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.     

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.     

In vitro functions of neutrophils induced by treatment with rhG-CSF in severe congenital neutropenia.

Neutrophils (and monocytes) from 5 patients suffering from severe congenital neutropenia (SCN) were investigated in vitro after induction of this cell type by treatment with recombinant human granulocyte colony-stimulating factor (rh G-CSF) in vivo. Some abnormal morphological features were seen, such as anomalies of nuclei of phagocytes. No limitations were found 1) in the ability of neutrophils and monocytes to produce reactive oxygen intermediates (ROI) following stimulation with phorbol-myristate-acetate (PMA), 2) in the ability of neutrophils to phagocytose particles of zymosan A and to produce ROI simultaneously and 3) in the ability to kill bacteria of the species staphylococcus aureus. However the specific migration of neutrophils in a gradient of FMLP under soft agar was decreased to approximately 50% in all patients tested as compared to healthy controls. In addition, spontaneous motility was decreased in one patient. Nevertheless, the good clinical improvements of patients suffering from SCN after treatment with rh G-CSF appeared to be due to induction of neutrophils displaying overall good functional activities with respect to natural defense.     

Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with severe congenital neutropenia

OBJECTIVE: To investigate further the cellular defect responsible for impaired granulopoiesis in severe congenital neutropenia (SCN), we have evaluated bone marrow (BM) stem cell reserve and function and BM stromal cell myelopoiesis supporting capacity in two patients with SCN. METHODS: BM primitive stem cells and myeloid progenitor cells were assessed using flow cytometry, limiting dilution assay, clonogenic assays, and long-term BM cultures (LTBMC). BM stroma function was assessed by evaluating the ability of irradiated stromal layers from the patients to induce granulocyte-macrophage colony formation (CFU-GM) by normal CD34+ cells. RESULTS: Compared to the normal controls (n = 37), SCN patients displayed a low percentage of CD34+/CD38+ cells (P < 0.05), low CFU-GM colony formation by highly purified CD34+ cells (P < 0.05), low CFU-GM recovery in LTBMC (P < 0.05), and normal primitive stem cells as indicated by the frequency of CD34+/CD38- cells and the number of long-term culture initiating cells. Patient BM stromal layers exhibited normal myelopoiesis supporting capacity as shown by the CFU-GM content of irradiated LTBMC recharged with normal CD34+ cells. In addition, patient LTBMC supernatants displayed 20-fold normal granulocyte colony stimulating factor and 2-fold normal granulocyte-macrophage colony stimulating factor levels. CONCLUSION: These data show that primitive BM stem cells and stromal cells are not affected in SCN patients, while they support further the concept of a primary defect at the myeloid progenitor cell level. To know the differentiation stage at which the underlying defect causes the malfunction will be relevant for further elucidation of its nature at the molecular level.     

Successful treatment of chronic wound infection in neutropenia and rheumatoid arthritis with filgrastim (rhG-GSF)

Summary A 73-year-old woman was diagnosed with seropositive destructive rheumatoid arthritis in 1981. She was treated with cortisone, chloroquine, and cyclophosphamide (Sendoxan) in 1982 and 1984 and contracted severe neutropenia. After that she only received cortisone. During 1991, again low neutrophilic counts were registered, especially granulocytopenia. At first, B-cell lymphoma was suspected, but later Felty's syndrome was established. The patient was treated with high-dose cortisone with some success and had a few minor septic episodes. In May 1992 she contracted a traumatic wound on the back of the lower leg. Conservative treatment resulted in a worsening of the condition and an increased wound area, most likely related to the neutropenic condition. In mid July the patient was hospitalized. Bacterial isolates yielded mixed gramnegative enteric bacteria from the wound. Parenteral antibiotic treatment was started, followed by oral drugs. rhG-CSF (filgrastim) was given subcutaneously once a day, starting 3 days after admission. This resulted in increased numbers of peripheral granulocytes. The ulcer started to heal and by mid August the patient received a transplant with autologous skin grafting. In mid September the wound was completely healed. It is concluded that the combination of antibiotics, skin transplantion, and G-CSF was necessary for the successful result. Actually, the bacterial growth did not call for antibiotics, but it was considered necessary to cover for staphylococci. No worsening of the underlying arthritis was observed.     

