Understanding the Myelodysplastic Syndromes

Abstract

The myelodysplastic syndrome (MDS) remains challenging to the clinician in terms of diagnosis and management. The diagnosis is essentially one of exclusion in first ruling out other disorders that can also cause peripheral blood/bone marrow cell dysplasia and cytopenias. The distinguishing biological characteristic of MDS is that it is a clonal disorder of the marrow with impaired differentiation. Recent studies implicate extensive apoptosis as the explanation of the paradoxical observation of marrow hyperplasia but peripheral blood cytopenia. Neutropenia and/or neutrophil dysfunction account for the primary clinical manifestation of MDS in terms of an increased risk for infection, which is the leading cause of death in MDS. The clonal nature of MDS places it also at continual risk for transformation to acute leukemia. Predicting overall survival as well as the risk of AML transformation has been improved by the recent development of a scoring system (International Prognostic Scoring System) that incorporates three laboratory variables: percent of marrow blasts, degree of cytopenias, and presence of chromosomal abnormalities. Based on these variables, four prognostic subgroups can be delineated ranging from low risk with a median survival of 5.7 years, to high risk with a median survival of 0.4 years. Management of MDS can now be based on the patient's respective prognostic subgrouping, with low‐risk patients being considered for hematopoietic growth factor singly or in combination if at the point of red cell transfusion dependence and/or neutropenia with recurrent infections, while high‐risk patients should be offered AML‐induction therapy or novel agents such as Topotecan. One must individualize further in patients in the remaining intermediate groups, I and II, in choosing the most appropriate therapy. Future advances upon understanding the molecular details of the MDS clone should ultimately improve the care of patients with MDS.

Efficacy and Safety of Erythropoiesis-Stimulating Proteins in Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

“…The incidence and prevalence of MDSs are difficult to determine, in part because of changing definitions of MDS over the years, the lack of consistent tracking systems, and the fact that, as general populations are aging, MDS incidence may also be changing. In Europe, new cases of MDS have been estimated at 3-20 per year per 100,000 (higher in older age groups) [2]. In the U.S., the American Cancer Society estimates 7,000 -12,000 new cases per year [3].…”

The reduced GM-CSF priming of ROS production in granulocytes from patients with myelodysplasia is associated with an impaired lipid raft formation

“…The myelodysplastic syndromes (MDS) are a group of clonal hematological disorders, which are characterized by an impaired differentiation of the hematopoietic stem cell compartment, affecting the erythroid, megakaryocytic, and myeloid lineages [4,5]. With regard to the latter, it is known that the impaired hematopoiesis might not only result in peripheral neutropenia but that the remaining neutrophils do not function properly, resulting in a high incidence of recurrent bacterial infections [6]. For instance, we and others have shown previously that GM-CSF priming of the fMLP-mediated ROS production was impaired severely in most MDS patients, potentially contributing to the increased susceptibility to infections [7][8][9].…”

Impaired interleukin-8- and GROα-induced phosphorylation of extracellular signal-regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia

“…The myelodysplastic syndromes (MDS) are a group of clonal haematological disorders that are characterized by a disturbed proliferation and differentiation of the erythroid, myeloid, and megakaryocytic cell lineages [1]. The observation that the high mortality rate in MDS patients is generally a direct result of recurrent bacterial infections underscores the importance of granulocytes in the pathology of the disease [2]. The responses of neutrophils leading to the eradication of invading bacteria can be divided into a number of steps: adhesion to and rolling along endothelial lining of blood vessels, migration toward the site of inflammation, diapedesis through the endothelial layer, degranulation, and finally, phagocytosis of bacteria in conjunction with production of bactericidal reactive oxygen species (ROS).…”