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Cardiac iron overload in transfusion-dependent patients with myelodysplastic syndromes.
Transfusion-dependent myelodysplastic (MDS) patients are prone to iron overload. We evaluated 43 transfused MDS patients with T2* magnetic resonance imaging scans. 81% had liver and 16·8% cardiac iron overload. Liver R2* (1000/T2*), but not cardiac R2*, was correlated with number of units transfused (r=0·72, P<0·0001) and ferritin (r=0·53, P<0·0001). The area under the curve of a time-ferritin plot was found to be much greater in patients with cardiac iron loading (median 53·7x10(5) Megaunits vs. 12·2x10(5) Megaunits, P=0·002). HFE, HFE2, HAMP or SLC40A1 genotypes were not predictors of iron overload in these patients.
c-Myb and GATA-1 alternate dominant roles during megakaryocyte differentiation.
BACKGROUND: Transcription factors are essential for blood cell formation. Mice expressing low levels of c-Myb (c-Myb(low)) have an increased number of bone marrow megakaryocytes (MKs) and corresponding thrombocytosis. In contrast, mice engineered to express low levels of GATA-1 (GATA-1(low)) in the megakaryocytic lineage exhibit aberrant megakaryocytopoiesis with hyperproliferation of progenitors and defective terminal differentiation leading to thrombocytopenia. These seemingly opposite roles may affect platelet turnover and thus be of clinical relevance. OBJECTIVE: To determine how these two transcription factors act together to control megakaryocytopoiesis and platelet formation. METHODS: We used a combination of cellular and molecular in vitro assays to examine the ability of bone marrow cells from mice expressing low levels of both c-Myb and GATA-1 (referred to as double(low)) to produce MKs and platelets. RESULTS: Double(low) cells, or those with low GATA-1 levels in which c-Myb is conditionally deleted, lack the hyperproliferative capacity of GATA-1(low) cells, allowing the cells to proceed towards more committed MKs that are, however, impaired in their capacity to produce fully differentiated cells, as confirmed by the abundance of morphologically aberrant cells that lack the ability to form proplatelets. CONCLUSION: c-Myb and GATA-1 act in concert to achieve correct megakaryocytic differentiation. GATA-1 regulates both the proliferation of megakaryocytic progenitors and their terminal maturation. c-Myb also acts at the level of the progenitor by influencing its commitment to differentiation, but in contrast to GATA-1 it does not have any effect on the process of terminal differentiation.
Measurement of utility values in the UK for health states related to immune thrombocytopenic purpura.
OBJECTIVE: To measure utility values associated with immune (idiopathic) thrombocytopenic purpura (ITP), as perceived by the United Kingdom (UK) general public. RESEARCH DESIGN AND METHODS: A multi-step process, including clinical trial data, literature review, and patient focus group, was used to develop ITP health states valued in a web survey. Six ITP health states were defined based on platelet levels, risk of bleeding and key adverse events/disease complications. Clinical trial data on bleeding and ITP-specific quality of life data were key sources for developing health-state descriptions. 359 respondents, randomly selected from a managed web panel in the UK, completed the web-based Time Trade-Off survey. Wilcoxon signed-rank test was used to compare differences between each pair of health states. RESULTS: Sample characteristics (mean age: 47.9 +/- 16.9 years; 54% female) were comparable to the UK general population. ITP health states were valued as significantly worse than perfect health. Experiencing bleeding episodes was a more important driver than low platelet levels in valuing a health state to be worse. Substantial disutilities were associated with surviving an intracranial haemorrhage. Mean (SD) utility values for each ITP health state are: HS1: platelets >or=50 x 10(9)/L, no outpatient bleed: 0.863 +/- 0.15; HS2: platelets >or=50 x 10(9)/L, outpatient bleed: 0.734 +/- 0.19; HS3: platelets <50 x 10(9)/L, no outpatient bleed: 0.841 +/- 0.19; HS4: platelets <50 x 10(9)/L, outpatient bleed: 0.732 +/- 0.19; HS5: intracranial haemorrhage (2-6 months): 0.038 +/- 0.46; HS6: steroid treatment adverse events: 0.758 +/- 0.20. Potential limitations relate to web user population characteristics and lack of comparative testing of web-based TTO methods. CONCLUSIONS: Results provide evidence that the UK general population associate substantial loss of value living with ITP, suggesting an important role for new ITP treatments. Utility values based on these health states may be useful in future cost-effectiveness studies of existing and/or new ITP treatments.
Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes.
The myelodysplastic syndromes are a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more cell lineages and increased risk of evolution to acute myeloid leukemia (AML). Recent advances in immunophenotyping of hematopoietic progenitor and maturing cells in dysplastic bone marrow point to a useful role for multiparameter flow cytometry (FCM) in the diagnosis and prognostication of myelodysplastic syndromes. In March 2008, representatives from 18 European institutes participated in a European LeukemiaNet (ELN) workshop held in Amsterdam as a first step towards standardization of FCM in myelodysplastic syndromes. Consensus was reached regarding standard methods for cell sampling, handling and processing. The group also defined minimal combinations of antibodies to analyze aberrant immunophenotypes and thus dysplasia. Examples are altered numbers of CD34(+) precursors, aberrant expression of markers on myeloblasts, maturing myeloid cells, monocytes or erythroid precursors and the expression of lineage infidelity markers. When applied in practice, aberrant FCM patterns correlate well with morphology, the subclassification of myelodysplastic syndromes, and prognostic scoring systems. However, the group also concluded that despite strong evidence for an impact of FCM in myelodysplastic syndromes, further (prospective) validation of markers and immunophenotypic patterns are required against control patient groups as well as further standardization in multi-center studies. Standardization of FCM in myelodysplastic syndromes may thus contribute to improved diagnosis and prognostication of myelodysplastic syndromes in the future.
