Myelodysplastic syndromes (MDS) are a challenging group of diseases for clinicians and researchers, as both disease course and pathobiology are highly heterogeneous. In (suspected) MDS patients, ...multi-parameter flow cytometry can aid in establishing diagnosis, risk stratification and choice of therapy. This review addresses the developments and future directions of multi-parameter flow cytometry scores in MDS. Additionally, we propose an integrated diagnostic algorithm for suspected MDS.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis with abnormal blood cell development (dysplasia) leading to ...cytopenias and an increased risk for progression to acute myeloid leukemia (AML). Patients with MDS can generally be classified as lower- (LR-MDS) or higher-risk (HR-MDS). As treatment goals for patients with LR-MDS and those with HR-MDS differ significantly, appropriate diagnosis, classification, and follow-up are critical for correct disease management. In this review, we focus on the diagnosis, prognosis, and treatment options, as well as the prediction of the disease course and monitoring of treatment response in patients with LR-MDS. We discuss how next-generation sequencing, increasing knowledge on mechanisms of MDS pathogenesis, and novel therapies may change the current treatment landscape in LR-MDS and why structured assessments of responses, toxicities, and patient-reported outcomes should be incorporated into routine clinical practice.
The a priori risk for infections in patients with myelodysplastic syndromes (MDS) is unknown. This study examines prescription rates of anti‐infective agents in MDS patients before and after ...diagnosis, in both in‐ and outpatient settings, to provide information on infection management in clinical practice.
We performed a population‐based study using the HemoBase registry, containing data of all MDS patients diagnosed since 2005 in Friesland, the Netherlands. Community and hospital pharmacies provided prescription data from 1995 to 2020.
Data were obtained for 203 of 292 patients (70%). Patients received significantly more anti‐infective agents, predominantly antibacterials (70%), after diagnosis compared to before: 148.7 defined daily dose/1000 days (DID) (95% CI: 146.9–150.5) and 55.1 DID (95% CI: 54.5–55.8, p < 0.01), respectively, corresponding to median 23.5 and 7.6 treatment days/year. Higher‐risk (449.9 DID) and lower‐risk patients (129.1 DID) both received significantly more anti‐infective agents after diagnosis; comorbidities, neutropenia, and age did not show significant differences relative to prescription rates. Before diagnosis, 10% of patients had infection‐related hospital admissions versus 38% after diagnosis.
In conclusion, MDS patients received significantly more anti‐infective agents compared to before diagnosis. This is the first study that has quantified the prescription rate of anti‐infective agents within and beyond the clinical setting in MDS.
The bone marrow of patients with low-risk myelodysplastic syndromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response ...generally contributes to antitumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an important aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and destabilizing inflammation in lower-risk disease. In this study we investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of MDS patients in different risk groups. Patient-derived classical monocytes showed high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombomodulin. The presence of thrombomodulin on monocytes from MDS patients correlated with lower-risk disease groups and better overall and leukemia-free survival. Using multidimensional mass cytometry, in an
setting, we showed that thrombomodulin-positive monocytes could polarize naïve T cells toward cell clusters which are closer to T helper type 2 and T regulatory cell phenotypes and less likely to contribute to effective immune surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low-risk MDS and may represent a new mechanism in the protection against disproportionate immune activation.
Background: It was proposed that peripheral blood (PB) monocyte profiles evaluated by flow cytometry, called “monocyte assay,” could rapidly and efficiently distinguish chronic myelomonocytic ...leukemia (CMML) from other causes of monocytosis by highlighting an increase in the classical monocyte (cMo) fraction above 94%. However, the robustness of this assay requires a large multicenter validation and the assessment of its feasibility on bone marrow (BM) samples, as some centers may not have access to PB.
Methods: PB and/or BM samples from patients displaying monocytosis were assessed with the “monocyte assay” by 10 ELN iMDS Flow working group centers with harmonized protocols. The corresponding files were reanalyzed in a blind fashion and the cMo percentages obtained by both analyses were compared. Confirmed diagnoses were collected when available.
Results: The comparison between cMo percentages from 267 PB files showed a good global significant correlation (r = 0.88) with no bias. Confirmed diagnoses, available for 212 patients, achieved a 94% sensitivity and an 84% specificity. Hence, 95/101 CMML patients displayed cMo ≥94% while cMo <94% was observed in 83/99 patients with reactive monocytosis and in 10/12 patients with myeloproliferative neoplasms (MPN) with monocytosis. The established Receiver Operator Curve again provided a 94% cut‐off value of cMo. The 117 BM files reanalysis led to an 87% sensitivity and an 80% specificity, with excellent correlation between the 43 paired samples to PB.
