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 our previous studies, short-course high-dose methylprednisolone (HDMP) has been shown to shorten the chemotherapy-induced neutropenic period by stimulating the CD34(+) hematopoietic progenitor cells in children with acute leukemia. In this study, we investigate the role of short-course HDMP on induction of a myeloprotective effect when administered before consolidation therapy consisting of high-dose cytosine arabinoside and daunorubicin. Thirty-four consecutive newly diagnosed children with acute myeloblastic leukemia (AML) who received 64 courses of consolidation regimen were entered into the study. The patients received HDMP (group A) at a daily dose of 30 mg/kg methylprednisolone starting 4 days before the initiation of consolidation therapy. The control group did not receive HDMP (group B). There were no differences in the white blood cell (WBC) and absolute neutrophil counts (ANC) between group A (at day -4) and group B (at day 0) at the beginning of the study (medians: 3 x 10(9)/L vs. 3.2 x 10(9)/L and 1.5 x 10(9)/L vs. 1.7 x 10(9)/L, respectively). The WBC count increased significantly from 3 x 10(9)/L to 6.4 x 10(9)/L, and ANC increased from 1.5 x 10(9)/L to 3.9 x 10(9)/L after 4 days of HDMP treatment in group A (P < 0.01). Following high-dose chemotherapy, the median values of WBC and ANC also remained higher than the control values during the 16 days of the follow-up period. The neutropenic period was significantly shorter in the HDMP group than in the control group (9 +/- 5.2 days vs. 22 +/- 4.7 days) (P < 0.05). The duration of hospitalization and the interval between two chemotherapy cycles were significantly decreased in group A when compared group B (9 +/- 2.7 vs. 14 +/- 2.7 days; 22 +/- 4.7 vs. 26 +/- 4.2 days, respectively) (P < 0.05). Moreover, following consolidation therapy, the number of patients with ANC values below 0.5 x 10(9)/L was lower in group A when compared the group B. In conclusion, the administration of short-course (4 days) HDMP before high-dose chemotherapy has been found to be beneficial for reducing the duration and severity of neutropenia. Further studies with short-course HDMP are required to evaluate its myeloprotective effects in patients with other malignancies.
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PMID:Myeloprotective effect of short-course high-dose methylprednisolone treatment before consolidation therapy in children with acute myeloblastic leukemia. 1613 33

From 2000 to 2004, 152 patients with multiple myeloma aged <or=65 years, enrolled in high-dose programs, were treated with two schedules of DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin): 106 patients (group I) were mobilized with the infusional version of DCEP (infusional-DCEP), and 46 patients (group II) with a shorter version (DCEP-short). The median number of CD34(+) cells collected was similar in the two groups as was the percentage of patients yielding >or=4 x 10(6) cells/kg. The proportion of patients in whom mobilization failed was similar in the two groups. The incidence of WHO grade III neutropenia was higher in group II, although the difference was not statistically significant; the percentage of patients requiring hospitalization for severe infections was similar in the two groups. The incidence of WHO grade IV thrombocytopenia did not differ between the two groups. The response rate was 72% in group I and 80% in group II with similar percentages of patients achieving good responses. DCEP-short is a good mobilizing regimen, sharing the same characteristics as infusional-DCEP: high mobilizing efficacy, low toxicity and good antitumor activity. This new schedule of DCEP does, however, allow complete outpatient management and so could be advantageously included in any high-dose therapy program.
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PMID:Efficacy, toxicity and feasibility of a shorter schedule of DCEP regimen for stem cell mobilization in multiple myeloma. 1618 79

