Current Pharmaceutical Design - Volume 18, Issue 22, 2012

Myelodysplastic syndromes (MDS) are characterized by an ineffective hematopoiesis and functional abnormalities of hematopoietic lineages. Patients with MDS present with cytopenia(s) associated with morphological dysplasia and /or increase in number of blasts, and can progress to acute myeloid leukemia. The pathogenesis of MDS is exceedingly complex and involves the hematopoietic stem cells, bone marrow microenvironment and an interaction between these two compartments. The laboratory diagnostic strategy in MDS has evolved significantly over the years from a purely morphological one based almost exclusively on peripheral blood smear and bone marrow aspirate cytology to the integrated multiparametric approach used in the 2001 and 2008 WHO classification schemes. An evolution has also occurred in the prognostic assessment and the evaluation of treatment response to include novel disease related factors as well as patient specific characteristics such as non-hematologic comorbidities. This progress in clinically relevant subclassification of MDS and inclusion of specific variables related to treatment response are particularly important considering the increasing treatment options available for MDS. This review is largely focused on the diagnostic approach to MDS including discussion of the significance of cytogenetic/genetic and immunophenotypic features. We present the overview of the minimal diagnostic criteria for diagnosing MDS and a detailed description the current World Health Organization (WHO) classification scheme.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic neoplasms characterized by ineffective hematopoiesis and a risk for progression to acute myeloid leukemia. A number of cytogenetic changes have been described that are characteristic to MDS and of clinical relevance; the specific gene targets of these alterations were largely unknown. On the other hand, over the past decade, technologies have been dramatically improved to enable high-throughput analysis of entire MDS genomes, leading to identification of frequent copy number neutral events and a number of novel gene targets implicated in the pathogenesis of MDS. In this review, we briefly overview the recent progress in the genetics of MDS, focusing on the newly identified gene targets in MDS.

MicroRNAs (miRNAs) are significant regulators of human hematopoietic stem cells (HSC), and their deregulation contributes to hematological malignancies. Myelodysplastic syndromes (MDS) represent a spectrum of hematological disorders characterized by dysfunctional HSC, ineffective blood cell production, progressive marrow failure, and an increased risk of developing acute myeloid leukemia (AML). Although miRNAs have been primarily studied in AML, only recently have similar studies been performed on MDS. In this review, we describe the normal function and expression of miRNAs in human HSC, and describe mounting evidence that deregulation of miRNAs contributes to the pathogenesis of MDS.

In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, the most distinct of all the myelodysplastic syndromes. It is now recognized that p53 activation, caused by haploinsufficiency for the ribosomal gene RPS14 (mapping to the commonly deleted region), is the probable cause of the erythroid defect in the 5q- syndrome. A mouse model of the human 5q- syndrome has been generated by large-scale deletion of the Cd74-Nid67 interval (containing Rps14) and the crossing of these ‘5qmice’ with p53-deficient mice ameliorated the erythroid progenitor defect. Recent evidence suggests that haploinsufficiency of the microRNA genes miR-145 and miR-146a may contribute to the thrombocytosis seen in the 5q- syndrome. Emerging data shows that p53 mutation may play a role in disease progression.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases characterized by bone marrow failure, marrow dysplasia, and a tendency to evolve to acute leukemia. Pathophysiologically, low risk MDS are separated from the high risk category by an increased rate of apoptosis of the bone marrow cells which causes the morphological paradoxon of a peripheral cytopenia and hypercellular bone marrow known as ineffective hematopoesis. Laboratory findings and clinical evidence suggest that some patients with myelodysplastic syndrome have immunologically mediated disease. MDS shares some of the features of acquired aplastic anemia and up to 30% of patients with MDS respond to immunosuppressive treatment. In the last decades, significant advances have been made in the diagnostic and prognostic classifications of myelodysplastic syndromes. While allogeneic transplantation still offers the only available option with a probability of cure in a minority of patients, the mainstay of therapy in low-risk patients remains supportive care, stimulation of ineffective hematopoiesis with growth factors, and immunomodulatory therapy. However, the correct selection of patients for the respective therapeutic intervention continues to be an enormous challenge as this will decide about the probability of therapeutic efficacy. This is important not only because of the high costs involved but also because of the possible side effects that can be difficult to manage. Here we review the pathophysiologic basis for the use of immunosuppressive agents in MDS and summarize the trials leading to the establishment of these therapy strategies in a subgroup of low-risk MDS patients.

