Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with severe congenital neutropenia (SCN), sepsis mortality is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported. We studied 374 patients with SCN and 29 patients with Shwachman-Diamond syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. In SCN, sepsis mortality was stable at 0.9% per year. The hazard of MDS/AML increased significantly over time, from 2.9% per year after 6 years to 8.0% per year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for sepsis mortality and 21% for MDS/AML. A subgroup of SCN patients (29%) received more than the median dose of G-CSF (> or = 8 microg/kg/d), but achieved less than the median absolute neutrophil count (ANC) response (ANC < 2.188 x 10(9)/L [2188/microL] at 6-18 months). In these less-responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared with 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. Risk of MDS/AML may be similar in SDS and SCN. In less-responsive SCN patients, early hematopoietic stem cell transplantation may be a rational option.
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PMID:The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. 1649 69

Granulocyte colony stimulating factors (G-CSF) are largely used in the treatment of hematologic disorders to improve both the myelosuppression which might directly result from the disease or indirectly induced by the numerous chemotherapy regimen. G-CSF reduces the depth and duration of neutropenia in lymphoma patients and thus allows the design of more dose intense chemotherapy regimen which were shown to improve outcome particularly in patients with diffuse large B-cell and Hodgkin's lymphoma. G-CSF has been studied in patients with acute leukemias (ALL and AML) both concomitantly to induction chemotherapy to sensitize leukemic cells and after chemotherapy to reduce the duration of neutropenia and incidence of severe infection but it's benefit in these settings is still controversial. Myelodysplastic syndromes (MDS) can benefit from G-CSF in association with erythropoietin, particularly for patients with relative good prognosis according to the IPSS score at diagnosis. Still, an improvement of Quality of life needs to be demonstrated in the vue of the cost of these strategies. In aplastic anemia (AA), G-CSF has been used as a support during infection or in association with immunosuppressive treatments but caution is needed regarding the risk of clonal evolution in AA. The benefit of low dose G-CSF in chronic severe neutropenia is well established but the long term consequences of continuous G-CSF support are not known. Finally, G-CSF given alone or after chemotherapy as become one of the key components of hematopoietic stem cell mobilization allowing the use of high dose therapies with autologous or allogeneic stem cell support.
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PMID:[Indications of G-CSF administration in hematologic disorders]. 1677 23

Cyclophosphamide and doxorubicin, two important drugs in the treatment of lymphoma, exhibit a relationship between dose and fractional cell kill, and because of their toxicity profiles, they are candidates for significant dose escalation. We performed a phase II trial to determine the response rate, toxicity, and feasibility of escalated doses of both drugs as part of high dose CHOP in diffuse aggressive lymphoma. Patients who had advanced, previously untreated diffuse aggressive lymphomas (IWF E-H) and an International Prognostic Index of intermediate to high risk were eligible. Treatment was cyclophosphamide 2 gm/m(2)/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m(2)), doxorubicin 35 mg/m(2)/day as a continuous infusion on Days 1 and 2 (total 70 mg/m(2)), vincristine 1.4 mg/m(2) (maximum 2 mg) on Day 1 and prednisone 100 mg/day orally on Days 1 - 5 repeated every 3 weeks for a total of four cycles. G-CSF, prophylactic antibiotics, and mesna were provided. A total of 99 patients were enrolled; 98 received therapy. Major toxicities were Grade 4 neutropenia and thrombocytopenia occurring in 97% and 92%, respectively. Serious infections occurred in 53%. Treatment-related mortality was 2%. The overall response rate is 85%, and two-year failure free and overall survival are 39% and 64%, respectively. Persistent or relapsed lymphoma was the overwhelming cause of death. Six patients have developed AML or MDS. In view of the substantial toxicity accompanying high dose CHOP, the observed outcome suggests that its efficacy is not sufficient to make further study feasible.
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PMID:High dose CHOP: a phase II study of initial treatment in aggressive non-Hodgkin lymphoma. Cancer and Leukemia Group B 9351. 1748 22

Severe congenital neutropenia (SCN) is a heterogeneous bone marrow failure syndrome predisposing to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We studied 82 North American and Australian SCN patients enrolled in the Severe Chronic Neutropenia International Registry who were on long-term treatment with granulocyte colony-stimulating factor and for whom the neutrophil elastase (ELA2) gene was sequenced. There was no significant difference in the risk of MDS/AML in patients with mutant versus wild-type ELA2: the respective cumulative incidences at 15 years were 36% and 25% (P = 0.96). Patients with either mutant or wild-type ELA2 should be followed closely for leukaemic transformation.
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PMID:Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. 1802 88

