Treatment Of Severe Chronic Neutropenia Research Articles

Peg-Filgrastim for the Treatment of Severe Chronic Neutropenia

Background: Peg-filgrastim (peg-G) is widely used in oncology to accelerate hematopoietic recovery after cancer chemotherapy. It is used occasionally for the treatment of severe chronic neutropenia (SCN). Because of frequent questions from clinicians, we reviewed the use of peg-G, its effectiveness and associated adverse effects for SCN patients followed prospectively through the Seattle office of the Severe Chronic Neutropenia International Registry (SCNIR).Methods: The SCNIR is a long-term observational study of children and adults with congenital, cyclic, idiopathic and autoimmune neutropenia. They are enrolled according to a protocol requiring a minimum of 3 absolute neutrophil counts (ANCs) <0.5 x 109/L over at least a 3 month period. Patients are treated according to the practices of individual physicians; treatments are not prescribed by the study protocol or the SCNIR. Patients and their physicians regularly report treatments for neutropenia including drug doses, schedules, blood counts, infections and associated adverse events. SCNIR-Seattle includes patients in North and South America and Australia. Patients are followed through annual report forms and notes whenever serious illness or adverse events occur.Results: Peg-G has been administered to 37 of 1571 patients enrolled in the SCNIR-Seattle: 12 children (age <18 years) and 25 adults (age >18 years). Common reasons for peg-G treatment were: convenience, patient dislike of injections, or poor response to filgrastim. Table 1 summarizes peg-G exposures:All of the patients responded to peg-G with an increase in ANC over their baselines, but detailed pharmacodynamics to show the patterns of the rise and fall of the counts were not available. As shown in Table 1, the duration of treatment was relatively short for three groups: idiopathic, autoimmune and cyclic patients. In these patients, bone pain is a common adverse effect of the fixed doses of peg-G usually administered. Sweet syndrome was reported for only 1 patient with idiopathic neutropenia.The majority of the reported use of peg-G is for patients with congenital neutropenia who are relatively refractory to G-CSF; 4 of 9 peg-G treated congenital neutropenia patients had been previously treated with G-CSF >10 mcg/kg/day. In the congenital subgroup, adverse events included splenomegaly (8), hepatomegaly (4) and AML (2). Following are brief descriptions of the cases of MDS/AML:Patient #1: A 38 year old female initially diagnosed with SCN in 1989 at age 11 (ELANE mutation C223ter) and started G-CSF at 11.5 mcg/kilograms per day. Because of a poor response, G-CSF was increased to 24 mcg/kg/day. After 15 years she was switched to peg-G (3mg/injection) approximately every 10 days for the next 11 years. At age 37 she had increased blasts in the blood and marrow, leading to the diagnosis of AML and HSCT.Patient #2: A 25 year old female (unrelated to patient #1) was initially diagnosed with SCN at 4.5 months of age (also ELANE mutation C223ter). At age 5 months she started G-CSF (5 mcg/kg/day increased soon to 20 mcg/kg/day). After 12 years, she was switched to peg-G (6 mg/injection) because of poor neutrophil response, and she received peg-G every 14 days for the next 12 years. She became pregnant (previously 3 pregnancies: 2 terminations and one live birth). Early in the pregnancy she appeared to be losing her response to peg-G. Her gums were infiltrated by immature myeloid cells and there were excess blasts in her bone marrow leading to the diagnosis of AML. With intensive care, she delivered a male infant at 30 weeks via C-section and then underwent an HSCT five weeks thereafter.Conclusions: Patients with severe chronic neutropenia respond to treatment with peg-G but it is not easy to determine the proper dose and dosing interval. Bone pain is a common early adverse effect and Sweet syndrome may occur. In patients with congenital neutropenia who are refractory to G-CSF prolonged responses have been achieved lasting for many years with regular injections of peg-G at approximately 14 day intervals. However, 2/9 refractory congenital neutropenia patients developed AML after 11 and 12 years, respectively. Based on this experience, we recommend that peg-G should only be used in congenital neutropenia patients who are refractory to G-CSF (>20 mcg/kg/day) while searching for a donor for HSCT. [Display omitted] DisclosuresBoxer:Amgen: Equity Ownership. Dale:Amgen: Consultancy, Honoraria, Research Funding.