Unprecedented progress continues to be made in the treatment strategies for the myelodysplastic syndromes (MDS). This review provides an introduction to DNA methyltransferase inhibitors. These agents include 5-azacytidine (azacitidine; AZA) and 5-aza-2'- deoxycytidine (decitabine; DAC). In particular, AZA was shown for the first time to significantly prolong the life expectancy of high-risk MDS patients in international multicenter clinical studies. The selection of responders and assessment of the long-term efficacy warrant further study.

Lenalidomide is a second generation immunomodulatory agent (IMiD), which currently represents the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndrome (MDS) patients with deletion (5q). Lenalidomide has unique activity with a high transfusion independence rate observed in this subset of patients. In this article we summarize the clinical experience using lenalidomide for treatment of del (5q) MDS. We highlight the mechanism of action and the recent advances in understanding the biology of del (5q) MDS. We also explore its potential use and the efforts to further improve its activity in non-del (5q) MDS.

Myelodysplastic syndromes (MDS) are a group of aquired hematopoietic disorders characterized by ineffective hematopoiesis, and increased risk of progression of acute myeloid leukemia. For a long period of time, the standard therapy for MDS was hematopoietic stem cell transplantation, however DNA methyltransferase inhibitors (DNMT inhibitors) including decitabine (DAC) and azacitidine (AZA), and lenalidomide, a derivative of thalidomide have been highlighted as new chemotherapeutic agents for MDS. However, the underlying mechanisms of action of these drugs have not been fully defined yet. Therefore, we investigated the in vitro effects of DNMT inhibitors and lenalidomide on an MDS-derived cell line, MDS92 and its blastic subline MDS-L, both of which carry del(5q). MDS-L cells were found to be quite sensitive to DAC, which induced to cell death through DNA damage-mediated G2 arrest via p53- independent pathways. Gene expression profiling suggested that DAC affects biogroups representing hematological systems, cellular development, cell death and apoptosis. Next, we examined the effects of lenalidomide on MDS-L. Cell growth was inhibited and multinucleated cells were frequently formed prior to cell death by lenalidomide treatment. Time-lapse microscopic observation and DNA ploidy analysis revealed that lenalidomide does not affect DNA synthesis itself but inhibits cytokinesis of MDS-L cells. The gene expression profiling showed decreased expression of M phase-related genes. These data contribute to the understanding of action mechanisms of lenalidomide on MDS with del(5q).

Hematopoietic cell transplantation (HCT) offers potentially curative therapy for patients with myelodysplastic syndromes (MDS). However, as most patients with MDS are in the 7th or 8th decade of life, only few of these were transplanted in the past, using high-dose conditioning regimens. The development of reduced-intensity conditioning has allowed to offer HCT also to older patients and those with clinically relevant comorbid conditions. Dependent upon disease status and the type of clonal chromosomal abnormalities present at the time of HCT, some 25%-75% of patients will be cured of their disease and survive long-term. Recent results with HLA matched unrelated donors are comparable to those with HLA genotypically identical siblings. The increasing use of cord blood and HLA haploidentical donors is expected to make HCT available to a growing number of patients. However, post-transplant relapse and graftversus- host disease remain problems requiring further investigation.

The majority of patients with myelodysplastic syndromes (MDS) become transfusion-dependent during the course of disease and may thus develop transfusional iron overload. As a further contributor to iron overload there is increased absorption of dietary iron from the gut, as a consequence of ineffective erythropoiesis. Compared with thalassemia, it is less clear how frequent patients with MDS develop clinical complications of iron overload, and whether the accumulation of iron shortens their survival. This review aims to summarize our current knowledge of the detrimental effects of transfusional iron overload in MDS, point out the risks associated with ironinduced oxidative stress, describe the tools available for diagnosing iron overload, indicate the treatment options with currently available iron chelators, and discuss the measurement of labile plasma iron (LPI) as a tool to monitor the efficacy of iron chelation therapy.

