Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490). (9/5352)

PURPOSE: Considerable morbidity and mortality and costs occur during induction therapy for acute myeloid leukemia (AML). Colony-stimulating factors (CSFs) can shorten neutropenia, and may lower costs. We performed a cost-minimization analysis of granulocyte macrophage colony stimulating factor (GM-CSF) for AML patients > 55 to 70 years of age during an Eastern Cooperative Oncology Group Study. PATIENTS AND METHODS: Clinical data were from a randomized double-blind phase III trial of 117 AML patients. Estimates of costs were from financial accounts from seven participating institutions. Costs were reported from the third party payor perspective. Analyses were conducted utilizing a decision analytic model. The primary source of event probabilities was in-hospital care with or without an active infection. Sensitivity analyses were also reported. RESULTS: When compared to AML patients who received placebo. GM-CSF patients had fewer grade 4-5 infections (9.6% versus 36.2%, P = 0.002) and grade 3-5 infections (52% versus 70%. P = 0.07) and $2.310 in savings. Sensitivity analyses indicated that similar cost estimates applied over a range of clinical and economic assumptions. CONCLUSIONS: This analysis can serve as a template for cooperative group cost analyses. Cooperation on study methodologies may allow for results that are relevant to both clinicians and policy makers.  (+info)

Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia. (10/5352)

Mutations of the p53 tumour suppressor gene are infrequent at presentation of both acute myeloblastic leukaemia (AML) and acute lymphoblastic leukaemia (ALL), being found in between 5-10% of AML and 2-3% of ALL. Here we have studied the frequency of detection of p53 mutations at relapse of both AML and B-precursor ALL. In those patients with detectable mutations at relapse we investigated whether the mutation was detectable at presentation and was thus an early initiating event or whether it had arisen as a late event associated with relapse. Bone marrow samples from 55 adults and children with relapsed AML (n = 41) or ALL (n = 14) were analysed for p53 gene alterations by direct sequencing of exons 5-9. For samples where a p53 mutation was found at relapse, analysis of presentation samples was carried out by direct sequencing of the exon involved, or by allele-specific polymerase chain reaction (PCR) if the mutation could not be detected using direct sequencing. A p53 mutated gene was found at relapse in seven out of 55 cases. The frequency was higher in relapsed ALL (four out of 14 cases; 28.6%) compared to AML (three out of 41 cases; 7.3%). In five out of the seven cases presentation samples were available to study for the presence of the mutation. In two out of two AML patients the p53 mutation was detectable in the presentation sample by direct sequencing. In three ALL patients analysis of presentation material by direct sequencing showed a small mutant peak in one case, the other two being negative despite the sample analysed containing > 90% blast cells. However in both of these patients, the presence of p53 mutation was confirmed in the presentation sample using allele-specific PCR. In one of these patients the emergence of a subclone at relapse was confirmed by clonality analysis using IgH fingerprinting. Our results confirm that in ALL p53 mutations are present in a proportion of patients at relapse. Furthermore cells carrying the mutation are detectable at presentation in a minor clone suggesting that p53 mutations in ALL may be a mechanism contributing to disease relapse.  (+info)

Progressive multifocal leucoencephalopathy with peripheral demyelinating neuropathy after autologous bone marrow transplantation for acute myeloblastic leukemia (FAB5). (11/5352)

Progressive multifocal leucoencephalopathy is an opportunistic JC virus-related pathology occurring in immunocompromised patients. We report a case of severe cellular immunodeficiency in a patient who underwent autologous bone marrow transplantation for acute myeloblastic leukemia, and who subsequently developed progressive multifocal leucoencephalopathy, an unusual pathology in this context. Progressive multifocal leucoencephalopathy was preceded by a peripheral demyelinating neuropathy. We discuss the possible link between these two neuropathies, the possible aggravation or activation from CMV infection, as well as the possible contribution of bone marrow purging in the resultant cellular immunodeficiency.  (+info)

Behenoyl cytarabine-associated reversible encephalopathy in a patient with acute myelogenous leukemia. (12/5352)

We report a case of reversible encephalopathy syndrome in a 16-year-old girl with acute myelogenous leukemia (AML), who is undergoing during consolidation chemotherapy composed of BH-AC (N4-behenoyl-1-beta-D-arabinofuranosyl cytosine) and idarubicin. On the 6th day of chemotherapy, she was in a drowsy state following generalized tonic clonic seizure lasting 20 minutes. MR images revealed extensive cortical and subcortical white matter brain edema. Alertness returned over the 24 hr following by the discontinuation of BH-AC and intravenous administration of diphenylhydantoin, although she complained of intermittent headaches and visual disturbance. She gradually recovered from these symptoms during subsequent 7 days. Previously noted abnormal signal intensities have nearly disappreared on follow-up MRI obtained on the 22nd day after the first seizure. She was discharged without any neurologic sequela. This case suggests that BH-AC, a derivative of cytosine arabinoside (1-beta-D-arabinofuranosylcytosine) could be a cause of reversible encephalopathy syndrome.  (+info)

Induction of apoptosis in myeloid leukaemic cells by ribozymes targeted against AML1/MTG8. (13/5352)