How I diagnose and treat neutropenia.

Neutropenia absolute neutrophil count (ANC) less than 1.5 × 10(9)/l is a common hematological finding, and severe neutropenia, that is, ANC less than 0.5 × 10(9)/l is a well known risk factor for susceptibility to bacterial infections. This review provides a succinct clinical approach to the diagnosis and treatment of neutropenia with specific recommendations on the treatment of severe chronic neutropenia with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF). Experts agree that patients with acute febrile neutropenia should be treated with antibiotics and that patients at high risk of severe neutropenia (>20% risk) after myelosuppressive chemotherapy should be treated prophylactically with a myeloid growth factor, usually G-CSF. The diversity of causes and consequences of chronic neutropenia make the diagnosis and management of these patients more complicated. The review provides a stepwise approach to neutropenia focusing first on reaching a provisional diagnosis and treatment plan then steps to a final diagnosis. It also provides specific recommendations on the treatment of severe chronic neutropenia with G-CSF.

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.

Spontaneous Recovery and Normalization of Blood Neutrophil Counts in Young Children with Severe Chronic Neutropenia

Severe chronic neutropenia is a general term used to organize and study the inherited and acquired diseases causing blood neutrophils to be less than 0.5 × 109/L for months, years or a lifetime. The inherited or congenital disorders include severe congenital neutropenia (SCN) (the autosomal recessive form often called Kostmann syndrome), cyclic neutropenia, Shwachman-Diamond syndrome, Barth syndrome, myelokathexis or WHIM syndrome, and several other rare conditions. The genetic bases for many of these conditions are now known and the molecular, cellular and pathophysiological mechanisms are rapidly being discovered. The acquired disorders are less well characterized and include the immune, autoimmune and idiopathic neutropenias of childhood and adults. These disorders are often confused with the inherited disorders, particularly early in life. In 1994, the Severe Chronic Neutropenia International Registry (SCNIR) was established to study the causes, consequences, and treatment of severe chronic neutropenia with offices in Seattle WA, USA and Hannover, Germany. The total enrollment in the SCNIR-Seattle is currently 1100; 289 children (age less than 33 months at enrollment) and 811 patients (age greater than 33 months at enrollment). Of the 289 children, 119 were diagnosed with either idiopathic or autoimmune neutropenia. This analysis describes twenty children (8 male, 12 female, current age 3.6 to 16.6 years) with clinical diagnoses of idiopathic (11), autoimmune (5), cyclic (3), and congenital (1). These patients were enrolled in the SCNIR, followed with or without treatment of granulocyte colony stimulating factor (G-CSF), and spontaneously normalized their blood neutrophil counts. The median ANC for this population prior to G-CSF treatment was 0.263 × 109/L (range 0.061 to 0.926). All 20 patients had a pre G-CSF bone marrow examination read by a referring hematologist or pathologist and normal cytogenetics. In 15 patients there was normal maturation of the myeloid line. Five patients had “maturation arrest” at the myelocyte (1), metamyelocyte (1), or band (3) stage of neutrophil development. None were described as having early stage “maturation arrest” as is characteristically observed in SCN patients.Neutrophil recovery was defined by an increase in blood neutrophils to 2.0 × 109/L. Two patients had only mild symptoms and did not receive G-CSF before recovery occurred. The other 18 patients were treated with G-CSF, (median dose 1.375 mcg/kg/day, range 0.192 to 4.839 mcg/kg/day; duration median months 24.18, range 0.07 to 102.27 months). Before recovery, these 18 patients responded to G-CSF with an increase in the median ANC to 3.151 × 109/L, (range 0.120 to 14.553 × 109/L, all counts on G-CSF). All were reported to have diminution of recurrent fevers, mouth ulcers, and infections with G-CSF therapy. The daily dose during the first year of G-CSF treatment was positively correlated to the length of treatment: A low initial daily dose corresponded to less time to resolution (r=0.529; p=0.024). A similar relationship existed between a narrower dose range and the length of time a patient was neutropenic. Variability of dosing for this population ranged from 0.045 to 3.354 mcg/kg/day. Low variability between the highest and lowest doses was correlated to less time to resolution (r=0.66; p=0.0029). After recovery, the median ANC for 12 of the 18 patients was 3.337 × 109/L (range 2.181 to 9.282 × 109/L); the referring physicians reported normalization of blood cell counts in the other 6 cases, but did not submit documentation of these counts. No relapses and no evolution to myelodysplasia or leukemia (MDS/AML) have been reported with up to 8 years of follow-up for patients in this report. Similarly, the other 103 young children in the SCNIR with a diagnosis of idiopathic or autoimmune neutropenia have not transformed to MDS/AML. A retrospective review suggests that the patients in this report who were identified as having a diagnosis of cyclic or congenital neutropenia were probably misdiagnosed.These data confirm previous reports that spontaneous remissions may occur in children with idiopathic and autoimmune neutropenia. The data suggest that a normal marrow, normal cytogenetic analysis and response to a low dose of G-CSF are predictors of future recovery. In this patient group, treatment with G-CSF should be individualized and reserved for patients with a history of recurrent fevers and infections.