High dose cyclophosphamide (HD-Cy) is commonly used to mobilize stem cells in multiple myeloma (MM). However, timing of collection is variable and incidence of side effects is substantial. We evaluated a combination of vinorelbine (VNB) (25 mg/m(2) day 1) plus Cy (1.5 g/m(2) day 2) and G-CSF as mobilizing regimen in 37 patients with MM. Results were compared to those achieved in 41 previously diagnosed patients mobilized with Cy at 4 g/m(2). Overall, 36/37 patients receiving VNB-Cy (97%) mobilized, as opposed to 40/41 (97%) in the controls (p:0.51). Median CD34+ cells peak was 94/mul for VNB-Cy patients and 96 for controls, p=0.36; median number of CD34+ cells collected was 9.2x10(6)/kg and 8.7x10(6)/kg, respectively (p=0.85). Median number of days to the highest CD34 count was shorter for VNB-Cy patients (nine vs 11, p=0.001). No VNB-Cy patient experienced grade 3-4 neutropenia and thrombocytopenia, as opposed to 63 and 19% in the controls (p=0.001 and 0.01, respectively). Hospitalization from toxicity was never required in VNB-Cy patients as compared to 19% in control group (p=0.01). We conclude that an outpatient combination of VNB plus intermediate dose Cy plus G-CSF is a safe, predictable, and highly effective mobilization regimen for patients with newly-diagnosed MM.
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PMID:Vinorelbine plus intermediate dose cyclophosphamide is an effective and safe regimen for the mobilization of peripheral blood stem cells in patients with multiple myeloma. 1653 2

We have treated 75 transplant-eligible patients with relapsed or refractory lymphoma using an outpatient-based fractionated regimen of ifosfamide, carboplatin and etoposide (ICE) for both salvage and stem cell mobilisation. Patients included DLBC (n = 33), follicular (n = 23), NK/T-cell (n = 3), mantle cell (n = 3) and Hodgkin's lymphoma (n = 13). Cycles of outpatient ICE were given every 21 days and consisted of: ifosfamide 5000 mg/m(2) i.v. fractionated into three equally divided doses and infused over 2-3 h on days 1-3, carboplatin (mg dose = 5 x AUC) i.v. over 1 h on day 1; and etoposide 100 mg/m(2) i.v. daily on days 1-3, plus filgrastim 5 microg/kg/day. Most patients with indolent lymphoma also received rituximab. The median age of patients was 52 years (range 26-69 years). Patients received a mean of 2.8 cycles of ICE. Non-haematological toxicities included grade 1/2 CNS toxicity in four patients, cardiac toxicity in two, reversible renal impairment and haematuria in one each. Haematological toxicity included grades III/IV thrombocytopenia and neutropenia with at least one cycle of ICE in 71% and 72% of patients, respectively. The median time to PBSC harvest was 14 days (range 10-20 days), while the median CD34(+) cell yield was 4.8 x 10(6)/kg (range 2.3-37.8). Five patients (7%) failed to mobilise PBSCs. The overall response rate to ICE was 89%, comprising 29% who achieved a CR and 60% who achieved a PR; for DLBCL, the overall response rate was 85% including 36% who achieved a CR and 49% who exhibited a PR. At a median follow-up of 24 months, the Kaplan-Meier estimates of the overall and event-free survival for all patients were 65% and 42%, respectively. For patients with DLBCL overall and event-free survival figures were 51% and 35%, respectively, at a median follow-up of 14 months. These data confirm the efficacy and tolerability of outpatient fractionated ICE as both a salvage and mobilisation regimen in relapsed/refractory lymphoma.
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PMID:Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in relapsed and refractory non-Hodgkin's and Hodgkin's lymphoma. 1670 81