Impaired response of granulocyte-committed progenitor cells to stem cell factor and granulocyte colony-stimulating factor in human cyclic neutropenia

 Although cyclic neutropenia (CN) has been the subject of extensive studies due to its striking clinical picture, the abnormality of hematopoietic progenitor cells in patients with CN has been poorly defined. We studied the sensitivity of progenitor cells of a CN patient to colony-stimulating factors (CSF) including G-CSF, interleukin-3 (IL-3), and stem cell factor (SCF). Peripheral blood progenitor cells of the patient required a significantly higher dose of G-CSF to give rise to colonies than those of normal controls. While the presence of SCF enhanced the number of G-CSF-induced colonies regardless of the concentration of G-CSF in normal controls, this synergistic effect of SCF was limited to the high concentration of G-CSF in the patient, indicating that the abnormality in hematopoiesis in CN involved more immature progenitor cells responsive to SCF. Received: July 30, 1998 / Accepted: November 12, 1998     

Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete

 The aim of the present study was to investigate the prevalence of chronic idiopathic neutropenia of adults (CINA) among an apparently healthy population born and living on the island of Crete. The study was carried out with 778 subjects, 392 men aged 16–78 years (median 43 years) and 386 women aged 15–79 years (median 40 years). All were employees of the Medical School or the adjacent University hospital and members of their families. Among these there were 64 subjects (8.23%) who fulfilled the diagnostic criteria of CINA applied in our department. Mild neutropenia (neutrophils 1700–2499/μl) accounted for 6.81% and moderate neutropenia (neutrophils 600–1699/μl) for the remaining 1.41%. No cases of CINA with severe neutropenia (neutrophils below 600/μl) were found. CINA was more frequent in women, with a women to men ratio of about 3 : 2. Approximately two thirds of the cases appeared in patients aged 30–59 years. Concomitant thrombocytopenia was found in three of the 64 subjects with CINA. Neutropenic subjects had chronic (perennial) rhinitis 3.4 times more frequently than non-neutropenics. No influence of occupation, use of insecticides and pesticides, contact with industrial chemicals, or administration of nonsteroidal anti-inflammatory drugs on the development of CINA was documented. We conclude that, despite the biased character of the study (population not randomly selected), our data provide a valuable estimation of the prevalence of CINA in the general population, given that our sample was sufficiently large, was derived from all major regions of the island, and was composed of subjects of both genders and of all age-groups from 15 to 79 years. Received: September 10, 1998 / Accepted: February 11, 1999     

Bone mineralization and turnover in children with congenital neutropenia, and its relationship to treatment with recombinant human granulocyte-colony stimulating factor

Bone mineral content (BMC) of the radius was measured using single photon absorptiometry (SPA) in nine children with congenital neutropenia. Five had normal values. Two children with severe congenital neutropenia (SCN) had low BMC, and two boys with Schwachman syndrome had biochemistry suggestive of rickets.     

Coexistence of sickle cell disease and severe congenital neutropenia: first impressions can be deceiving

We report an Omani family in whom the propositus had a rare coexistence of sickle cell disease and severe congenital neutropenia associated with a mutation in ELANE. In contrast to his siblings with sickle cell disease, the severity of HbSS-associated complications such as painful crises and acute chest syndrome was significantly reduced. His course of the disease had markedly worsened after initiating G-CSF therapy. These clinical observations suggest that neutropenia may ameliorate inflammatory responses and thus display a modulating factor with respect to the clinical course of sickle cell disease.     

Interferon-α in the idiopathic hypereosinophilic syndrome: consideration of five cases

 The therapy of the idiopathic hypereosinophilic syndrome (HES) is largely directed at controlling symptoms and preventing organ damage. Universally accepted therapeutic protocols for HES are still lacking. Patients are treated by different drugs and drug doses, and therapy appears to be mostly aimed at treating symptoms. However, in order to prevent organ damage the roles of the variously employed agents need to be clarified. Interferon was reported to be an effective agent in 44 patients, and our evaluation of five new cases suggested that IFN-α may be suitable as a first-line therapy. Received: January 8, 1998 / Accepted: June 9, 1998     

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.     

