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)

Fludarabine phosphate selectively eliminates normal and malignant mononuclear cells in large animals and man through the inhibition of DNA synthesis. The drug depletes mononuclear cells from culture within 24 hours of initial exposure, CD4 and CD8 T cells being more sensitive than either CD20 B cells or CD34 bone marrow precursors. Mitogenic activation of lymphocytes enhances cellular elimination from culture. Fludarabine inhibits PHA-induced T-cell proliferation by >90 per cent and mixed lymphocyte reactions (allogeneic and xenogeneic) by >95 per cent. Fludarabine exerts its cytolytic effects through the induction of endonuclease-independent apoptosis. A 5-day course of fludarabine (50 mg/m2 intravenously once daily) induces both T- and B-cell lymphopenia in Cynomolgus monkeys and Papio baboons. Transient neutropenia was the only side-effect seen in experimental animals. Pretreatment of Cynomolgus monkeys with this regimen of fludarabine causes a prolongation of ABO-compatible skin allograft survival from 8 days (control) to 16 days (drug treated group). Secondary allotransplantation into presensitized recipients showed a similar prolongation of graft survival with fludarabine pretreatment (8 days vs 5 days control). Fludarabine promises to be a potent immunosuppressive agent with low clinical toxicity.
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PMID:Fludarabine phosphate: A DNA synthesis inhibitor with potent immunosuppressive activity and minimal clinical toxicity. 865 23

The case of a 33 year old woman with a large granular lymphocytic leukemia is presented. The main symptoms were neutropenia and recurrent respiratory bacterial infections. No enlargement of the liver, spleen or lymph nodes was noted. Circulating lymphocytes averaged 3000/microliter with 35% of large granular cells. The bone marrow biopsy showed lymphatic infiltration with both nodular and interstitial pattern. Lymphocytes bore the T suppressor phenotype (CD8+, CD45 RO+, CD20-, kappa-, lambda-). Cytogenetic studies revealed a low expression clone with 7q-: del (7)(q36). Gene rearrangements for immunoglobulins or T-cell receptors could not be demonstrated by Southern Blot. Bone marrow cultures grew normally while both normal and patient bone marrow showed marked inhibition when incubated with patients serum. Normalization of the peripheral granulocytic count was obtained with prednisone, while granulocytic-stimulating factors, chlorambucil, and cyclosporine A were partially active or inactive. We suggest that this case represents a form of the lymphoproliferative disease of granular lymphocytes. To our knowledge, the deletion of the long arm of chromosome 7 has not been described in this disease.
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PMID:[Large granular lymphocytic leukemia. Case report with scarce expression in peripheral blood]. 964 Jul 67

Research in chronic lymphocytic leukemia (CLL) has undergone a resurgence of interest in the last decade. While it is obvious that most patients with CLL have typical mature B cells, a number of variants such as splenic lymphoma villous lymphocytes, mantle cell leukemia, and prolymphocytic leukemia need to be considered in the differential diagnosis. This can be established by immunophenotype studies and morphology. Cytogenetic abnormalities are emerging as being of interest, with abnormalities in chromosomes 11 and 17 having major prognostic significance. Immune disregulation is complicated in that along with hypergammaglobulinemia and T-cell dysfunction, the emergence of antibodies directed against hematopoietic cells causes autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. A number of prognostic factors are emerging as being more influential in prognosis and stage, such as serum beta2-microglobulin and soluble CD23. Apoptosis dysregulation is a major feature of CLL, and while no clear pattern has emerged, abnormal levels of bcl2 are common in CLL and bcl2 to bax ratios are also commonly disturbed. Bcl1 levels are commonly increased. Treatment has changed radically. The purine analogs have been demonstrated to be the most active group of drugs in CLL. Combinations of purine analogs, such a fludarabine or 2-chlorodeoxyadenosine, with alkylating agents are emerging as new treatments. The most recent development has been the emergence of two monoclonal antibodies, rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA; directed against CD20) and Campath-1H (directed against CD52 in CLL). The activity of rituximab in lymphoma has been less prominent in small lymphocytic lymphoma (the lymphomatous counterpart of CLL) and this has led to dose escalation studies in CLL with a good level of response. Campath-1H is emerging as another major antibody with marked effect against disease, particularly in the blood and bone marrow. Autologous, allogeneic, and mini-transplant are also being explored extensively. The prognosis for patients with CLL is changing as these new treatments become available.
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PMID:Chronic lymphocytic leukemia. 1056 Oct 25

