Severe Chronic Neutropenia Patients

The longest exposure to daily administration of filgrastim has been in patients with SCN. Daily subcutaneous injections of filgrastim for >10 yr in over 1000 patients worldwide, documented in the Severe Chronic Neutropenia International Registry (SCNIR), lead to neither exhaustion of myelopoiesis nor to anti-G-CSF antibody production.

Chronic daily administration of filgrastim to patients with SCN neither exhausts myelopoiesis nor produces anti-G-CSF antibodies, and causes relatively few adverse events; those that do occur are mild and easily managed. The number and duration of reported adverse events related to filgrastim decreases with the duration of treatment. Bone pain is noted early in treatment and tends to decrease in frequency with long-term therapy.

7.2.1. Severe Congenital Neutropenia (Kostmann's Syndrome)

7.2.1.1. Pathophysiology. The underlying genetic defect of this group of disorders, including Kostmann's syndrome, has been only partially identified. The original hypothesis for Kostmann's syndrome included a genetic predisposition resulting in defective production of G-CSF or defective response of the neutrophilic precursors to G-CSF or other HGFs; however, serum from these patients contains normal or increased amounts of G-CSF, and in vitro assays demonstrate a normal biologic activity of the endogenous G-CSF. Myeloid cells from patients with Kostmann's syndrome express slightly increased numbers of G-CSF receptors with a normal binding constant for G-CSF to its receptor.

Kostmann (18) originally described a Swedish kindred with congenital neutropenia inherited as an autosomal recessive trait without additional hematologic changes or other congenital abnormalities. With the recent detection of various mutations within the neutrophil elastase gene as the cause of cyclic neutropenia (19), genetic screening for mutations of the neutrophil elastase was started in patients diagnosed with congenital neutropenia (19-21). Despite phenotypical uniformity, characterized by congenital neutropenia and a maturation arrest of myelopoiesis in the bone marrow at the promye-locyte/myelocyte stage, neutrophil elastase mutations were present only in a major subgroup of patients with congenital neutropenia. All mutations identified to date are present in only one allele. Analysis of families with Kostmann's syndrome showed that only one parent carried the mutated elastase gene, suggesting an autosomal dominant inheritance (19).

In patients with Kostmann's syndrome who developed leukemia, acquired G-CSF receptor mutations affecting the cytoplasmic domain were present in most patients tested (22-25), suggestive of an important role of these mutations in the leukemogenesis. None of the G-CSF receptor mutations was detectable from birth, indicating that these mutations are not causative for the neutropenia. A small subgroup of patients develops these mutations during the course of life, most likely caused by genetic instability. G-CSF receptor analyses cannot be used to discriminate between the different diseases causing severe neutropenia, but they might be helpful for screening for risk of leukemia. The time between acquisition of a G-CSF receptor mutation and development of leukemia varies considerably. In a few patients, a G-CSF receptor is only present in the leukemic cells, whereas other patients show single or multiple mutations of the G-CSF receptor gene several years before leukemic transformation (24). Like the elastase mutations, the G-CSF receptor mutations affect only one allele in most patients. No evidence exists that a G-CSF receptor mutation leads to a change in the clinical response to G-CSF treatment irrespective of any increase or decrease in G-CSF dose.

7.2.1.2. Clinical Features. All patients with SCN have absolute neutrophil counts (ANCs) continuously <200 ^L, and in many patients peripheral blood neutrophils are completely absent. The estimated frequency of SCN is approx 1-2 cases per million with equal distribution between males and females. If the disease is diagnosed during the first months of life, antineutrophil antibodies should be excluded.

In patients with SCN, severe bacterial infections frequently occur during the first year of life. Postnatal omphalitis may be the first symptom, but later otitis media, pneu-monitis, infections of the upper respiratory tract, and abscesses of the skin or liver are also common infections, which often lead to the diagnosis of SCN. Blood cultures are positive for staphylococci or streptococci, but other bacteria, e.g., Pseudomonas and Peptostreptococcus, and fungi were reported. In addition, rare infections like a clostridial gas gangrene infection may occur in these patients. The outcome of these fulminant infections is often lethal owing to lack of neutrophil defense. Most patients have frequent aphthous stomatitis and gingival hyperplasia, leading to an early loss of permanent teeth.

7.2.1.3. Blood Values. To confirm the diagnosis, repeated differential blood counts are required indicating persistent ANC within a range of 0-0.2 x 109/L. Blood counts often indicate additional mild anemia and thrombocytosis. Blood monocytes and eosinophils may be increased. Immunoglobulin concentrations for IgG are increased for most patients independent of their infectious status. The specific immunologic competence after vaccination is normal. Blood chemistry is within the normal, age-dependent range for electrolytes, and kidney and liver function values.

