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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe congenital neutropenia (CN; Kostmann syndrome) is a hematologic disorder characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia with absolute neutrophil counts (ANC) less than 0.2 x 10(9)/l associated with severe systemic bacterial infections from early infancy. Data on over 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) since 1994 indicate that > 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (rHuG-CSF) treatment with an ANC > 1.0 x 10(9)/l. In these patients rHuG-CSF is required daily as subcutaneous injection with individual doses ranging between 0.27 and 120 mcg/kg/day to maintain ANC above 1.0 x 10(9)/l. Adverse events documented in this group of patients include splenomegaly, thrombocytopenia, osteoporosis and malignant transformation into MDS/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. For those patients who are refractory to rHuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation (HSCT) is still the only currently available treatment.
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PMID:[Severe congenital neutropenia: trends in diagnosis and therapy]. 1099 41

Thrombocytopenia is generally of central origin in MDS, but can be due to peripheral platelet destruction in some cases. We studied platelet lifespan in 61 MDS cases with platelets < 70,000/mm3 and marrow blasts < 10%. Nine of them (15%) had a major platelet lifespan reduction (< 3.5 days), and were considered for splenectomy. Three of them were not splenectomized due to rapid death, patient refusal and older age plus liver predominance of platelet sequestration, respectively. The remaining six patients (two females and four males, median age 50 years, range 32 to 65) were splenectomized 3 to 21 months after diagnosis. Before splenectomy, five of them had RA and one had CMML. Platelets counts ranged from 5000 to 30,000/mm3 and did not durably respond to other treatments. Three of the patients has a relapse of platelet counts, concomitantly required platelet transfusion due to recurrent blending, whereas three had anemia (two required erythrocyte transfusion) and four had neutropenia. Three months after surgery, platelet counts ranged from 55,000 to 160,000/mm3 (> 100,000/mm3 in four cases), no patient required platelet or erythrocyte transfusion, but there was no effect on neutrophil counts. Three patients had a relapse of platelet counts, concomitant with progression to AML in two of them, whereas the third relapsing case achieved normal platelet counts with further danazol. One patient died with normal platelet counts 12 months after splenectomy (from sepsis, probably related to neutropenia rather than splenectomy). Two patients remained with normal platelet counts 10 and 52 months after surgery. Our findings suggest that the mechanism of thrombocytopenia should be studied more often in 'low risk' MDS (i.e. with low bone marrow blast counts) with thrombocytopenia, as about 15% of them appear to have peripheral platelet destruction. Some of those patients may benefit from splenectomy.
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PMID:Role of splenectomy in the treatment of myelodysplastic syndromes with peripheral thrombocytopenia: a report on six cases. 1141 82

An 80-year-old man with MDS-refractory anemia (RA) suffered transformation to a leukemic state after 18 months. The karyotype of the bone marrow cells was 47, XY, +8 in 8 cells among 20 dividing cells analyzed. Combination therapy of 150 micrograms of granulocyte colony-stimulating factor (G-CSF) and 250 mg of cytarabine ocfosfate (SPAC) for 3 weeks had no beneficial effect. Then, the patient was subjected to low-dose (2 mg daily) melphalan therapy. Gradual and concurrent improvement in anemia, thrombocytopenia, and neutropenia occurred, and the patient became free of transfusions at 2 weeks after the treatment began. Since then, his performance status has improved from grade 4 on his diagnosis of AML to grade 2. Cytogenetic analysis was normal in all 20 dividing cells in the bone marrow examination and melphalan had no adverse effect. Recently, several reports of low dose chemotherapy for elderly patients or high risk leukemia have been described, and have sustained for the QOL therapy. In the present case, low-dose melphalan therapy was effective and, moreover the abnormal karyotype of trisomy eight had disappeared.
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PMID:[Low dose melphalan therapy was effective in an elderly patient with MDS-AML]. 1143 99

Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c-mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G-CSF receptor gene that lead to the truncation of the carboxy-terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c-mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
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PMID:Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias. 1145 19

The IPSS scoring system is useful to establish the appropriate treatment plan in MDS. Growth factors may alleviate both anemia and neutropenia in some MDS patients. Serum Epo levels and need for transfusion serve as good predictors of the erythroid response to the combination of Epo and G-CSF. Subgroups of MDS patients may respond favorably to immunosuppressive therapies such as CyA and ATG. Low-dose chemotherapy may also improve peripheral blood counts. Platelet counts, bone marrow cellularity, chromosome aberrations, and ringed sideroblasts combine to create a model predicting the response to low-dose ara-C. High-dose chemotherapy may lead to complete remission in about half of MDS patients, but the duration of remission is often short. The only proven curative therapy for MDS is allogeneic stem cell transplantation, resulting in an overall disease-free survival rate of about 40%. Only a minority of patients, however, can undergo allogeneic transplantation, both because of patient age and the availability of suitable donors. Autologous stem cell transplantation may be an option for selected patients who are unable to find allogeneic donors. Because the clinical features of patients with MDS are quite heterogeneous, the development of more accurate predictive models may be necessary to improve the efficacy of treatment.
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PMID:Treatment of myelodysplastic syndromes. 1170 53

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on the management of "severe chronic neutropenia" (SCN), a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia and Shwachman-Diamond syndrome (SDS) have developed myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS or AML as part of their natural history. To address this, the Severe Chronic Neutropenia International Registry (SCNIR) used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics. No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. In murine models, the latter produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival. Since congenital neutropenia and SDS are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an "innocent bystander" that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. In patients who transform to overt MDS or AML, hematopoietic stem cell transplantation is the only chance for cure. In those with "soft" signs of MDS, such as an isolated clonal cytogenetic change but without other evidence of MDS, or with an isolated G-CSF receptor mutation, there is room for conservative management. One option is to reduce the G-CSF dosage as much as possible, and observe the tempo of progression, if any, to more overt signs of malignancy.
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PMID:Risk of myelodysplastic syndrome and acute myeloid leukemia in congenital neutropenias. 1195 96