The Shwachman-Diamond syndrome (SDS) is a rare congenital disorder for which inheritance by an autosomal recessive trait has been suggested. Shwachman-Diamond syndrome is defined by exocrine pancreatic insufficiency combined with severe neutropenia. Moreover, SDS patients are at risk to develop neoplastic hematologic diseases. We describe 2 SDS-affected daughters of consanguine parents who were born 1 year apart, at 35 and 36 weeks of gestation, and who died at the age of 4 and 3.5 months, respectively, due to respiratory infections. Histologic bone marrow evaluation of the second-born child revealed a diffuse proliferation of immature B cells, which comprised 40% of the total cellularity. These cells were identified as precursor B cells by immunophenotyping studies (CD79a(+)/CD10(+)/CD20(-)/CD22(-)/CD34(-)/ terminal deoxynucleotidyl transferase(-)). Molecular determination of the immunoglobulin heavy-chain gene status did not reveal clonality. The emergence of this peculiar B-cell population was interpreted as a marked increase of hematogones. Although the clinical significance and the exact function of hematogones is still obscure, they may play a critical regenerative role in the regulation of hemopoiesis, but without malignant potential in SDS. Immunophenotyping and molecular studies, therefore, have potential value in the differential diagnosis of primary bone marrow failures. This report adds SDS to the spectrum of conditions in which a prominent number of hematogones may be observed.
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PMID:Emergence of an unusual bone marrow precursor B-cell population in fatal Shwachman-Diamond syndrome. 1097 44

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is an effective agent for the treatment of CD20-positive B-cell lymphomas. Because its toxicities are minimal and do not overlap with the toxicities of standard chemotherapy, it is an appealing agent to use in combination with chemotherapy. Moreover, there is evidence for synergy between rituximab and some chemotherapeutic agents. The combination of fludarabine/ mitoxantrone/dexamethasone (FND) has been a well-tolerated and effective regimen for the treatment of indolent lymphomas. When given together with prophylaxis for Pneumocystis carinii, infectious complications with FND have been modest. We report on preliminary safety data using FND in conjunction with rituximab, along with maintenance alpha interferon. Toxicity has been modest. The concurrent use of rituximab with FND modestly increases neutropenia, but has not resulted in any change in the pattern of infectious or other toxicity that occurs with FND alone.
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PMID:Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. 1122 99

Lymphomas are the fifth most common malignancy in the United States and are increasing in incidence. Despite being among the most responsive malignancies to radiation and chemotherapy, the majority of patients relapse or have progressive disease. Monoclonal antibodies (MAbs) directed at cell-specific surface antigens have been useful in the diagnosis of lymphomas and, more recently, the therapeutic mouse-human chimeric MAb rituximab has demonstrated effectiveness in B cell lymphomas. Conjugating MAbs to radionuclides is a strategy for improving the efficacy of MAb lymphoma therapy by delivering radiation in close proximity to the tumour (radioimmunotherapy or RIT). In addition, the low dose rate of the delivered radiation may exert a greater antitumour activity than an equivalent dose of conventional external beam radiation. The antigenic targets for MAb therapy have included CD20, CD22, HLA-DR, and B cell idiotype. Radionuclides that have been used include iodine-131, yttrium-90, and copper-67; there are relative merits and disadvantages to each source of radiation. Clinical studies to date have focused on relapsed and refractory patients with both indolent and aggressive lymphomas, although more recent studies have included previously untreated patients with indolent lymphoma. Radioimmunoconjugate has been delivered as either single or multiple doses. Response rates have varied widely, dependent on the patient population and the response criteria. Of note, complete responses can be achieved in this typically refractory patient group. Toxicities have generally consisted of mild infusion-related nausea, fever, chills, and asthenia. Neutropenia and thrombocytopenia are the dose-limiting toxicities and have prompted the incorporation of autologous stem cell support as a means of achieving dose escalation. To date, RIT has been delivered to highly selected patients in relatively few centres with requisite equipment and specialised personnel. In addition to these requirements, cost is likely to be a barrier to widespread use. The combination of RIT with chemotherapy at conventional or high dose, or with biological agents is a fertile area for investigation. The potential of RIT in the treatment for lymphomas will be defined only by well designed comparative prospective clinical studies.
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PMID:Radioimmunotherapy: potential as a therapeutic strategy in non-Hodgkin's lymphoma. 1143 81