The use of rh-G-CSF in chronic autoimmune neutropenia: reversal of autoimmune phenomena, a case history

An 8-year-old boy had been suffering from chronic autoimmune neutropenia for more than 5 years. The neutropenia proved to be resistant to high-dose steroids and intravenous (either low- or high-dose) immunoglobulin (Ig) therapy. The chronic autoimmune thrombocytopenia and recurrent phases of autoimmune haemolytic anaemia did, however, respond to high-dose prednisone. Other signs of immune dysregulation in this patient consisted of insulin-dependent diabetes mellitus type I (IDDM) and an acquired hypogammaglobulinaemia, most compatible with common variable immunodeficiency (CVI). Prior to rhG-CSF therapy the child had suffered for more than 2 years from recurrent life-threatening bacterial infections.
Anti-neutrophil autoantibodies had pan-FcγRIII (CD16, NA1/NA2) specificity. The neutropenia as well as the anti-neutrophil autoantibodies disappeared when subcutaneous rhG-CSF therapy was started. Upon tapering rhG-CSF, anti-FcγRIII antibodies reappeared together with an absolute neutropenia. Renewed administration resulted again in the normalization of symptoms.
Soluble FcγRIII (sFcγRIII) antigen levels in plasma increased dramatically during rhG-CSF treatment. These high levels of sFcγRIII together with increased numbers as well as decreased apoptotic reactions of neutrophils apparently result in adsorption of the autoantibodies in vivo , contributing to the normalization of autoimmune-mediated neutropenia upon rhG-CSF treatment. Long-term administration of rhG-CSF represents an alternative in the treatment of autoimmune neutropenia.     

Early detection of chronic disseminated Candida infection in leukemia patients with febrile neutropenia: value of computer-assisted serial ultrasound documentation

 Computer tomography (CT) is known to be as sensitive as magnetic resonance imaging (MRI) in detecting fungal microabscesses in chronic disseminated candidiasis. However, all imaging techniques have to be repeated in cases of suspected fungal infection. Therefore, use of the CT or MRI scan is limited. Only ultrasound (US) examinations can be repeated as often as needed. The disadvantage of US is a lack of sufficient documentation. We analyzed the value of computer-assisted documentation in serial ultrasonography of leukemia patients with suspected chronic disseminated candidiasis. From November 1996 until October 1997, a total of 220 ultrasound examinations (Kranzbühler Logiq 500, 3.5 MHz convex array) were performed in 58 patients undergoing intensive chemotherapy. Initial US pictures were stored on a personal computer and compared with the live US at the time of reevaluation in cases of persistent fever. Ultrasound detected microabscesses in liver and/or spleen in eight of the 58 patients. Diagnosis was confirmed by autopsy/biopsy (n=6), blood culture (n=1), and a significant Candida antibody titer (n=1). Focal lesions occurred only after neutrophil recovery. However, a newly evolving nonhomogeneous, micronodular pattern of liver and spleen occurred during febrile neutropenia in three patients, and two of these developed focal lesions subsequently. Follow-up was easy, since US pictures could be compared directly with stored examinations on screen. We conclude that serial US is sensitive in detecting microabscesses in the liver or the spleen. Computer-assisted US documentation proved to be a helpful tool for detection as well as in the follow-up of patients with chronic disseminated candidiasis. Received: January 6, 1998 / Accepted: May 6, 1998     

Helicobacter pylori infection is probably the cause of chronic idiopathic neutropenia (CIN)-associated splenomegaly

Splenic volume and Helicobacter pylori (H. pylori) infection were evaluated in 67 patients with chronic idiopathic neutropenia (CIN) and 39 healthy individuals. Using ultrasound, splenomegaly was found in 61.7% of H. pylori-infected subjects compared to only 8.7% noted in the group of H. pylori-non-infected individuals (P < 0.0001). Splenomegaly was also found in 47.8% of CIN patients compared to 12.8% in the group of non-CIN subjects (P = 0.0003). However, applying the two-way ANOVA test, a statistically significant effect on splenic volume was documented for "factor H. pylori " (F1(102) = 16.800, P < 0.0001) but not for "factor CIN" (F1(102) = 3.213, P = 0.0760), suggesting that CIN-associated splenomegaly is probably due to H. pylori infection.     

A case of systemic lupus erythematosus with severe acute pancreatitis

 A 39-year-old woman with systemic lupus erythematosus (SLE) developed severe acute pancreatitis during a well-controlled disease stage. Treatment with intraarterial injections of antipancreatic enzyme and a small amount of prednisone (20 mg/day) led to remission of the pancreatitis. Disease activity of the SLE did not flare up throughout the course of this treatment. The development of severe acute pancreatitis in SLE is rare. We discuss the cause of pancreatitis in SLE, and whether corticosteroids may induce or improve pancreatitis. Received: January 30, 2001 / Accepted: October 4, 2001