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21

The purpose of this prospective phase II trial was to investigate the safety and efficacy of a modified baseline BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen in the treatment of intermediate and advanced stage Hodgkin's disease (HD). From October 1997 to November 2001, 51 consecutive, previously untreated patients with stage IIA (bulky), IIB, III, and IV disease were treated with a modified baseline BEACOPP regimen with the etoposide administered i.v. on day 1 and orally at a dose of 100 mg/m2, on days 2 and 3. Each patient was scheduled to receive eight courses of BEACOPP with consolidation radiotherapy to bulky (> or =5 cm) or residual disease. There were 25 males and 26 females with a median age of 32 yr (16-65 yr); 80.3% of the patients had nodular sclerosis HD, 41% had bulky disease (> or =5 cm), 10 were in stage IIA (bulky > or =10 cm), 15 in stage IIB, 19 in stage III, and seven in stage IV. Thirty-seven patients (72.5%) achieved a complete response and 17.6% partial response. No significant difference in overall response rate was observed between patients with: (i) 0-2 vs. > or =3 negative prognostic factors, (ii) in stage II vs. stages III/IV, LDH level, and bulky disease. With a median follow up period of 39.5 months, actuarial 3-yr survival rate is 82% and time to progression rate 72.5%. Treatment with this combination was well tolerated. Grades 3 and 4 leukopenia and neutropenia occured in 26% and 28% of the patients, respectively, whereas in 16.3% of the patients infection was observed. Support with granulocyte colony-stimulating factor was given to 59% of the patients. No case of secondary MDS/leukemia has been observed. The results of the present study demonstrate that the modified baseline BEACOPP regimen with radiotherapy used in our patients was well tolerated and effective therapy for intermediate and advanced stage HD. Further follow up time is required to evaluate long-term toxicity.
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PMID:Treatment of intermediate and advanced stage Hodgkin's disease with modified baseline BEACOPP regimen: a Hellenic Co-operative Oncology Group Study. 1295 Feb 34

The demethylating agents 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine at low doses induce hematologic and cytogenetic remissions in a subset of patients with MDS. It is unclear whether the correction of neutropenia involves differentiation of abnormal granulocyte precursors, or emergence of normal granulopoiesis. A previous study in three MDS patients, analyzing a differentiating activity of GM-CSF, had shown heterogenous granulocyte responses. The objective of our study was to determine the ratio of clonal and nonclonal peripheral blood granulocytes in MDS patients treated with DAC using FISH analysis. In two patients with initial severe neutropenia, an informative cytogenetic marker, complete normalization of peripheral blood neutrophils and a bone marrow cytogenetic response following DAC, >90% of the cells contributing to neutrophil normalization lacked this clonal marker. In one of them, an early and transient increase in clonal neutrophils was compatible also with a modest differentiating effect upon the dysplastic granulocyte precursors, whereas in a third patient, resistant to re-treatment with DAC, no expansion of either granulocyte population occurred. In the responders, leukocyte nadirs following DAC appeared less pronounced after conversion to normal cytogenetics. In conclusion, restoration of nonclonal hematopoiesis may be the predominant effect of DAC both in early and late stages of treatment, at least in patients achieving a hematologic and cytogenetic response.
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PMID:Nonclonal neutrophil responses after successful treatment of myelodysplasia with low-dose 5-aza-2'-deoxycytidine (decitabine). 1547 67

One hundred twelve patients with geriatric acute myeloid leukemia (AML), refractory or relapsed AML, or myelodysplastic syndrome and refractory anemia with excess of blasts in transformation (MDS-RAEBt) were entered into this study to receive CAG (aclarubicin and low-dose cytosine arabinoside [Ara-C]in combination with granulocyte colony-stimulating factor [G-CSF]) with the objective of evaluating the efficacy and tolerance of this regimen. Low-dose Ara-C was given subcutaneously at a dosage of 10 mg/m2 every 12 hours on days 1 to 14. Aclarubicin was administered intravenously at a dosage of 14 mg/m2 per day on days 1 to 4 (CAG regimen A) or 7 mg/m2 on days 1 to 8 (CAG regimen B). Recombinant G-CSF was given subcutaneously at a dosage of 200 3g/m2 per day on days 1 to 14. We demonstrated comparable overall complete remission rates for the 4 groups of patients: 30.8% (8/26) in the elderly patients, 48.4% (30/62) in the refractory AML patients, 44.4% (8/18) in the relapsed AML patients, and 38.5% (5/13) in the MDS-RAEBt patients. Of the 52 patients followed up, the 12-month progression-free survival (PFS) and overall survival (OS) rates estimated by the Kaplan-Meier method were 40.73% 3 8.15% and 42.85% 3 8.23%, respectively. The median PFS and OS times were 9.0 3 2.2 months and 11.0 3 1.6 months, respectively. Toxic effects were very rare and mainly consisted of neutropenia and thrombocytopenia due to myelosuppression; approximately 70% to 80% of patients had neutropenia or thrombocytopenia that exceeded National Cancer Institute grade II. Nonhematologic toxicities were not observed in this study. The CAG regimen seems promising, with acceptable toxicity, for the treatment of various categories of poor-prognosis AML and MDS-RAEBt.
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PMID:Aclarubicin and low-dose Cytosine arabinoside in combination with granulocyte colony-stimulating factor in treating acute myeloid leukemia patients with relapsed or refractory disease and myelodysplastic syndrome: a multicenter study of 112 Chinese patients. 1610 59


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