The translocation (8;21)(q22;q22) is a karyotypic abnormality detected in acute myeloid leukaemia (AML) M2 and results in the formation of the chimeric fusion gene AML1/MTG8. We previously reported that two hammerhead ribozymes against AML1/MTG8 cleave this fusion transcript and also inhibit the proliferation of myeloid leukaemia cell line Kasumi-1 which possesses t(8;21)(q22;q22). In this study, we investigated the mechanisms of inhibition of proliferation in myeloid leukaemic cells with t(8;21)(q22;q22) by ribozymes. These ribozymes specifically inhibited the growth of Kasumi-1 cells, but did not affect the leukaemic cells without t(8;21)(q22;q22). We observed the morphological changes including chromatin condensation, fragmentation and the formation of apoptotic bodies in Kasumi-1 cells incubated with ribozymes for 7 days. In addition, DNA ladder formation was also detected after incubation with ribozymes which suggested the induction of apoptosis in Kasumi-1 cells by the AML1/MTG8 ribozymes. However, the ribozymes did not induce the expression of CD11b and CD14 antigens in Kasumi-1 cells. The above data suggest that these ribozymes therefore inhibit the growth of myeloid leukaemic cells with t(8;21)(q22;q22) by the induction of apoptosis, but not differentiation. We conclude therefore that the ribozymes targeted against AML1/MTG8 may have therapeutic potential for patients with AML carrying t(8;21)(q22;q22) while, in addition, the product of the chimeric gene is responsible for the pathogenesis of myeloid leukaemia.  (+info)

Maturation and apoptosis of primary human acute myeloblastic leukemia cells are determined by TNF-alpha exclusively through CD120A stimulation. (14/5352)

BACKGROUND AND OBJECTIVE: Tumor necrosis factor-a plays an important role in hematopoiesis. Its effects are mediated through two membrane-bound receptors: TNF-R I (p55; CD 120a) and TNF-R II (p75; CD 120b). The aim of our study was to investigate the relative roles of these receptors. DESIGN AND METHODS: We analyzed in 16 acute myeloid leukemia cases whether TNF-alpha could induce in vitro maturation and apoptosis. We then investigated which of the two receptors was provoking monocytic maturation and which was responsible for apoptosis by using the agonistic MoAb HTR-9, directed at CD120a, and the CD120b antagonistic MoAb UTR-1. RESULTS: Monocytic maturation (morphologic and immunologic) was induced in all cases studied, although to different rates, by TNF-alpha and by HTR-9 incubation. The addition of UTR-1 to TNF-alpha did not abolish maturation, nor did it affect apoptosis, which was present in primary AML cultures after 4 and 10 days. INTERPRETATION AND CONCLUSIONS: We present here evidence that the sole stimulation of CD 120a, but not of CD120b, by TNF-alpha is responsible for bot monocytic maturation and apoptosis of primary AML blasts.  (+info)

Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias. (15/5352)

The AML1 and ETS families of transcription factors play critical roles in hematopoiesis; AML1, and its non-DNA-binding heterodimer partner CBFbeta, are essential for the development of definitive hematopoiesis in mice, whereas the absence of certain ETS proteins creates specific defects in lymphopoiesis or myelopoiesis. The promoter activities of numerous genes expressed in hematopoietic cells are regulated by AML1 proteins or ETS proteins. MEF (for myeloid ELF-1-like factor) is a recently cloned ETS family member that, like AML1B, can strongly transactivate several of these promoters, which led us to examine whether MEF functionally or physically interacts with AML1 proteins. In this study, we demonstrate direct interactions between MEF and AML1 proteins, including the AML1/ETO fusion protein, in t(8;21)-positive acute myeloid leukemia (AML) cells. Using mutational analysis, we identified a novel ETS-interacting subdomain (EID) in the C-terminal portion of the Runt homology domain (RHD) in AML1 proteins and determined that the N-terminal region of MEF was responsible for its interaction with AML1. MEF and AML1B synergistically transactivated an interleukin 3 promoter reporter gene construct, yet the activating activity of MEF was abolished when MEF was coexpressed with AML1/ETO. The repression by AML1/ETO was independent of DNA binding but depended on its ability to interact with MEF, suggesting that AML1/ETO can repress genes not normally regulated by AML1 via protein-protein interactions. Interference with MEF function by AML1/ETO may lead to dysregulation of genes important for myeloid differentiation, thereby contributing to the pathogenesis of t(8;21) AML.  (+info)

Surface phenotype analysis of CD16+ monocytes from leukapheresis collections for peripheral blood progenitors. (16/5352)

In peripheral blood progenitor cell (PBPC) collections from patients with solid tumour or haematological malignancy, monocytes were separated into two subpopulations. The majority of monocytes expressed CD14 at a high density without CD16 antigen (the CD14+CD16- monocytes). The remaining monocytes co-expressed CD14 and CD16 (the CD14+CD16+ monocytes). These CD14+CD16+ monocytes amounted to 20.6 +/- 15.8%, while those in peripheral blood (PB) obtained from healthy volunteers were 7.3 +/- 3.1% (P < 0.05). When subdividing the CD14+CD16+ monocytes into CD14brightCD16dim and CD14dimCD16bright cells, both populations were found to be increased in PBPC collections. Since typical CD14+CD16+ monocytes are the CD14dimCD16bright population, we compared the additional surface antigens on CD14dimCD16bright monocytes with those of CD14+CD16- monocytes. In PBPC collections, the CD14dimCD16bright monocytes exhibited lower levels of CD11b, CD15, CD33 and CD38 expression and higher levels of CD4, CD11a, CD11c and MHC class II, and also revealed a higher percentage of CD4+ cells and a lower percentage of CD15+ cells and CD38+ cells, compared with the CD14+CD16- monocytes. When compared with the CD14dimCD16bright monocytes in PB, those in PBPC collections exhibited higher expression of CD4 and lower expression of CD11b, and also showed higher percentages of CD4+ cells and CD38+ cells and a lower percentage of CD11b+ cells. These results suggest that PBPC collections may be rich in the CD14+CD16+ monocytes in which the proportion of the immature population is increased. It is likely that these monocytes participate in the haematological and immune recovery after PBPC transplantation.  (+info)