We randomized 66 elderly patients with AML unfit for conventional chemotherapy to receive GCSF from d6 or from d12 after induction-chemotherapy with cytarabine/idarubicin. There was no difference in duration of neutropenia (17 days vs. 19 days, p=0.67) or rate of complications. Delayed treatment can reduce the administration of G-CSF without adverse consequences.
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PMID:A randomized comparison of immediate versus delayed application of G-CSF in induction therapy for patients with acute myeloid leukemia unfit for intensive chemotherapy. 1805 4

Acute leukaemia is known as the most common cancer in childhood. Febrile neutropenia is a common serious side effect of the cytostatic treatment of malignancies. The clinical use of Granulocyte Colony Stimulating Factor (G-CSF) has become widespread to minimize chemotherapy-induced myelosuppression and febrile neutropenia in childhood solid tumors, acute lymphoid leukaemia (ALL) and in several trials with AML. In case of ALL this seems to be reasonable because, due to the absence of G-CSF receptor (G-CSFR) on the surface of normal lymphoid cells, G-CSF does not have any influence on the pathways of proliferation and differentiation of lymphoid lineage cells. It has been suggested, however, that ALL blasts with B or T cell surface antigens as well as biphenotypic leukaemia cells express G-CSFR, and they are able to respond to exogenously added G-CSF with proliferation. In this study we investigated how G-CSF might influence the sensitivity of leukemic cells to daunorubicin induced cell death using MTT assay, flow cytometry and Western blot analysis. After pretreatment of KG-1 leukaemic cells with G-CSF a moderate increase in the resistance of these cells to daunorubicin could be observed. These results draw attention to the risk of G-CSF application as an adjuvant therapy of childhood ALL. In addition, adjuvant treatment of AML patients with G-CSF in order to prevent neutropenia, or its use in priming regimens might result resistance to daunorubicin.
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PMID:Granulocyte colony stimulating factor increases drug resistance of leukaemic blast cells to daunorubicin. 1849 67

Fanconi anaemia (FA) is a rare genetic disease characterized by chromosomal instability, somatic abnormalities, marrow failure and cancer proness. The main cause of morbidity and mortality is bone marrow failure, which typically arises in the first decade of life and progresses to full-blown transfusion dependence and severe neutropenia in a variable number of years. Myelodysplastic syndrome (MDS) and AML may arise on the background of marrow failure, although cases of patients diagnosed with MDS or overt leukaemia before the full appearance of marrow aplasia are reported. This article reviews the current options for treatment of bone marrow failure in FA and provides an algorithm for supporting decisions on treatment. The use of androgens, corticosteroids and growth factors is reviewed, as well as the results in recent cohorts of matched sibling donor haematopoietic stem cell (HSC) transplants and unrelated donor HSC transplants, including cord blood graft. The conditioning regimens used are analysed and commented. Up-to-date information on second tumours after HSC transplant and on experimental treatments such as gene therapy, prenatal and preimplantation diagnosis and inhibition of pro-inflammatory cytokines is provided.
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PMID:Fanconi anaemia: new strategies. 1854 54