Idiopathic autoimmune thrombocytopenia and neutropenia (ITN) is a primary haemocytopenic disorder clinically characterised by recurrent mucocutaneous bleeding episodes and infections. Unlike in simple idiopathic thrombocytopenic purpura, the platelet deficiency of ITN tends to be chronic and difficult to treat. We describe two patients with ITN who obtained sustained remission of their platelet counts after therapy with the chimeric monoclonal anti-CD20 antibody Rituximab. In one of two cases, Rituximab also induced prolonged normalisation of the neutrophil count and disappearance of auto-antibodies. Our observations indicate that disturbed B-cell function plays a central role in the pathogenesis of ITN. Anti-CD20 antibody therapy seems to constitute a safe and efficient alternative to corticosteroids for the management of ITN patients with chronic thrombocytopenia.
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PMID:Sustained remission of platelet counts following monoclonal anti-CD20 antibody therapy in two cases of idiopathic autoimmune thrombocytopenia and neutropenia. 1148 41

Infusional CDE (cyclophosphamide, doxorubicin, etoposide; iCDE) is one of the most effective chemotherapeutic regimen for human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL), with a complete remission rate of 46% and a median overall survival of 8.2 months (Sparano JA, Blood 1993; 81:2810). Since the majority of HIV-associated NHL are CD20-positive we reasoned that the addition of rituximab to iCDE (R-iCDE) could also improve the poor outcome of these patients. As a first step we investigated the safety of R-iCDE in a phase I/II study. Thirty patients with aggressive HIV-associated NHL were enrolled between June 1998 and October 2000. Characteristics of 29 evaluable patients were: median age: 38 years (range 29-65 years); male sex 24/29; histology: DLCL 16 (55%), Burkitt 10 (35%), ALCL 2 (7%), unclassified 1 (3%); stage: I (35%), II (10%), III (10%), IV (45%); International Prognostic Index: 0, 1 (59%), 2 (24%), 3 (17%), 4, 5 (0); CD4 count: median 132/ mm3 (range 3-470/mm3). Patients received rituximab (375 mg/m2) in conjunction with iCDE (five or six cycles). All patients were treated with G-CSF and highly active antiretroviral therapy (HAART). Twenty-six of 29 patients received treatment as planned, while chemotherapy had to be discontinued in three patients (2 persistent thrombocytopenias, 1 cerebral hemorrhage). Grade 3 or 4 toxicity was observed as follows: neutropenia 79%, anemia 45%, thrombocytopenia 34%, bacterial infection 34%, opportunistic infection 7%, mucositis 17%. A dose reduction was necessary in 22%. Complete remission was achieved in 86% of the patients, partial remission in 4%. Ten percent had progressive disease. After a median follow-up of 9 months the median overall survival is not reached. The actuarial survival at 2 years is 80% and the actuarial progression-free survival is 79%. Four of 29 patients (14%) have died, three from NHL and one from cryptosporidiosis. These findings suggest that the combination of rituximab with iCDE in patients with HIV-associated NHL is safe and feasible and that the addition of the anti-CD20 antibody does not increase the risk for infections. The high complete remission rate also indicates a potential therapeutic benefit and warrants further randomized trials.
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PMID:Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: preliminary results of a phase I/II study. 1178 39

