Old Dogs, New Tricks: Revisiting Immune Modulatory Approaches for Myelodysplastic Syndromes

Götze, Katharina; Platzbecker, Uwe

doi:10.1097/hs9.0000000000000162

Cited by 6 publications

(11 citation statements)

References 57 publications

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“…MDS is associated with immune dysregulation and an increased release of inflammatory cytokines, including tumor-necrosis factor alpha, interferon-gamma, transforming growth factor-ß, and interleukins (e.g., IL-6, IL-10), which are expressed by mesenchymal stromal cells, hematopoietic cells, and T cells in the bone marrow microenvironment [ 29 , 30 ]. Mesenchymal stromal cells are critical for the regulation of hematopoietic stem and progenitor cells, aiding in the reinforcement of clonal dominance of MDS cells, and additionally suppress T-cell proliferation and activation [ 30 ]. MDS is also associated with an increase in myeloid-derived suppressor cells (MDSCs), which mediate a pro-inflammatory response and potently suppress T-cell function [ 29 , 30 ].…”

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

“…Mesenchymal stromal cells are critical for the regulation of hematopoietic stem and progenitor cells, aiding in the reinforcement of clonal dominance of MDS cells, and additionally suppress T-cell proliferation and activation [ 30 ]. MDS is also associated with an increase in myeloid-derived suppressor cells (MDSCs), which mediate a pro-inflammatory response and potently suppress T-cell function [ 29 , 30 ]. MDSCs are activated through the binding of S100A8 and S100A9 to toll-like receptor (TLR)-4 and CD33 and contribute to innate immune activation.…”

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

“…The expression of the secretion of S100A8 and S100A9 by activated MDSCs results in autocrine and paracrine stimulation, with downstream activation of the NLRP3 pattern recognition receptor and subsequent inflammasome assembly and pyroptosis. In MDS patients who have a del(5q) phenotype, the induction of S100A8 and S100A9 also leads to a p53-dependent defect in erythroblast differentiation [ 29 , 30 ]. In addition to the pro-inflammatory state and innate immune activation seen in MDS, adaptive immune cell function is also impaired.…”

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

“…Regulatory T-cell counts are decreased in the peripheral blood of patients with low-risk MDS but undergo expansion in patients with higher-risk MDS, indicating progressive immunosuppression with advancing disease. Cytotoxic CD8 + T-cell and natural killer cell counts are increased in MDS patients compared to healthy individuals [ 30 ].…”

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

“…While some patients with low-risk MDS respond well to immunosuppressive therapy with ATG or lenalidomide, more recent efforts are focused on modulation of the innate immune system and pro-inflammatory phenotype. The expression of TLRs is upregulated in the bone marrow of MDS patients and TLR signaling by MDSCs is integral to the pro-inflammatory microenvironment in MDS, and there has thus been some interest in employing therapies that target TLR signaling [ 30 ]. In addition, MDSCs express high levels of CD33, and therapies directed against CD33 to deplete MDSC counts in the bone marrow are in development, including both a monoclonal antibody against CD33 (BI 836858) that has been evaluated in preclinical models [ 84 ] and a novel bispecific tetravalent antibody against CD33 and CD3 (AMV564) that is being evaluated in a phase 1 study in patients with intermediate- or high-risk MDS after HMA failure (NCT03516591 [ 85 ]).…”

Section: Therapeutic Approaches For Mdsmentioning

confidence: 99%

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Current challenges and unmet medical needs in myelodysplastic syndromes

et al. 2021

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Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.

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Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

Section: Pathophysiology and Diagnosis Of Mdsmentioning

confidence: 99%

Section: Therapeutic Approaches For Mdsmentioning

confidence: 99%

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Current challenges and unmet medical needs in myelodysplastic syndromes

et al. 2021

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Acquired Pure Red Cell Aplasia Associated with Chronic Myelomonocytic Leukemia: Too Many of One, Not Enough of the Other

Gonsalves¹,

Bazargan²,

Ku³

2020

Case Rep Oncol

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There is a growing body of literature outlining the association between certain hematological malignancies, such as chronic myelomonocytic leukemia (CMML), and systemic autoimmune diseases. Diagnosis and management can be difficult, particularly when autoimmune phenomena overlap with features of the underlying illness. This is especially the case in patients who develop immune-mediated cytopenias in the context of underlying bone marrow disease. CMML associated with immune thrombocytopenia and hemolytic anemia has been reported a number of times in the literature; however, there are only scattered case reports describing CMML associated with acquired pure red cell aplasia. Here, we describe the diagnostic and management approach to a patient who developed both diseases.

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Treatment of MDS

Platzbecker

2019

Blood

186

201

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The heterogeneous nature of myelodysplastic syndromes (MDS) demands a complex and personalized variety of therapeutic approaches. Among them, allogeneic hematopoietic stem cell transplantation remains the only potentially curative option and is accessible to only a small number of fit patients. For the majority of patients with MDS, treatment strategies are nonintensive and risk-adapted (by the revised version of the International Prognostic Scoring System), ranging from iron chelation and growth factors to lenalidomide and hypomethylating agents. These approaches are noncurative and aimed instead at improving cytopenias and quality of life and delaying disease progression. These limitations underpin the need for more translational research-based clinical trials in well-defined subgroups of patients with MDS. Indeed, much progress has been made over the past decade in understanding the complex molecular mechanisms underlying MDS. Unfortunately, this has not yet translated into approval of novel treatment options. There is a particularly urgent medical need in patients failing current first-line therapies, such as with erythropoiesis-stimulating or hypomethylating agents. Nevertheless, actual developments are expected to pave the way for exciting novel therapeutic opportunities. This review provides an overview of the current therapeutic landscape in MDS focusing on recent advances in clinical and translational research.

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Old Dogs, New Tricks: Revisiting Immune Modulatory Approaches for Myelodysplastic Syndromes

Cited by 6 publications

References 57 publications

Current challenges and unmet medical needs in myelodysplastic syndromes

Current challenges and unmet medical needs in myelodysplastic syndromes

Acquired Pure Red Cell Aplasia Associated with Chronic Myelomonocytic Leukemia: Too Many of One, Not Enough of the Other

Treatment of MDS

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