Patients with chronic idiopathic neutropenia (CIN) display relatively low peripheral blood platelet counts and hypo-lobulated megakaryocytes in the bone marrow (BM). The underlying pathogenetic mechanismswere probed by studying the reserves and clonogenic potential of BM megakaryocytic progenitor cells using flow-cytometry and a collagen-based clonogenic assay for the identification of megakaryocyte colony-forming units (CFU-Meg). Thrombopoietin (TPO) and transforming growth factor-beta1 (TGFbeta1) levels were also evaluated in long-term BM culture supernatants using an enzyme-linked immunosorbent assay. CIN patients (n = 39) showed a low proportion of BM CD34(+)/CD61(+) megakaryocytic progenitor cells and low frequency of early and mixed CFU-Meg in the BM mononuclear, but not CD34(+), cell fraction, compared with healthy controls (n = 20). TPO and TGFbeta1 levels were significantly higher in patients compared with controls. TPO levels inversely correlated with platelet counts whereas TGFbeta1 values correlated inversely with CD34(+)/CD61(+) and CFU-Meg megakaryocytic progenitor cell numbers and positively with TPO levels. The addition of an anti-TGFbeta1 neutralising antibody significantly increased the numbers of CFU-Meg in CIN patients but not in controls, compared with baseline. These data suggest that increased local production of TGFbeta1 probably affects the BM megakaryocytic progenitor cell growth in CIN whereas the compensatory production of TPO finally balances the TGFbeta1-induced inhibitory effect.
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PMID:Impaired megakaryopoiesis in patients with chronic idiopathic neutropenia is associated with increased transforming growth factor beta1 production in the bone marrow. 1693 19

WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34(+) peripheral blood-mobilized stem cells (PBSCs) with retrovirus vector encoding wild-type (wt) CXCR4 or WHIM-type mutated CXCR4 and studied these cells ex vivo in culture and after engraftment in a nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model. Neither wt CXCR4 nor mutated CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by a CXCR4 agonist, stromal cell-derived factor-1 (SDF-1 [CXCL12]). Excess wt CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated CXCR4.
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PMID:WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4. 1694 1

A total of 143 patients with relapsed (n = 90), primary refractory (n = 32) and first line chemotherapy responsive (n = 21) non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were treated with IVE (ifosphamide, etoposide and epirubicin) chemotherapy with the intent to proceed to high-dose therapy with either autologous or allogeneic transplantation, following peripheral blood stem cell mobilisation. A major response (complete/partial response) to IVE was seen in 115 patients (80.4%) with 5-year overall survival (OS) and event free survival (EFS) of 53% and 43%, respectively. Subgroup analysis showed overall response rates of 93.1% for HD with a 5-year OS and EFS of 62% and 52% respectively, while NHL showed response rates of 78.0% with 5-year OS and EFS of 50% and 39% respectively. The median number of CD34 +ve cells mobilised following IVE was 7.86 x 10(6) (range 1.72-42.91 x 10(6)), with 60% mobilising >2 x 10(6)/kg in a single collection. Grade IV neutropenia was seen in 79.6% patients and 77/270 cycles required intravenous antibiotic treatment. We conclude that IVE has a high response rate across a range of refractory and relapsed lymphoma with acceptable toxicity and excellent PBSC mobilising characteristics.
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PMID:Ifosphamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilisation regimen for transplant-eligible patients with non-Hodgkin lymphoma and Hodgkin disease. 1731 78

Pure white cell aplasia (PWCA) is a rare hematologic disorder characterized by agranulocytosis, a lack of virtually all neutrophil-lineage cells (from neutrophils to myeloblasts) in the bone marrow, and normal erythropoiesis and megakaryocy-topoiesis. We report the first case of PWCA that developed in a patient with primary biliary cirrhosis (PBC). An 83-year-old woman, who had had an elevated serum alkaline phosphatase level and shown positivity for serum antimitochondrial antibodies for 10 years, was referred to us because of a perianal abscess. She had severe neutropenia, and her bone marrow showed typical findings of PWCA. Although methylprednisolone pulse therapy induced complete neutrophil recovery, this effect was transient. She died of infection, and the autopsy confirmed the diagnosis of PBC. In vitro investigations showed that factors inhibitory to normal CD34 cell-derived granulopoiesis were present in the patient's serum.
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PMID:Pure white cell aplasia: report of the first case associated with primary biliary cirrhosis. 1732 84