Neutropénies constitutionnelles et acquises

Evaluating a neutropenia induces first documenting its aetiology. Beside the specific aspects of the newborn, neutropenia in a child may be 1) acquired - the most frequent type -, 2) constitutional, part of a complex genetic disease, 3) constitutional, isolated. Primary acquired neutropenia, also called benign chronic neutropenia, is the most frequent cause of chronic neutropenia in children. It is usually well tolerated and has a frequent favourable outcome in 12-36 months. Many complex genetic diseases include a neutropenia, among which several immunologic disorders that must be ruled out before considering the diagnosis of isolated constitutional neutropenia. Severe congenital neutropenia is the main primary constitutional neutropenia. It is profound, usually < 500 polymorphonuclear leukocytes/mm 3 and exposes to severe pyogenic and fungal infections. Mutations in the gene encoding neutrophil elastase (ELA2) are the most common genetic abnormalities in this group of patients, as well as for patients with cyclic neutropenia. In the neonatal period, neutropenia must primarily suggest a bacterial infection, although other aetiologies have to be known, particularly neonatal neutropenia caused by passive transfer of maternal antibodies and neutropenia related to gravidic hypertension. In adulthood, most neutropenias are related to an infection, to the side effect of a drug, to a malignant haemopathy or to an autoimmune disease. A clinical entity, the idiopathic neutropenia, is described, however, apparently completely primitive and acquired. The treatment of severe chronic neutropenia is directed towards the prevention of infections. It includes prophylactic antibiotherapy such as the trimetroprim-sulfamethoxazole association, the most commonly used, and granulocyte colony stimulating factor (G-CSF). G-CSF has considerably improved patients' conditions. It is usually well tolerated, but side effects have been reported (bone pain, thrombocytopenia, glomerulonephritis, vasculitis). Long-term treatment by high-dose G-CSF has been shown to increase the spontaneous natural risk of leukaemia in patients with congenital severe neutropenia.

Gene Expression Profiles for Normal Human Bone Marrow-Derived CD34+ Stem Cells and CD34−/CD33+ Myeloid-Committed Progenitor Cells in Response to Daily Granulocyte-Colony-Stimulating Factor (G-CSF) Treatment.

G-CSF is widely used to accelerate marrow recovery after cancer chemotherapy, to facilitate collection of hematopoietic progenitor cells, and to treat severe chronic neutropenia. Although G-CSF was originally defined as a stimulus for myeloid cell proliferation, it has potent anti-apoptotic properties, affects synthesis of proteins stored in neutrophil granules, and has many other effects on cells of the myeloid lineage. To improve understanding of the molecular and cellular effects of G-CSF, particularly related to its use for the treatment of severe chronic neutropenia, we performed gene expression profile studies using Affymetrix oligonucleotide arrays and purified bone marrow cell sub-populations from normal volunteers treated with daily subcutaneous G-CSF (300 mcg/sc/qd) for five days. Under local anaesthesia, paired marrow aspirates were obtained from the posterior iliac crest before and after 5 daily doses of G-CSF. CD34+ and CD34−/CD33+ cells were purified using Miltenyi immunomagnetic beads. Two rounds of amplification of total RNA isolated from purified CD34+ or CD33+cells was used to obtain sufficient cRNA for hybridization. Expression data from scanned chips were first analyzed using the RMA algorithm. The limma package of the Bioconductor project was used to identify differentially expressed genes. Limma uses an empirical Bayes method to moderate the standard errors of the estimated log-fold changes. The statistical analysis of CD33+ cells revealed that 150 of more than 12,000 genes examined were up- or down-regulated >2-fold in response to G-CSF treatment. The top 10 genes with up- or down-regulated level of expression include clusterin, neutrophil elastase, two transcription factors, gelsolin, Grb2, phospholipase D3, protein kinase C, the major vault protein, and serine-threonine kinase. In the myeloid-committed CD34-/CD33+ progenitor cells, genes with altered expression level represent those with gene products involved in the cell cycle, regulation of apoptosis, the cytoskeleton, the inflammatory response, or serine proteases and transcription factors. Most of the genes up-regulated in CD33+ cells (e.g. neutrophil elastase, phospholipase D, protein kinase C) were down-regulated in CD34-positive cells in response to G-CSF. The results of the comparative analyses revealed the normal signature gene expression profiles for CD34+ and CD34−/CD33+ cells and identified genes that may mediate specific G-CSF effects.