This paper will summarize the clinical features of transfusion-related acute lung injury (TRALI) before the experimental and clinical literature on the pathogenesis of TRALI is reviewed. Several mechanisms by which leukocyte antibodies induce TRALI have been unraveled. Significant advances have also been made in the field of recipient-related factors that contribute to the development of TRALI. In contrast, the pathomechanism behind non-immune TRALI (associated with the transfusion of blood components which do not contain antibodies) is less well understood, especially since the relevance of mechanisms proposed earlier is questioned by recent findings. The diversity of newly described factors contributing to TRALI supports the previously proposed threshold model of TRALI, and an extension of that model including newly defined multipliers and attenuators of TRALI is emerging.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion related morbidity and mortality. Immunemediated TRALI is caused by leucocyte and neutrophil antibodies in the transfused blood products that react with white blood cell antigens of the recipient, hereby inducing endothelial damage and lung injury. About two thirds of TRALI cases are thought to be immunemediated. Both Human Leucocyte Antibodies (HLA Class I and II) and Human Neutrophil Antibodies (HNA) are involved in TRALI. Most antibodies result from allo-exposure of the blood donor, with multiparous donors having the highest incidence of antibodies. Detection of anti-leucocyte and anti-neutrophil antibodies is complex and many uncertainties still exist regarding the interpretation of the test results. In this review we discuss the evidence and effectiveness of measurements to prevent immune-mediated TRALI from a bloodbank and bedside perspective. From a bloodbank perspective various preventive measures have been implicated. In some countries bloodbanks have successfully implemented donor selection strategies, ranging from testing of allo-exposed donors for leucocyte antibodies to the exclusion of all females from donating high plasma volume products. Another strategy involves dilution of antibodies present by pooling of plasma donations of multiple donors. From a bedside view, the most important measure to prevent TRALI is to limit patients' exposure to allogenic bloodproducts. Furthermore recognition and awareness of the syndrome need to be heightened among clinicians.

Transfusion-related acute lung injury (TRALI) is a severe form of pulmonary insufficiency induced by transfusion. TRALI is the leading cause of transfusion-related death, and is caused by the infusion of either anti-leukocyte antibodies in plasma containing blood products or neutrophil priming substances that accumulate during storage of cellular blood products. Among these neutrophil priming substances are bioactive lipids, such as lyso-phosphatidylcholines (lysoPCs) and arachidonic acid, soluble CD40L (sCD40L) and possibly other, as yet unidentified substances. The accumulation of these substances during cellular blood product storage and their role in the induction of “non-immune mediated” TRALI pathogenesis are highly relevant for the current debate of the use of longer vs. shorter stored blood products. In this review, the accumulation of these different substances during storage, as well as their mode of action in inducing TRALI are discussed. In addition, different improvements in current blood banking procedures to prevent TRALI due to these non-immune mediators will be proposed.

Priming of polymorphonuclear leukocytes (PMNs) enhances their adhesion to endothelium, the release of their granule content and their production of reactive oxygen species. These effects are etiological in transfusion related acute lung injury (TRALI) and many clinically important mediators of TRALI prime PMNs. A priming activity that develops over time in stored blood products has been shown to be due to the accumulation of lysophospatidylcholines (lyso-PCs) and has been found to be related clinically to TRALI. Lyso- PCs prime PMNs activating the G2A receptor and several inhibitors of this receptor, which could potentially be therapeutic in TRALI, have been identified. Recent work has described early steps in the signaling from the G2A receptor which has revealed potential targets for novel antagonists of lyso-PC mediated priming via G2A. Additionally, characterization of the process by which lyso-PCs are generated in stored blood products could allow development of inhibitors and additive solutions to block their formation in the first place.