Reduced CD38 expression on CD34+ cells as a diagnostic test in myelodysplastic syndromes.
Diagnosis of myelodysplastic syndrome can be difficult especially in cases with a low blast count and a normal karyotype. Flow cytometry has been used to distinguish myelodysplastic syndrome from non-clonal cytopenias. No one single simple flow cytometric parameter has been proposed to be diagnostic of myelodysplastic syndrome. We have studied samples from 100 myelodysplastic syndrome patients and as control samples; 70 non-clonal cytopenias, 5 subjects with normal hematology, 31 patients with acute myeloid leukemia and 11 with chronic myelomonocytic leukemia or myeloproliferative disorder. We show that reduced relative mean fluorescence of CD38 below a threshold value on CD34(+) cells diagnosed low-grade myelodysplastic syndrome with 95% sensitivity (95% confidence interval, 87-99%) and 92% specificity (95% confidence interval, 82-97%). This simple flow cytometric test may be of value in the routine clinical diagnosis of myelodysplastic syndrome, especially in cases with a low blast count and normal karyotype.
An immunophenotypic pre-treatment predictor for poor response to induction chemotherapy in older acute myeloid leukaemia patients: blood frequency of CD34+ CD38 low blasts.
Many older patients with acute myeloid leukaemia (AML) that receive standard intensive chemotherapy fail to achieve complete remission (CR). Upfront identification of patients unlikely to benefit from standard induction chemotherapy would be important for exploration of novel therapies. This study evaluated if a flow cytometric assay measuring pre-treatment CD34(+) CD38(low) blast frequency could predict therapeutic-resistance in 736 AML patients entered into the UK National Cancer Research Institute AML16 trial. High peripheral blood CD34(+) CD38(low) blast frequency (>7% of leucocytes), present in 18% of assessable patients, conferred significantly reduced CR rates (38% vs. 76%, P < 0.0001) and poor survival, and was independently prognostic for all endpoints of treatment resistance by multivariate analysis.
Severe TMD/AMKL with GATA1 mutation in a stillborn fetus with Down syndrome.
BACKGROUND: A 34-year-old woman was referred for evaluation of a recent stillborn male fetus, gestational age 27 6/7 weeks, found to have congenital myeloid leukemia at autopsy. Autopsy findings included high weight for gestational age, hepatomegaly, and extensive intravascular leukemic infiltrates in the placenta, heart, liver, thymus, lung, kidneys, and brain. Genetic consultation and examination of photographs of the fetus revealed dysmorphic features. INVESTIGATIONS: Immunoperoxidase staining of placental tissue, fluorescence in situ hybridization of paraffin-embedded sections of the placenta using probes for t(12;21)(p13;q22), t(8;21)(q22;q22) and t/del(11q23), cytogenetic analysis of fetal tissue (tendon), sequence analysis of GATA1 in placental leukemic cells, and parental chromosome studies. DIAGNOSIS: Down syndrome with in utero onset of GATA1 mutation-positive severe transient myeloproliferative disorder/acute megakaryoblastic leukemia. MANAGEMENT: Genetic counseling for the recurrence risk of Down syndrome on the basis of maternal age.
GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia.
Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34(+)-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. Although GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1(Δe2) knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.
Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia.
BACKGROUND: Reduced intensity conditioning regimens permit the delivery of a potentially curative graft-versus-leukemia effect in older patients with acute myeloid leukemia. Although T-cell depletion is increasingly used to reduce the risk of graft-versus-host disease its impact on the graft-versus-leukemia effect and long-term outcome post-transplant is unknown. DESIGN AND METHODS: We have characterized pre- and post-transplant factors determining overall survival in 168 patients with acute myeloid leukemia transplanted using an alemtuzumab based reduced intensity conditioning regimen with a median duration of follow-up of 37 months. RESULTS: The 3-year overall survival for patients transplanted in CR1 or CR2/CR3 was 50% (95% CI, 38% to 62%) and 44% (95% CI, 31% to 56%), respectively compared to 15% (95% CI, 2% to 36%) for patients with relapsed/refractory disease. Multivariate analysis demonstrated that both survival and disease relapse were influenced by status at transplant (P=0.008) and presentation cytogenetics (P=0.01). Increased exposure to cyclosporine A (CsA) in the first 21 days post-transplant was associated with an increased relapse risk (P<0.0001) and decreased overall survival (P<0.0001). CONCLUSIONS: Disease stage, presentation karyotype and post-transplant CsA exposure are important predictors of outcome in patients undergoing a T-cell depleted reduced intensity conditioning allograft for acute myeloid leukemia. These data confirm the presence of a potent graft-versus-leukemia effect after a T-cell depleted reduced intensity conditioning allograft in acute myeloid leukemia and identify CsA exposure as a manipulable determinant of outcome in this setting.