been correlated with an increased incidence of Listeria monocytogenes infections. We observed a patient with chronic lymphocytic leukaemia who received fludarabine plus prednisone and developed a fatal listeriosis 7 months later. A further case of listeriosis has recently been described in a man who developed the infection 2 years after successful fludarabine treatment while he had a normal CD4 lymphocyte count. These cases suggest that the risk period for the development of such an unusual infection could be unexpectedly and unpredictably long. This data could be important in the evaluation of a possible antibacterial prophylaxis schedule and in the wariness about the potential danger of food known to contain L. monocytogenes .     

Acquired factor VIII inhibitors—successful treatment with an oral outpatient regimen

A rare cause of a spontaneous, life threatening coagulopathy in adults is the development of autoantibodies to factor VIII. We recently had the opportunity to treat seven patients with this disorder. After stabilization, they were given a regimen consisting of prednisone and oral cyclophosphamide. All patients had a complete response to treatment. The median time to response was three weeks. Durable remissions were achieved, making this oral regimen an acceptable treatment for this disorder. Am. J. Hematol. 60:70–71, 1999. © 1999 Wiley-Liss, Inc.     

Autoimmune neutropenia in pregnant women causing neonatal neutropenia

Autoimmune neutropenia (AIN) can occur during pregnancy. However, neonatal neutropenia occurring in an infant born to a mother with AIN has only rarely been documented. Recently, we have experienced two cases of AIN during pregnancy, both of which caused severe yet transient neonatal neutropenia (< 0.3 x 10(9)/l), probably as a result of transplacental maternal anti-neutrophil autoantibodies. The anti-neutrophil antibodies seemed to be against antigens other than NA1/NA2 because the autoantibodies did not bind to neutrophils of specific NA types selectively in the granulocyte indirect immunofluorescence test. Although AIN is a relatively uncommon disease, neonatal neutropenia caused by maternal AIN may not be quite as rare.     

Autoimmune neutropenia successfully treated with cyclosporine

A case history is presented concerning a 59-year-old female patient with chronic autoimmune neutropenia complicated by recurrent skin infections, mucositis, and conjunctivitis. For subjective reasons she refused treatment with prednisone, but eventually cyclosporine led to an important clinical improvement and an increase of the peripheral granulocyte count. Treatment modalities of autoimmune neutropenia are briefly discussed.     

Granulopoiesis in patients with congenital neutropenia

Granulopoiesis was investigated in five patients with congenital neutropenia (CN) (one Kostmann type, four benign forms). In semisolid agar culture, the marrow cells of all five patients produced normal numbers of CFU-c (colony-forming unit-culture). The size and classification of colonies were normal. In suspension culture in vitro with exogenous colony-stimulating factor (CSF) generated from omental-conditioned medium (OMCM), the myeloid precursors of all patients could proliferate and differentiate into normal polymorphonuclear neutrophils (PMNs). But in the absence of exogenous CSF, myeloid precursors of the patient with Kostmann-type CN did not proliferate or differentiate into PMNs at all. In the four patients with benign neutropenia, however, PMNs were found even without exogenous CSF similar to normal individuals. These results suggest that patients with CN may have normal granulopoietic stem cells with normal proliferative and differentiating capacity in response to exogenous CSF. When a small amount of normal human serum was added to normal marrow cultures stimulated by exogenous CSF, the colony growth increased in a superadditive manner. The enhancing activity of serum from neutropenic patients differed from that of normal serum. Especially, the addition of serum from the patient with Kostmann type CN to normal marrow cultures did not show this enhancement effect. The sera of patients with benign neutropenia had less enhancement effect than did normal control serum. These findings might be interpreted as showing an imbalance between CSF enhancer and inhibitors in the patients' serum.     

How I investigate neutropenia

Neutropenia is a common laboratory finding in adults and children. Its underlying causes are extremely heterogeneous and include benign conditions, autoimmune disorders, infections, and malignancies. The clinical laboratory plays a central role in the diagnosis of these disorders, including data derived from hematology, microbiology, molecular biology/cytogenetics, and clinical chemistry. The purpose of this review is to (a) highlight the clinical, hematologic, and molecular genetic features of the major entities resulting in neutropenia and (b) outline an algorithm‐based approach to permit the classification of neutropenias.     

Familial severe congenital neutropenia associated with infantile osteoporosis: a new entity

A new entity manifested by severe congenital neutropenia associated with osteoporosis and recurrent bone fracture is described in a family. A possible role for a new recognized cytokine system involved in bone remodeling, the osteoprotegerin/receptor activator of nuclear factor-kappa B ligand, is suggested.