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1.
Pathophysiology and treatment of severe chronic neutropenia 总被引:7,自引:0,他引:7
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 相似文献
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Cornelia Zeidler Ulrike A.H. Grote Anna Nickel Beate Brand G?ran Carlsson Emília Cortes?o Carlo Dufour Caroline Duhem Gundula Notheis Helen A. Papadaki Hannah Tamary Geir E. Tj?nnfjord Fabio Tucci Jan Van Droogenbroeck Christiane Vermylen Jaroslava Voglova Blanca Xicoy Karl Welte 《Haematologica》2014,99(8):1395-1402
Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment. 相似文献
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Paul S. Malchesky Anna P. Koo Lisa A. Rybicki 《Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy》2001,5(3):193-206
Abstract: The developments in apheresis technologies and techniques and their clinical applications worldwide are technologically, sociologically, and economically driven. In the past, apheresis survey statistics have highlighted both the differences by geographical region in clinical practices and in the types of technologies utilized. While a national view of apheresis is critically important, an international view of apheresis may be more representative overall of this therapeutic modality than national results that are highly dependent on the local economics and the available technologies. These regional differences have provided a basis for the scientific and clinical assessments of these apheresis technologies and their clinical outcomes and have impacted the marketing and business developments of new technologies worldwide. The results of the International Apheresis Registry for 2000 reporting on 39 centers on 4 continents are presented. This survey collected data on 1,080 patients for a total of 15,257 treatments. Information gathered included patient demographics, medical history, treatment diagnoses, treatment specifics (type, methodology, access type, anticoagulants, drugs, equipment usage), side effects, clinical response, and payment provider. As in the prior International Apheresis Registry for 1983, the survey results highlighted the regional differences in apheresis usage and treatment specifics, indicating that an international overview of apheresis may be more representative of the impact of this therapeutic modality. 相似文献
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Kobayashi M Ueda K Kojima S Nishihira H Ishiguro A Shimbo T Nakahata T 《British journal of haematology》1999,106(2):486-490
The serum G-CSF levels of eight patients with severe congenital neutropenia (SCN) were found to be significantly higher than those of 22 patients with chronic benign neutropenia (CBN). The relative number of cells expressing the G-CSF receptor in light density bone marrow cells (LDBMC) was lower in patients with SCN than in patients with CBN or in normal subjects. When recombinant human G-CSF was incubated with LDBMC, G-CSF levels were decreased by LDBMC from normal subjects and CBN patients, but not by those from SCN patients. Serum G-CSF concentrations, which are affected by mature neutrophils, may also be modulated by myeloid precursor cells in the bone marrow. 相似文献
7.
Severe congenital neutropenia (SCN) is characterized by profound neutropenia, recurrent severe bacterial infections and maturation arrest in the myeloid lineage. Granulocyte colony-stimulating factor (G-CSF) treatment results in clinical improvement in over 90% of cases. Point mutations of the G-CSF receptor (G-CSFR) have been implicated in the progression of SCN to acute myeloid leukaemia (AML). Data are presented here on the 9-year follow-up of seven patients and the further screening of 18 other cases. One of the two original cases with a G-CSFR mutation has improved clinically; nevertheless, mutant DNA could still be detected at a very low level > 8 years after identification. The second child with a mutation progressed to myelodysplasia/AML 5 years after her mutation was detected. No mutations were found in the 18 new cases. One of three transformed cases had a G-CSFR mutation. This work is in agreement with the suggestion that G-CSFR mutations may provide a survival advantage to haemopoietic stem cells, but argues against the inevitability of leukaemic progression in their presence. Furthermore, the low frequency of G-CSFR mutations in SCN and the importance of regular screening and close clinical and laboratory follow-up if a mutation is found were demonstrated. 相似文献
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Granulopoietic assessment was made in 14 patients with chronic idiopathic neutropenia (CIN) whose neutrophils were consistently less than 1.5 × 109/ liter and in whom there was absence of splenomegaly and recent drug ingestion. Granulopoiesis was studied using a combination of bone marrow culture in nutrient agar and granulocyte kinetics. Agar colony growth assessed bone marrow concentration of granulocyte progenitor cells (GPC) and the proportion of GPC in DNA synthesis by in vitro 3HTdR suicide. Granulocyte kinetics with in vitro DF32P labelling of patient granulocytes measured granulocyte half-life (T1/2), turnover rate (GTR), and the circulating, marginated, and total blood granulocyte pools. The results indicated that either GPC concentration or the proportion of GPC in DNA synthesis was outside the normal range in all but one patient and decreased in ten out of 14 patients. CIN was also characterized by reduced total, circulating, and marginated blood granulocyte pools, reduced GTR, and normal granulocyte half-life. The neutropenia appeared to be due to a variety of intra-marrow causes, including either a reduction in the GPC compartment, a reduction in GPC proliferation, a maturation arrest, or a reduced amplication during granulopoiesis. Increased granulocyte utilization, intra-vascular destruction or excessive margination could be excluded as possible causes of CIN in this series. Although GPC parameters tended to be reduced, suggesting a production defect, there were signs in nine patients that the bone marrow was attempting to compensate for the peripheral neutropenia. It is suggested that for a complete assessment of granulopoiesis in man, granulocyte kinetic studies need to be combined with quantitative studies of the bone marrow granulocyte progenitor compartment using the agar colony system. 相似文献
9.
