Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform ...to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between ´normal´, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice.
As curative therapies for pediatric AML remain elusive, identifying potential new treatment targets is vital. We assessed the cell surface expression of CD74, also known as the MHC-II invariant ...chain, by multidimensional flow cytometry in 973 patients enrolled in the Children's Oncology Group AAML1031 clinical trial. 38% of pediatric AML patients expressed CD74 at any level and a comparison to normal hematopoietic cells revealed a subset with increased expression relative to normal myeloid progenitor cells. Pediatric AML patients expressing high intensity CD74 typically had an immature immunophenotype and an increased frequency of lymphoid antigen expression. Increased CD74 expression was associated with older patients with lower WBC and peripheral blood blast counts, and was enriched for t(8;21), trisomy 8, and CEBPA mutations. Overall, high CD74 expression was associated with low-risk status, however 26% of patients were allocated to high-risk protocol status and 5-year event free survival was 53%, indicating that a significant number of high expressing patients had poor outcomes. In vitro pre-clinical studies indicate that anti-CD74 therapy demonstrates efficacy against AML cells but has little impact on normal CD34+ cells. Together, we demonstrate that CD74 is expressed on a subset of pediatric AMLs at increased levels compared to normal hematopoietic cells and is a promising target for therapy in expressing patients. Given that nearly half of patients expressing CD74 at high levels experience an adverse event within 5 years, and the availability of CD74 targeting drugs, this represents a promising line of therapy worthy of additional investigation.
Abstract The classification, scoring systems, and response criteria for myelodysplastic syndromes (MDS) have recently been updated and have become widely accepted. In addition, several new effective ...targeted drugs for patients with MDS have been developed. The current article provides a summary of updated and newly proposed markers, criteria, and standards in MDS, with special reference to the diagnostic interface and refinements in evaluations and scoring. Concerning the diagnostic interface, minimal diagnostic criteria for MDS are proposed, and for patients with unexplained cytopenia who do not fulfill these criteria, the term ‘idiopathic cytopenia of uncertain significance’ (ICUS) is suggested. In addition, new diagnostic and prognostic parameters, histopathologic and immunologic determinants, proposed refinements in scoring systems, and new therapeutic approaches are discussed. Respective algorithms and recommendations should facilitate diagnostic and prognostic evaluations in MDS, selection of patients for therapies, and the conduct of clinical trials.
Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the ...evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117
erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84-94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86-97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage.
There is increasing evidence for the potential benefits and harms of cardiovascular disease (CVD) medications in older people (>75 years) prompting updating of clinical guidelines. We explored the ...views of older people about CVD medication to inform guideline development.
Qualitative study using semistructured interviews and focus groups. An ethnically diverse group of community dwelling older people were purposefully recruited from northern New Zealand using flyers in primary care clinics, local libraries, social groups, and places of worship, and by word of mouth. Interviews and focus groups were digitally recorded, transcribed verbatim, and analysed using an iterative and inductive approach to thematic analysis.
Thirty-nine participants from 4 ethnic groups were recruited (mean 74 years; range 61-91 years; Māori (7), South Asian (8), European (9), and Pasifika (15)). Most participants were taking CVD medication/s. Four main themes emerged: (i) emphasizing the benefits of CVD medication and downplaying the harms; (ii) feeling compelled to take medication; (iii) trusting "my" doctor; and (iv) expecting medication to be continued.
Findings raise questions about older people's agency in decision-making regarding CVD medication. CVD risk management guidelines for older people could include strategies to support effective communication of the potential benefits and harms of CVD medication in older people, balancing life expectancy, and the expected duration of therapy.
Background
Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress ...has been made in the FCM field concerning technical issues (including software and hardware) and pre‐analytical procedures.
Methods
Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group.
Results
We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies.
Conclusions
These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.
This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes ...(MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow‐up of MDS patients.