The characterization of leukemia-associated chromosome translocations has contributed relevant insights into our understanding of leukemia pathogenesis and has provided new specific tumor markers essential in prognostic assessment and minimal residual disease studies. The aim of this work is to study the frequency of AML1/ETO fusion gene in a series of Egyptian childhood AML cases. The clinical significance and prognostic implications of this aberration, including CR rate, duration of first CR, extramedullary leukemia (EML), and survival are investigated as well. Peripheral blood and/or bone marrow mononuclear cells were available for analysis from 78 children, all newly diagnosed with AML. AML1/ ETO fusion transcript was detected by the reverse transcriptase- polymerase chain reaction (RT-PCR) technique. Patients with de novo AML were treated by 2 courses of induction chemotherapy, followed by 4 courses of consolidation treatment if the patient achieved complete remission (CR). The marrow status was evaluated after each course in order to check bone marrow cellularity and presence of blasts. Patients with less than 5% blasts by the end of the second course of ADE passed to consolidation chemotherapy. Patients with more than 5% blasts by the end of the second course of ADE were excluded from the study. The AML1/ETO fusion transcript was detected by a singleround RT-PCR reaction and was found to be expressed in 15 out of 78 cases (19.2%). AML1/ETO positive patients were 7 girls and 8 boys, with ages ranging from 5 to 15 years. Seven cases (46.67%) belonged to FAB subtype M1, 7 (46.67%) M2, while only one case (6.67%) belonged to M5a subtype. Their total leukocytic counts ranged from 7.1 to 183.0 x 109/l with a median of 21.0 x 109/l. Their hemoglobin concentrations ranged from 4.8 to 10.3g/dl with a median of 7.4g/dl, while their platelet counts ranged from 6.0 to 96.0 x 109/l with a median of 25.5 x 109/l. Lymph nodes were enlarged in 8/15 cases (53.34%), hepatomegly was observed in 4/15 cases (26.67%), splenomegaly in 8/15 cases (53.34%), purpura in 6/15 cases (40%), while pallor was observed in all fifteen cases.Extramedullary leukemia occurred in 4/15 cases (26.67%). As regards the fate of the positive cases, thirteen cases (86.67%) attained complete remission (CR) following induction chemotherapy. Two patients (13.33%) died during induction in active disease. Eight patients were in complete continuous remission (CCR), four patients (26.67%) relapsed and died during relapse, and one patient (6.67%) died in complete remission due to severe neutropenia and infection. On comparing the AML1/ETO fusion gene status with overall survival, no significant difference was found between AML1/ETO positive and negative cases. Likewise, no difference could be found between positive and negative cases as regards disease-free survival (p=0.354). In conclusion, we report a frequency of 19.2% of AML1/ETO fusion gene in our newly diagnosed pediatric AML cases. Positive cases showed good response to induction therapy, as well as high complete remission rates, which are features of good prognosis. Key Words: Pediatric acute myeloid leukemia , AML1/ETO fusion gene , RT-PCR , Clinical outcome , Prognostic significance.
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PMID:AML1/ETO Fusion Gene in de novo Pediatric Acute Myeloid Leukemia: Clinical Significance and Prognostic Implications. 1883 34

Patients with severe infections are thought to be ineligible for cord blood stem cell transplantation (CBT) because the conventional 5-6 day-conditioning regimens potentially makes them susceptible to fatal infections by the time neutrophil engraftment occurs. Two patients were treated with minimum conditioning regimens consisting of 30 mg/m(2) fludarabin (Flu) and 2 g/m(2) cyclophosphamide (CY) on day-1 and total body irradiation (TBI) of 2 or 4 Gy on day -1 or 0 followed by single unit CBT. The reasons for adopting such weak regimen were febrile neutropenia due to the rejection of the first cord blood (CB) graft given to a patient with follicular lymphoma resistant to chemotherapy and pulmonary aspergillosis in another patient with AML who relapsed after CBT. The AML patient received 40 mg/m(2) of melphalan on day-2 to reduce the leukemia burden. Both patients achieved 100% donor chimerism by day 19 and day 20 after CBT without an apparent exacerbation of the infections and remained in remission at 23 and 18 months after the CBT. These findings suggest that the 1-2 day regimens excluding antihuman thymocyte globulin may be sufficiently potent to ensure engraftment of CB in immunocompromised patients and safely administered even when patients are complicated by active infections.
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PMID:Cord blood transplantation using minimum conditioning regimens for patients with hematologic malignancies complicated by severe infections. 1910 31

The application of myeloablative Allo-SCT is limited by its associated morbidity and mortality. Reduced-intensity conditioning regimens attempt to diminish these, but are associated with a higher risk of disease relapse. Given the evidence of activity of clofarabine and cytarabine in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), we explored a novel reduced-intensity conditioning regimen based on this backbone. Patients received clofarabine 40 mg/m(2) i.v. on days -6 to -2, cytarabine 1 g/m(2) i.v. on days -6 to -2 and anti-thymocyte globulin (ATG) 1 mg/kg on day -4 and 2.5 mg/kg x 2 days on days -3 and -2. Seven patients were enrolled. Their median age was 54 years; three were with MDS and four with AML. The median duration of neutropenia was 14 days and that of thrombocytopenia was 22 days. Toxicities included hand-foot syndrome (57% grade 2), elevated alanine aminotransferase (ALT) (57% grade 3), elevated aspartate aminotransferase (AST) (86% grade 3) and hyperbilirubinemia (29% grade 3-5). No acute GVHD was observed. Enrollment to the trial was halted after three of the first seven patients expired on days +15, +26 and +32. Three of the four surviving patients have relapsed with a median TTP of 152 days. This regimen was not sufficiently immunosuppressive to ensure engraftment, and was associated with substantial morbidity and mortality.
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PMID:Allo-SCT conditioning for myelodysplastic syndrome and acute myeloid leukemia with clofarabine, cytarabine and ATG. 1913 40


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