Conclusions: This ELN multicenter study demonstrates the robustness of the monocyte assay with only limited variability of cMo percentages, validates the 94% cutoff value, confirms its high sensitivity and specificity in PB and finally, also confirms the possibility of its use in BM samples.
Myelodysplastic neoplasms (MDS) encompass haematological malignancies, which are characterised by dysplasia, ineffective haematopoiesis and the risk of progression towards acute myeloid leukaemia ...(AML). Myelodysplastic neoplasms are notorious for their heterogeneity: clinical outcomes range from a near-normal life expectancy to leukaemic transformation or premature death due to cytopenia. The Molecular International Prognostic Scoring System made progress in the dissection of MDS by clinical outcomes. To contribute to the risk stratification of MDS by immunophenotypic profiles, this study performed computational clustering of flow cytometry data of CD34
cells in 67 MDS, 67 AML patients and 49 controls. Our data revealed heterogeneity also within the MDS-derived CD34
compartment. In MDS, maintenance of lymphoid progenitors and megakaryocytic-erythroid progenitors predicted favourable outcomes, whereas expansion of granulocyte-monocyte progenitors increased the risk of leukaemic transformation. The proliferation of haematopoietic stem cells and common myeloid progenitors with downregulated CD44 expression, suggestive of impaired haematopoietic differentiation, characterised a distinct MDS subtype with a poor overall survival. This exploratory study demonstrates the prognostic value of known and previously unexplored CD34
populations and suggests the feasibility of dissecting MDS into a more indolent, a leukaemic and another unfavourable subtype.
Rapid advances over the past decade have uncovered the heterogeneous genomic and immunologic landscape of myelodysplastic syndromes (MDS). This has led to notable improvements in the accuracy and ...timing of diagnosis and prognostication of MDS, as well as the identification of possible novel targets for therapeutic intervention. For the practicing clinician, however, this increase in genomic, epigenomic, and immunologic knowledge needs consideration in a "real-world" context to aid diagnostic specificity. Although the 2016 revision to the World Health Organization classification for MDS is comprehensive and timely, certain limitations still exist for day-to-day clinical practice. In this review, we describe an up-to-date diagnostic approach to patients with suspected lower-risk MDS, including hypoplastic MDS, and demonstrate the requirement for an "integrated" diagnostic approach. Moreover, in the era of rapid access to massive parallel sequencing platforms for mutational screening, we suggest which patients should undergo such analyses, when such screening should be performed, and how those data should be interpreted. This is particularly relevant given the recent findings describing age-related clonal hematopoiesis.
Summary
The estimation of survival of myelodysplastic syndromes (MDS) and risk of progression into acute myeloid leukaemia is challenging due to the heterogeneous clinical course. The most widely ...used prognostic scoring system (International Prognostic Scoring System IPSS) was recently revised (IPSS‐R). The aim of this study was to investigate the prognostic relevance of flow cytometry (FC) in the context of the IPSS‐R. Bone marrow aspirates were analysed by FC in 159 patients with MDS. A flow score was calculated by applying the flow cytometric scoring system (FCSS). Patients were assigned to IPSS and IPSS‐R risk groups. The FCSS correlated with the World Health Organization classification, IPSS and IPSS‐R risk groups. Mild flow cytometric abnormalities were associated with significantly better overall survival (OS) and lower risk of disease evolution. The presence of aberrant myeloid progenitors was associated with transfusion dependency and disease progression. Most importantly, the FCSS identified prognostic subgroups within the IPSS‐R cytogenetic good risk and low risk group. Flow cytometric analysis in patients with MDS provides additional prognostic information and is complementary to the IPSS‐R. The addition of a flow cytometric score next to the clinical parameters within the IPSS‐R is a further refinement of prognostication of patients with MDS.
Monocytes are subdivided into three subsets, which have different phenotypic and functional characteristics and different roles in inflammation and malignancy. When in man CD14 and CD16 monoclonal ...antibodies are used to define these subsets, then the distinction of non-classical CD14low and intermediate CD14high monocytes requires setting a gate in what is a gradually changing level of CD14 expression. In the search for an additional marker to better dissect the two subsets we have explored the marker 6-sulfo LacNAc (slan). Slan is a carbohydrate residue originally described to be expressed on the cell surface of a type of dendritic cell in human blood. We elaborate herein that the features of slan+ cells are congruent with the features of CD16+ non-classical monocytes and that slan is a candidate marker for definition of non-classical monocytes. The use of this marker may help in studying the role of non-classical monocytes in health and in diagnosis and monitoring of disease.
PDF