Invasive aspergillosis (IA) remains a major complication following allogeneic hematopoietic stem cell transplant (HSCT). In contrast to conventional HSCT, few investigators have examined risk factors of IA associated with nonmyeloablative (NMA) regimens characterized by outpatient administration, immunosuppression rather than cytoreduction, and short duration of neutropenia posttransplant. We report our results on a cohort of 125 patients treated homogenously who received a 6/6 matched sibling NMA HSCT designed to be performed on an outpatient basis. Conditioning regimen included fludarabine (30 mg/m(2) x 5 days) and cyclophosphamide (300 mg/m(2) x 5 days) followed by reinfusion of a minimum of 4 x 10(6) CD34(+) cells/kg. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF). Overall, 13 patients developed IA (5 proved, 6 probable, 2 possible) 44-791 days (median 229) after NMA HSCT, with a risk of 7% at 1, 11% at 2, and 15% at 3 years. Patients who suffered from IA had poorer overall survival (crude hazard ratio 2.3; 95% confidence interval [CI] 1.0-5.4; P = .045). Intestinal aGVHD or chronic GVHD (cGVHD) was significantly associated with IA at 1 (27% versus 3%, P = .003), 2 (27% versus 8%, P = .01), and 3 years (37% versus 10%, P = .005). The use of daclizumab was also significantly associated with IA at 3 years (47% versus 12%, P = .02). Age, sex, diagnosis, previous autologous transplant, duration of neutropenia, occurrence of cytomegalovirus viremia, duration of steroids or MMF intake, aGVHD, cGVHD, and cumulative number of days spent in hospital were not associated with IA. After multivariate analysis, intestinal GVHD remained the only statistically significant risk factor for IA at 1 (P = .003), 2 (P = .01), and 3 years (P = .005). We conclude that in NMA HSCT, the risk of IA increases over time and is significantly associated with intestinal GVHD. Because there is currently no surrogate in vitro markers of immunocompetence following NMA HSCT, this clinical finding is of particular importance to identify a population at higher risk who should be targeted for antimold prophylaxis.
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PMID:High incidence of invasive aspergillosis associated with intestinal graft-versus-host disease following nonmyeloablative transplantation. 1788 56

Neutropenia as a consequence of bone marrow failure, severe infections, or intensive chemotherapy is frequently associated with life-threatening sepsis. Ex vivo expansion of CD34(+) stem cells has been shown to generate apparently functional neutrophils, and the use of autologous ex vivo-expanded cells can reduce the duration of neutropenia. Nonetheless, the principal antimicrobial capabilities of such cells, and thus their true therapeutic potential, is unknown. Using established protocols, we derived mature neutrophils from normal human adult bone marrow (BM) CD34(+) cells and compared them with freshly isolated peripheral blood neutrophils (PBN). Despite functional similarities between ex vivo-differentiated neutrophils (EDN) and PBN in assays of respiratory burst and phagocytosis, EDN showed marked impairment in their ability to kill both Escherichia coli and Streptococcus pneumoniae compared with PBN. We found that EDN were able to detect (through Toll-like receptor 2 [TLR2], TLR4, and CD14 expression), phagocytose, and mount a respiratory burst to microorganisms. EDN, however, were unable to release neutrophil elastase in response to formyl-met-leu-phe and showed a significantly reduced expression of neutrophil elastase, cathepsin G myeloperoxidase, and LL-37/human cathelicidin protein 18 (hCAP18) as determined by Western blotting. Ultrastructural analysis was consistent with a failure of normal granule development in EDN. Neutrophils derived from BM CD34(+) cells may therefore provide apparently functional cells as assessed by common methodologies; however, important deficiencies may still limit their therapeutic potential. The results presented here suggest additional key tests that such cells may need to undergo prior to clinical use and highlight the potential challenges of using ex vivo modified stem cells in therapeutic settings. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Ex vivo-expanded bone marrow CD34+ derived neutrophils have limited bactericidal ability. 1866 8


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