7.2.1.4. Bone Marrow. The bone marrow usually shows a maturation arrest of neutrophil precursors at an early stage (promyelocyte/myelocyte level) with few cells of the neutrophilic series beyond the promyelocyte stage. Promyelocytes often reveal morphologic atypical nuclei and vacuolization of the cytoplasma. The number of promyelocytes is slightly increased (26), with a median percentage of promyelocytes of 8% before filgrastim treatment. While receiving filgrastim, the percentage of promyelocytes decreases to 3%, whereas myelocyte and neutrophil counts increase. Marrow eosinophilia and monocytosis is common, and monocyte counts may change during treatment. Cellularity is usually normal or slightly decreased. Megakaryocytes are normal in number and morphology. The in vitro growth of granulocyte colonies in granulocyte-macrophage colony-forming unit (CFU-GM) assays is often defective, with a maturation arrest that mimics the disease.

7.2.1.5. Cytogenetic Evaluation and Molecular Testing. Normal bone marrow cytogenetics at diagnosis may change during the course of the disease, with mono-somy 7 being the most frequent aberration in approx 50% of abnormal cytogenetic results. Abnormal cytogenetics are often associated with morphologic changes of the bone marrow indicating the onset of myelodysplasia or leukemia (see Subheading 7.2.1.8 below).

Studies of the G-CSF receptor gene have shown that mutations occur mainly within a critical region (nucleotide position 2300-2500) of the intracellular part of the receptor (22,23). These are acquired mutations in a subgroup of patients. Individual patients may develop single or multiple mutations within this critical region. Analysis of the G-CSF receptor gene to detect acquired mutations can be performed from blood and bone marrow.

7.2.1.6. Differential Diagnosis. The most common of these rare diseases are cyclic neutropenia, Shwachman-Diamond syndrome, glycogen storage disease type 1b, and autoimmune neutropenia in infancy. A very important differential diagnostic evaluation is testing for neutrophilic antibodies: in children aged 1-3 yr with autoimmune neutropenia, the presence of neutrophil-specific autoantibodies can increase peripheral destruction of neutrophils. Although peripheral blood neutrophil counts may be as low as in SCN patients, these patients usually do not have severe bacterial infections. In the serum of these patients, granulocyte-specific antibodies are detectable by various immunologic tests (27).

7.2.1.7. Treatment. Since 1987, filgrastim has been available for the treatment of SCN. Phase 1-3 studies have demonstrated the efficacy of filgrastim for increasing the number of neutrophils and reducing infections (28,29). In contrast, granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment does not lead to an increase in blood neutrophils, but only blood eosinophils (30).

In 1994, the Severe Chronic Neutropenia Registry (SCNIR) was established to collect data on the clinical course and outcome of these rare disorders. As of December 2000, 383 patients with SCN were enrolled in the SCNIR. Of these 383 patients, >95% responded to filgrastim treatment with an increase in their ANC to 1.0 x 109/L and above (Fig. 1). Most patients with SCN respond to a dose between 3 and 10 Mg/kg/d.

After initiation of filgrastim at 5 Mg/kg/d, the dose should be increased to 10 Mg/kg/d and then by increments of 10 Mg/kg at 14-d intervals if the ANC remains <1.0 x 109/L. As soon as the ANC can be maintained at 1.0 x 109/L or above, the filgrastim dose does not need to be further increased since the occurrence of bacterial infection is dramatically reduced with an ANC at this level. The filgrastim dose can be reduced if the ANC increases to 5.0 x 109/L or above to maintain the patient at the lowest dose necessary for maintaining a sufficient neutrophil count to avoid and overcome infections. Patients who do not respond to filgrastim are defined as patients failing to respond to filgrastim doses exceeding 120 Mg/kg/d. Partial responders can increase their ANC to 0.5-1.0 x 109/L, but still have bacterial infections. In these patients, the dose of filgrastim cannot be increased because of the large volume and the frequency of injections required. In some of these patients, a combination of filgrastim with rHuSCF increases the ANC; however, because of potential allergic side effects from rHuSCF, this treatment combination was used exclusively during severe infections for hospitalized patients who receive concomitant antihistaminic medication (see Chap. 8 for further information). For patients who do not respond to filgrastim treatment alone or in combination with rHuSCF, transplantation of human stem cells (HSCT) is currently the only treatment available (31,32). After successful HSCT, the patients have a normal hematopoiesis and no longer require cytokine treatment.It appears difficult to recommend a transplantation, if patients benefit from filgrastim and do not show any evidence of an impending malignant transformation.The risks associated with a transplant from an HLA-identical sibling may outweigh the risk of leukemic transformation when filgras-

Treatment Years

Fig. 1. Mean absolute neutrophil count (ANC) by year of G-CSF treatment. Congenital: n = 323; cyclic: n = 128; idiopathic: n = 204.