Diagnostic biomarkers can be used to determine relapse risk in acute myeloid leukemia, and certain genetic aberrancies have prognostic relevance. A diagnostic immunophenotypic expression profile, ...which quantifies the amounts of distinct gene products, not just their presence or absence, was established in order to improve outcome prediction for patients with acute myeloid leukemia. The immunophenotypic expression profile, which defines each patient's leukemia as a location in 15-dimensional space, was generated for 769 patients enrolled in the Children's Oncology Group AAML0531 protocol. Unsupervised hierarchical clustering grouped patients with similar immunophenotypic expression profiles into eleven patient cohorts, demonstrating high associations among phenotype, genotype, morphology, and outcome. Of 95 patients with inv(16), 79% segregated in Cluster A. Of 109 patients with t(8;21), 92% segregated in Clusters A and B. Of 152 patients with 11q23 alterations, 78% segregated in Clusters D, E, F, G, or H. For both inv(16) and 11q23 abnormalities, differential phenotypic expression identified patient groups with different survival characteristics (
<0.05). Clinical outcome analysis revealed that Cluster B (predominantly t(8;21)) was associated with favorable outcome (
<0.001) and Clusters E, G, H, and K were associated with adverse outcomes (
<0.05). Multivariable regression analysis revealed that Clusters E, G, H, and K were independently associated with worse survival (
range <0.001 to 0.008). The Children's Oncology Group AAML0531 trial:
.
The authors compared the effectiveness of the Seeking Safety group, cognitive-behavioral treatment for substance use disorder and posttraumatic stress disorder (PTSD), to an active comparison health ...education group (Women's Health Education WHE) within the National Institute on Drug Abuse's Clinical Trials Network. The authors randomized 353 women to receive 12 sessions of Seeking Safety (
M
= 6.2 sessions) or WHE (
M
= 6.0 sessions) with follow-up assessment 1 week and 3, 6, and 12 months posttreatment. Primary outcomes were the Clinician Administered PTSD Scale (CAPS), the PTSD Symptom Scale-Self Report (PSS-SR), and a substance use inventory (self-reported abstinence and percentage of days of use over 7 days). Intention-to-treat analysis showed large, clinically significant reductions in CAPS and PSS-SR symptoms (
d
= 1.94 and 1.12, respectively) but no reliable difference between conditions. Substance use outcomes were not significantly different over time between the two treatments and at follow-up showed no significant change from baseline. Study results do not favor Seeking Safety over WHE as an adjunct to substance use disorder treatment for women with PTSD and reflect considerable opportunity to improve clinical outcomes in community-based treatments for these co-occurring conditions.
1 Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
2 Faculty of Medicine & CHU, Nancy Université, France
3 Department of Hematology and Oncology, Fondazione IRCCS ...Policlinico San Matteo, Pavia, and University of Pavia, Italy
4 Laboratoire dHématologie, CHU Dupuytren, Limoges, France
5 Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
6 Department of Hematology Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany
7 Department of Hematology and Oncology, Georg-August-University, Göttingen, Germany
8 Sanquin Research at CLB, Amsterdam, The Netherlands
9 Kings College Hospital, London, United Kingdom
10 Department of Hematology, St Radboud University Medical Center, Nijmegen, The Netherlands
11 MLL Munich Leukemia Laboratory, Munich, Germany
12 Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
13 Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan
14 Servicio Central de Citometría, Centro de Investigación del Cáncer, Instituto de Biologia Celular y Molecular del Cáncer (CSIC/USAL) and Department of Medicine, Universidad de Salamanca, Spain
15 Department of Pathology, Karolinska University Hospital, Stockholm, Sweden
16 HMDS, St. Jamess University Hospital, Leeds, United Kingdom
17 Department of Hematology, Fundación Jiménez Díaz, Madrid, Spain
18 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
19 Department of Hematology, Weatherall Institute of Molecular Medicine University of Oxford and John Radcliffe Hospital, Oxford, United Kingdom
20 Hematologics, Inc., Seattle, WA, USA
Correspondence: Arjan A. van de Loosdrecht, MD, PhD, Department of Hematology, VU-Institute of Cancer and Immunology, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. E-mail: a.vandeloosdrecht{at}vumc.nl
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.
Key words: myelodysplastic syndromes, flow cytometry, standardization, ELN, consensus.
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Flow cytometry immunophenotyping for diagnosis of myelodysplastic syndrome
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Haematologica 2009 94: 1041-1043.
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