The standard therapy for hairy cell leukemia (HCL) is with the nucleoside analogs, 2"-deoxycoformycin (dCF) or 2-chlorodeoxyadenosine (CdA), which produce morphologic complete remissions (CRs) in the majority of patients, although residual hairy cells can frequently be detected by molecular or immunologic techniques. Relapses continue to occur over time, but most patients respond well to retreatment with the same agent. The longest follow-up is for patients treated with dCF, where the 5- and 10-year relapse-free survival rates are 80% to 85% and 67% to 76%, respectively. dCF is usually administered as 4 mg/m2 intravenously every second week until CR followed by two additional treatments for consolidation. CdA is administered as 0.09 mg/kg/d x 7, by continuous intravenous infusion, although it may be equally effective when given as daily boluses or subcutaneously. More recent studies have suggested that CdA, 0.15 mg/kg intravenously weekly x 6, produces equivalent response rates, while reducing the risk of febrile neutropenia (which occurs in approximately 50% of patients using the standard regimen). We have found this to be a very simple, safe, and effective regimen. Both dCF and CdA should be used with caution in the presence of renal or hepatic dysfunction, and both are contraindicated in the presence of active infection. Interferon-alfa (3 x 10(6) U subcutaneously three times per week for 12 months) produces inferior response rates but is less likely to cause febrile neutropenia. It can be considered for initial treatment for patients with active infection, patients at high risk of febrile neutropenia, and patients who cannot tolerate or are resistant to the nucleoside analogs. Splenectomy is now rarely performed in HCL, but it is required for splenic rupture and may be of value in "splenic" HCL or those with massive splenomegaly and hypersplenism. In preliminary studies, monoclonal antibodies directed against CD20 or CD25 also show activity in HCL, but their roles in this disease require further study.
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PMID:Hairy cell leukemia. 1205 21

The major cause of treatment failure following high-dose therapy with autologous hematopoietic cell transplantation (AHCT) for low-grade lymphomas (non-Hodgkin's lymphoma [NHL]) is persistent disease or recurrence. Most patients whose disease progresses following AHCT have resistant disease and limited bone marrow reserve. In this setting, treatment options are limited and responses to conventional chemotherapy are generally poor. Rituximab is a chimeric immunoglobulin G1 kappa monoclonal antibody that recognizes the CD20 antigen on B-cells. Published data on the use of rituximab for the treatment of recurrent NHL after autologous transplantation are limited. We present a detailed report of anti-CD20 antibody treatment for 8 patients with recurrent follicular low-grade NHL after high-dose therapy and autologous transplantation. Rituximab was administered at 375 mg/m2 intravenously once weekly for a total of 4 infusions. Median follow-up for this study was 23.4 months. Six (75%) of 8 patients responded to rituximab (2 complete response, 4 partial response). The Kaplan-Meier estimated median time to progression was 17.8 months. Rituximab was generally well tolerated. One patient developed delayed neutropenia. Other side effects were infusion related and transient. Two patients were re-treated with rituximab for progressive disease and achieved partial response. In summary, this retrospective study suggests that anti-CD20 antibody treatment is feasible in the treatment of patients who relapse or progress with low-grade NHL after autologous transplantation. There appears to be a high proportion of patients who benefit and have durable responses. Anti-CD20 antibody should be considered as a first-line salvage treatment for patients with CD20+ recurrent low-grade NBL in whom high-dose therapy has failed.
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PMID:Efficacy and safety of monoclonal anti-CD20 antibody (rituximab) for the treatment of patients with recurrent low-grade non-Hodgkin's lymphoma after high-dose chemotherapy and autologous hematopoietic cell transplantation. 1243 49


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