Treatment Years

Fig. 1. Mean absolute neutrophil count (ANC) by year of G-CSF treatment. Congenital: n = 323; cyclic: n = 128; idiopathic: n = 204.

tim is continued in responding patients.If the risks of HSCT could be further decreased by new regimens, then HSCT from a matched sibling donor may be an early curative option in the future.

7.2.1.8. Long-Term Safety

7.2.1.8.1. Leukemia Development. Before the availability of cytokine therapy, it was recognized that leukemic transformation occurred in patients with congenital neutropenia (33,34); however, in the precytokine era, in 42% of all published cases the patients died in the first 2 yr of life, usually from sepsis or pneumonia. Thus, the true risk of congenital neutropenia patients developing MDS/acute myeloid leukemia (AML) could not be defined. Because filgrastim therapy is available, most of the patients survive well beyond 2 yr of age. Therefore, it is unknown whether prolonged survival unmasks the natural course of the disease with an increased risk of leukemic transformation independent of any treatment; however, the possibility cannot be excluded that filgrastim therapy further increases the basic risk of leukemic transformation.

From the initiation of clinical trials with filgrastim in 1987 through December 2000, 45 patients with SCN who developed MDS/AML were reported to the SCNIR, all of whom had a diagnosis of congenital neutropenia. The overall incidence or crude rate of MDS/AML conversion is 11.7% for SCN patients (45 cases among 383 exposed cases), with an average follow-up of approx 5-6 yr. Two of the 45 patients with congenital neutropenia and secondary MDS/leukemia were diagnosed as having Shwach-man-Diamond syndrome. No cases of MDS/AML occurred in the subgroup of patients with cyclic or idiopathic neutropenia.

Conversion to MDS/AML in SCN patients was associated with one or more cellular genetic abnormalities, e.g., monosomy 7, ras mutation, or G-CSF receptor mutation, which may be useful to identify subgroups of patients at high risk (22,23). Marrow cells from 11 patients with SCN who transformed to MDS/AML showed point mutations in the gene for G-CSF receptor, resulting in a truncated C-terminal cytoplasmic region of the receptor that is crucial for maturation signaling.

As illustrated by the cases described herein, the development of MDS/AML is a multistep process characterized by a series of cellular genetic changes indicating a genetic predisposition to malignant transformation. Whether and how filgrastim has an impact on this predisposition remains unclear; unfortunately, no historical controls are available for comparison available. To address further the issue of risk vs benefit of filgrastim in the SCN setting with regard to MDS/AML, all available data were critically reviewed (35). The advisory board of the SCNIR recommends annual marrow cytoge-netic testing for patients with congenital neutropenia to identify monosomy 7 or other changes indicating malignant transformation to allow early therapeutic intervention such as BMT.

7.2.1.8.2. Osteoporosis. The initial observation of bone pain and pathologic fractures in a number of our patients led us to investigate bone mineral density in a cohort of 30 patients (36); 15/30 patients (50%) showed evidence of osteopenia/osteoporosis, and in 5 of these 15 patients osteoporosis became a clinical problem with either pathologic fractures or moderate back pain.

Within the SCNIR, bone density measurements have been reported for 121 patients with congenital neutropenia measured by different techniques including quantitative computer tomography, dual-energy X-ray absorptiometry, single-photon absorptiometry, and lumbar X-ray. Sixty-six of the 121 patients (54.4%) had varying degrees of abnormal results; however, these results were not quantified. Most patients did not show clinical symptoms of osteopenia/osteoporosis, such as bone pain or fractures, explaining why diagnostic procedures for bone density evaluation were not reported in >70% of SCNIR patients. The real incidence continues to remain unknown. The pathophysiology of osteopenia/osteoporosis has not been elucidated. Serum chemistry did not reveal a typical pattern in patients with osteopenia/osteoporosis. Furthermore, patients did not receive a higher dose of filgrastim compared with all SCNIR patients.

7.2.1.8.3. Vasculitis. Vasculitis was reported in 3.3% (9/270) of patients with congential neutropenia. Symptoms of vasculitis generally developed simultaneously with an increase in ANC and abated when ANC decreased. Patients with recurrent vasculitis or with renal involvement need to be evaluated for other diseases. Vasculitis may be associated with autoimmune disorders or an underlying malignancy. After a temporary disruption of filgrastim administration, the vasculitis has abated in all patients.