Activated T-lymphocytes with myelosuppressive properties in patients with chronic idiopathic neutropenia 总被引:3,自引:0,他引:3
Papadaki HA Stamatopoulos K Damianaki A Gemetzi C Anagnostopoulos A Papadaki T Eliopoulos AG Eliopoulos GD 《British journal of haematology》2005,128(6):863-876
To characterize the cellular components responsible for the impaired granulopoiesis in chronic idiopathic neutropenia (CIN), we investigated the origin of the proapoptotic cytokine producing cells in the bone marrow (BM) microenvironment of CIN patients. We found that the interferon gamma (IFN gamma) and/or Fas-ligand expressing cells in patient BM mononuclear cells and long-term BM culture stroma cells were the CD3(+) T-lymphocytes but not the CD14(+) monocytes/macrophages. The percentage of activated T-lymphocytes was increased in patients' BM as indicated by the proportions of human leucocyte antigen (HLA)-DR(+), CD25(+), CD38(+), CD69(+) and Fas(+) cells within the CD3(+) fraction. Intracellular IFN gamma expression was higher in the BM than peripheral blood of the patients and was associated with increased BM T-lymphocyte numbers. In crossover experiments, patient CD3(+) T-lymphocytes conferred autologous and allogeneic haemopoietic progenitor cell colony inhibition. Patients' T-cell receptor repertoire and polymerase chain reaction analysis did not reveal any clonal T-lymphocyte expansion, suggesting the absence of a direct, antigen-driven recognition of CD34(+) myeloid progenitor cells by patient T-lymphocytes. We conclude that CIN patients have increased number of activated T-lymphocytes in the BM, probably in the setting of a localized polyclonal immune reaction and that these cells confer an inhibitory effect on myelopoiesis through myelosuppressive cytokines including Fas-ligand and IFN gamma. 相似文献
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OBJECTIVES: Chronic mild neutropenias (NP, i.e. absolute neutrophil blood counts/ANC/0.5-1.5 x 10(9) L(-1)) are accompanied by a variable infection susceptibility, which may or may not be as a result of concomitant conditions. Here, we assessed whether such patients also displayed an immunoglobulin deficiency and if this condition contributed to infection proneness. DESIGN, SETTING AND SUBJECTS: Thirty consecutive adult Caucasian patients with chronic mild NP were followed at one university hospital for up to 28 years. Comparisons were made with 49 IgG3 deficiency patients at an immunodeficiency clinic. MAIN OUTCOME MEASURES: Recorded infections, ANC and serum immunoglobulin levels; flow cytometry assessments of blood lymphocyte subsets and tests for autoimmunity were run to determine neutropenia subtypes. RESULTS: Forty per cent of the NP patients were treated for severe or recurrent infections. The mean IgG3 value for the NP patients was significantly lower than for healthy controls (P < 0.005) and 33% of the patients displayed IgG3 values below the reference values (i.e. below 0.21 g L(-1)), and an additional 13% had IgG3 values within the range others consider low (0.21-0.41 g L(-1)). Unexpectedly, neutropenic IgG3 deficiency patients exhibited less infection proneness than those with normal IgG3 values (P=0.03). Patients with autoimmune, large granular lymphocyte-associated or idiopathic NP had IgG3 deficiency in 63, 44 and 38%, respectively. In addition, none of IgG3 deficiency patients followed at the immunodeficiency clinic displayed neutropenia. CONCLUSION: IgG3 deficiency is common amongst chronic mild neutropenia patients, particularly in those with autoimmune background, but contributes not significantly to infection susceptibility. 相似文献
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Piero Farruggia Francesca Fioredda Giuseppe Puccio Daniela Onofrillo Giovanna Russo Angelica Barone Sonia Bonanomi Gianluca Boscarol Andrea Finocchi Roberta Ghilardi Paola Giordano Saverio Ladogana Giuseppe Lassandro Laura Luti Tiziana Lanza Rosalba Mandaglio Nicoletta Marra Baldassare Martire Elena Mastrodicasa Milena Motta Lucia Dora Notarangelo Marta Pillon Laura Porretti Jessica Serafinelli Angela Trizzino Fabio Tucci Marinella Veltroni Federico Verzegnassi Ugo Ramenghi Carlo Dufour 《American journal of hematology》2019,94(2):216-222
Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at ≤4–5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 antineutrophils autoantibody tests, after having excluded ethnic, postinfection, drug induced, or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by “idiopathic neutropenia” (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared with 336 children affected by AIN. The 2 groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (P = .00002). At bivariate analysis among AIN patients earlier detection age (P = .00013), male sex (P = .000748), absence of leucopenia (P = .0045), and absence of monocytosis (P = .0419) were significantly associated with earlier recovery; in the IN group only detection age (P = .013) and absence of monocytosis (P = .0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (P = 6.7e-05 and 4.4e-03, respectively) in the AIN group, whereas in the IN group only detection age stayed significant (P = .013). 相似文献
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Carlsson G Ahlin A Dahllöf G Elinder G Henter JI Palmblad J 《British journal of haematology》2004,126(1):127-132
In patients with severe congenital neutropenia (SCN), the absolute neutrophil count (ANC) is raised during treatment with granulocyte colony-stimulating factor (G-CSF), resulting in a marked reduction of bacterial infection. Some patients, however, still have recurrent but less severe bacterial infections and severe periodontal infections. As it has been suggested that the biological activity of glycosylated recombinant human G-CSF (rHuG-CSF, i.e. lenograstim) is higher than the non-glycosylated form (i.e. filgrastim), we compared the two given in equimolar doses. Seven SCN patients participated in an open, randomized, double crossover study comprising 60 weeks, with four 12-week periods when the two drugs alternated after a 12-week run-in-period. The mean ANC values, sampled every second week, were 5.1 x 10(9)/l during filgrastim treatment and 4.2 x 10(9)/l during lenograstim treatment (P = 0.042). The ANC levels were also significantly higher during filgrastim treatment, when comparing each complementary pair of ANC measurements (P = 0.011) as well as the mean ANC values during each 12-week treatment period (P = 0.033). There were no differences regarding the frequency of infection, antibiotic treatment, gingival bleeding and the number of hospital admissions between the groups. We conclude that filgrastim and lenograstim displayed equal clinical efficacy, but that ANC levels were higher during filgrastim treatment, when administered in equimolar doses. 相似文献
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Wali Y Beshlawi I Fawaz N Alkhayat A Zalabany M Elshinawy M Al-Kindi S Al-Rawas AH Klein C 《European journal of haematology》2012,89(3):245-249
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. 相似文献
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Koumaki V Damianaki A Ximeri M Pontikoglou C Axioti F Spanoudakis M Eliopoulos GD Papadaki HA 《British journal of haematology》2006,135(4):570-573
The levels of interleukin-10 (IL-10) were evaluated in long-term bone marrow (BM) culture supernatants from 54 patients with chronic idiopathic neutropenia (CIN) and 30 healthy volunteers using enzyme-linked immunoabsorbent assay. Cytokine levels were significantly reduced in patients, compared with controls, and strongly correlated with peripheral blood neutrophil counts. Low levels of supernatant IL-10 were associated with increased values of supernatant IL-1beta, tumour necrosis factor-alpha, IL-6 and transforming growth factor-beta(1). We suggest that the pro-inflammatory milieu in the BM of CIN patients may be causatively related to the impaired production of IL-10, a cytokine normally displaying strong anti-inflammatory properties. 相似文献
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Karlsson J Carlsson G Ramme KG Hägglund H Fadeel B Nordenskjöld M Henter JI Palmblad J Pütsep K Andersson M 《British journal of haematology》2007,137(2):166-169
Chronic neutropenia comprises several different diseases that vary in degree of severity and management. We analysed the levels of the neutrophil-derived protein pro-LL-37 in plasma of patients with chronic neutropenia to assess whether it could be used to differentiate different categories of chronic neutropenia. All patients with severe congenital neutropenia were pro-LL-37 deficient. This was in contrast to patients with autoimmune or idiopathic neutropenia, who exhibited normal pro-LL-37 levels while patients with cyclic neutropenia displayed an oscillation of pro-LL-37 in plasma. Plasma levels of pro-LL-37 may thus prove useful for differential diagnosis of chronic neutropenia. 相似文献
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Ruth Pettengell ré Bosly Thomas D. Szucs Christian Jackisch Robert Leonard Robert Paridaens Manuel Constenla Matthias Schwenkglenks for the Impact of Neutropenia in Chemotherapy - European Study Group 《British journal of haematology》2009,144(5):677-685
Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required. 相似文献