Risk and benefit of treatment of severe chronic neutropenia with granulocyte colony-stimulating factor

The Severe Chronic Neutropenia International Registry (SCNIR) was established in 1994 following four phase I/II and one phase III clinical trial on the use of filgrastim (recombinant human granulocyte colony-stimulating factor [r-metHuG-CSF]) as a treatment for severe chronic neutropenia (SCN). A primary purpose of the SCNIR is to monitor SCN patients treated with filgrastim for adverse events that might occur over time. As of December 31, 2000, 832 patients with SCN (384 congenital, 160 cyclic, 288 idiopathic) were enrolled. Clinical trial and Registry data show that filgrastim is an effective treatment for SCN; more than 90% of patients treated respond with normalization of blood neutrophil counts. The SCNIR has collected data on bone pain, splenomegaly, hepatomegaly, thrombocytopenia, osteopenia/osteoporosis, vasculitis, glomerulonephritis, growth and development, pregnancy and fertility, leukemic transformation, and mortality. Analysis of data from patients who received filgrastim for up to 11 years did not identify any adverse events associated with increased duration of treatment. Semin Hematol 39:134-140. Copyright 2002, Elsevier Science (USA). All rights reserved.

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 x 10(9)/ 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 x 10(9)/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.

Hematopoietic growth factors for the treatment of severe chronic neutropenia.

Severe chronic neutropenia (SCN) is a rare but important cause of recurrent fevers, oropharyngeal ulcerations and severe infections. In three forms of SCN, i.e., congenital neutropenia (Kostmann's syndrome and related syndromes), idiopathic neutropenia (both childhood and adult), and cyclic neutropenia, it is now established that long-term treatment with the hematopoietic growth factor, recombinant human granulocyte colony stimulating factor (rHuG-CSF or Filgrastim), can elevate blood neutrophil counts to the normal range in most patients, with a concomitant reduction in infection-related events including fever, oral ulcerations, antibiotic use and symptoms of inflammation. Treatment with this growth factor causes an increase in the number and maturity of marrow cells of the neutrophilic series; other cell lines are largely unaffected. Marrow stimulation and expansion are reflected by the occurrence of bone pain early in therapy, as well as some increase in spleen size in most cases. Adverse effects of therapy are infrequent in both children and adults, and long-term treatment with daily or every-other-day s.c. injections of rHuG-CSF are well accepted. Because of the risk that some patients with chronic neutropenia may have or develop myelodysplasia and/or leukemia, careful pretreatment evaluations (blood, bone marrow and cytogenetics) and long-term observations are extremely important. An international registry for patients with SCN has been established to maintain records and further investigate these conditions.

A Randomized Controlled Phase III Trial of Recombinant Human Granulocyte Colony-Stimulating Factor (Filgrastim) for Treatment of Severe Chronic Neutropenia

AbstractPatients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count <0.5 × 109/L) due to these diseases were enrolled in this multi-center phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony-stimulating factor (filgrastim) (3.45 to 11.50 µg/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of ≥ 1.5 × 109/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events.

A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia

Patients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count &lt; 0.5 x 10(9)/L) due to these diseases were enrolled in this multicenter phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony- stimulating factor (filgrastim) (3.45 to 11.50 micrograms/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of = or = 1.5 x 10(9)/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P &lt; .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events.