7.2.1.8.4. Splenomegaly. In patients with congenital neutropenia, the incidence of a palpable splenomegaly (2 cm below the costal margin) before treatment with filgras-tim was 20.6%. During the first year of filgrastim therapy, the incidence increased to 38.9% and remained approx at this level of occurrence (33.8-47.6%) through 10 yr of therapy. Spleen size appears to increase in relation to time on filgrastim treatment. Additionally, in some individuals, splenomegaly is associated with infections or with transformation to MDS/AML.

7.2.2. Cyclic Neutropenia

7.2.2.1. Pathophysiology. Cyclic neutropenia is another rare disorder characterized by repetitive infectious episodes, fever, and mouth ulcers during regularly recurring phases of severe neutropenia. This disorder was first described by Leale in 1910 (37) as recurrent furunculosis in an infant showing an unusual blood picture. Many years later the autosomal dominant inheritance was first recognized by a collection of affected families.

An oscillatory production of precursor cells in the bone marrow causes fluctuations of almost all types of blood cells. In most patients, the disease is autosomal domi-nantly inherited, but sporadic cases were also identified. Molecular genetic studies showed that different mutations in the gene for neutrophil elastase located on chromosome 19p13.3 are responsible for this disease in both autosomal dominant and sporadic cases (20,21).

7.2.2.2. Clinical Features. The diagnosis of cyclic neutropenia should be considered if a child presents with regularly recurring fever, mouth ulcers, pharyngitis, and lymphadenopathy, or recurrent skin infections. Usually these symptoms are already present in children <1 yr of age. Symptoms may last for >1 wk. Patients with painful deep mouth ulcers are often unable to eat and may present with loss of body weight. Almost all patients with periods of severe neutropenia (ANC < 0.2 x 109/L) every 3 wk show at least some symptoms with almost every cycle. The frequency of bacterial infections depends on the length of the neutropenic period and therefore patients with longer neutropenic periods are more susceptible to infections; however, severe bacterial infections like pneumonia and septicemia are usually rare (38). In between the neutropenic phases, patients are without symptoms and have normal physical examinations.

7.2.2.3. Blood Values. Blood cells show a cyclic pattern with a typical cycle length of 21 d (38,39). In clinically obvious cyclic neutropenia, neutrophil counts decrease to <0.2 x 109/L. After 3-5 d neutrophils increase and reach counts within the lower normal level.

If cyclic neutropenia is suspected, serial blood counts need to be performed at least three times per week over 6 wk to document the typical cyclic pattern of blood neutrophils. In most patients periodic oscillations of reticulocytes and platelets are detectable as well, and sometimes even eosinophils and lymphocytes cycle.

7.2.2.4. Bone Marrow. In cyclic neutropenia, bone marrow morphology changes during a cycle. Serial bone marrow aspirates have shown an early maturation arrest of myelopoiesis, comparable to that of congenital neutropenia, at the onset of the neu-tropenic phase. Usually, within 3-5 d myeloid maturation recovers and myelopoiesis up to band neutrophils is present in bone marrow aspirates. Erythroid precursors also show oscillations in the bone marrow. Colony assays from patients with cyclic neu-tropenia have shown that various types of cells fluctuate at the same periodicity.

7.2.2.5. Treatment. For patients with cyclic neutropenia, the availability of filgrastim changed the clinical course significantly, since there was no effective treatment before (38,39). Clinical trials have shown that daily application of filgrastim (2-5 Mg/kg) increased the amplitude of neutrophil oscillations and shortened the duration of the neutropenic phase. With filgrastim, the cycle length changes from 21 to approx 14 d. The significant decrease of infectious episodes is mainly owing to a shortening of the severe neutropenic period. A response to filgrastim could be main tained over >12 yr with daily or alternate-day administration of filgrastim at doses of 5 ^g/kg/d or less.

7.2.2.6. Long-Term Safety. For patients with cyclic neutropenia, filgrastim treatment significantly reduced mouth ulcers and febrile and infectious episodes (38,39). A modest increase in spleen size is probably common, but significant splenomegaly was not documented.

During the past 10 yr, leukemic development was not reported in patients with cyclic neutropenia with or without filgrastim treatment. In contrast to congenital neutropenia, cyclic neutropenia seems not to be a preleukemic disorder.

In light of the reported studies and longitudinal data from the SCNIR, we suggest that the use of filgrastim should remain the first-line treatment for most patients with chronic neutropenia and clinically symptomatic patients with cyclic neutropenia.

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