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Myelodysplastic syndromes: diagnosis, prognosis, and treatment.

ABSTRACT: BACKGROUND: Myelodysplastic syndromes (MDS) are malignant stem-cell diseases that are usually diagnosed in elderly patients who present with anemia or, less commonly, bi- or pancytopenia. Their incidence in persons over age 80 is above 50 new cases per 100,000 persons per year. Their clinical course is highly variable. About one-quarter of all patients with MDS develop acute leukemia. The median survival time from the moment of diagnosis is about 30 months. METHOD: We selectively searched the PubMed database for pertinent articles and guidelines from the years 2000-2013. We used the search term "myelodysplastic syndromes." RESULTS: MDS are diagnosed by cytology, with consideration of the degree of dysplasia and the percentage of blast cells in the blood and bone marrow, and on a cytogenetic basis, as recommended in the WHO classification. In particular, chromosomal analysis is necessary for prognostication. The Revised International Prognosis Scoring System (IPSS-R) enables more accurate prediction of the course of disease by dividing patients into a number of low- and high-risk groups. The median survival time ranges from a few months to many years. The approved treatments, aside from transfusion therapy, include iron depletion therapy for low-risk patients, lenalidomide for low-risk patients with a deletion on the long arm of chromosome 5, and 5-azacytidine for high-risk patients. High-risk patients up to age 70 who have no major accompanying illnesses should be offered allogenic stem-cell transplantation with curative intent. The cure rates range from 30% to 50%. Mucositis, hemorrhages, infections, and graft-versus-host diseases are the most common complications of this form of treatment. CONCLUSION: Myelodysplastic syndromes are treated on an individualized, risk-adapted basis after precise diagnostic evaluation and after assessment of the prognosis. More studies are needed so that stage-adapted treatment can be improved still further.

SUBMITTER: Germing U

PROVIDER: S-EPMC3855821 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Myelodysplastic syndromes: diagnosis, prognosis, and treatment.

Germing Ulrich U Kobbe Guido G Haas Rainer R Gattermann Norbert N

Deutsches Arzteblatt international 20131101 46

<h4>Background</h4>Myelodysplastic syndromes (MDS) are malignant stem-cell diseases that are usually diagnosed in elderly patients who present with anemia or, less commonly, bi- or pancytopenia. Their incidence in persons over age 80 is above 50 new cases per 100,000 persons per year. Their clinical course is highly variable. About one-quarter of all patients with MDS develop acute leukemia. The median survival time from the moment of diagnosis is about 30 months.<h4>Method</h4>We selectively se ...[more]

PMID: 24300826

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Project description:The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.

Project description:Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-?, TNF-? and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-? signaling has been therapeutically targeted by small molecule inhibitor of the TGF-? receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-? receptor kinase inhibition, members of TGF-? super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

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Myelodysplastic syndromes: diagnosis, prognosis, and treatment.

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Myelodysplastic syndromes: diagnosis, prognosis, and treatment.

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