Transfusion-related acute lung injury (TRALI) is a major cause of morbidity and mortality in transfused hosts and like other causes of acute lung injury, there is no effective pharmacologic treatment. The pathophysiology of TRALI is still being defined, but neutrophils have a major role in the pathogenesis of both human and experimental studies. Recently, MHC antibody-based experimental TRALI models have revealed that platelets sequester in the lung microvasculature and that platelet activation contributes to lung injury. Platelets, in general, have been increasingly implicated as major contributors to acute inflammation and injury in a variety of diseases. The role of platelets in TRALI may be through critical interactions with neutrophils and therapeutically this could present a target for pharmacologic intervention. Experimentally, aspirin pre-treatment of mice before TRALI is protective from acute lung injury and mortality. Other therapeutic interventions could include agents that uncouple neutrophils and platelets or prevent aggregation and activation, however targeting platelet activation in TRALI is complicated by the presence of bleeding as the indication for many transfusions. In conclusion, experimental studies are elucidating the role of platelets in acute lung injury and with this new understanding, clinical trials of anti-platelet agents should be considered.

Transfusion-related acute lung injury (TRALI) is a subcategory of acute lung injury (ALI). As such, there are many similarities between the syndromes, both clinically and pathophysiologically. Pulmonary changes in fibrin turnover have emerged as a hallmark of ALI, thereby initiating studies investigating the potential of therapeutic interventions aimed at ameliorating this so-called pulmonary coagulopathy. Enhanced coagulation and impaired fibrinolysis are probably also important features of TRALI. In particular, platelets play an important role in mediating injury during a TRALI reaction. In this narrative review, the evidence of the role of coagulopathy and platelet activation in TRALI is discussed. Given that host risk factors for acquiring TRALI have been identified and that there is a time frame in which a preventive strategy in patients at risk for TRALI can be executed, preventive strategies are suggested. In this review, we discuss potential preventive anticoagulant interventions.

Transfusion-Related Acute Lung Injury (TRALI) is the leading cause of transfusion-related mortality in most developed countries. Despite this fact, well-designed investigations on specific management strategies for TRALI are lacking. Indeed, current recommendations are primarily based on data extrapolated from trials of the histo-pathologically similar Acute Lung Injury and Acute Respiratory Distress Syndromes. The cornerstone of TRALI management is supportive care with oxygen supplementation and ventilatory assistance when needed. When mechanical ventilation is required, attenuating additional ventilator-induced lung injury through the avoidance of high tidal volumes and elevated airway pressures, with additional measures such as positive end-expiratory pressure to prevent lowvolume shear stress injury, are recommended. The literature is not currently sufficient to support either corticosteroids or statins as effective therapies in TRALI. Conservative fluid practices are desirable, provided care is taken to avoid hypotension. Preventative strategies have shown the most promise in mitigating this transfusion-related pulmonary complication. Specifically, conservative transfusion practices and deferral of high-plasma component donors who have, or at high risk of having, anti-human leukocyte antigen and/or anti-human neutrophil antigen antibodies have meaningfully impacted the incidence of TRALI. Future considerations for patients who are at increased risk for developing TRALI may include therapies such as anti-platelet agents and alternatives to traditional blood components such as prothrombin complex concentrates (PCC). However, these potential TRALI prevention strategies are insufficiently studied, have unclear risk/benefit profiles and cannot be currently recommended.

Transfusion-related acute lung injury (TRALI) has been the leading cause of transfusion-associated death for nearly a decade. Recent TRALI mitigation strategies focused on reduction of leukocyte antibodies in high volume plasma products appear to be successful in reducing TRALI events and deaths, but additional preventive measures are needed. Future possibilities include, screening of donors for neutrophil antibodies, processing of blood products to reduce or remove biologic response modifiers, and the more judicious use of blood. There are currently no specific TRALI therapies. The pathogenesis of TRALI and acute lung injury-acute respiratory distress syndrome (ALI-ARDS) is quite similar; both involving interactions of activated platelets, neutrophils, and pulmonary endothelium resulting in lung damage, capillary leak, and pulmonary edema. Greater understanding of these interactions and the key molecules involved will lead to development of potential new targets for therapy. In this review, future possible preventive measures to further reduce the occurrence of TRALI will be discussed, including TRALI caused by biologic response modifiers (BRMs), like bioactive lipids and sCD40L, which are not addressed by current preventive actions that only target leukocyte antibodies in high-volume plasma products. Insights already gained from studies of ALI-ARDS treatments will be summarized and discussed as possible therapeutic targets for treatment of patients experiencing TRALI.