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| {{Infobox_Disease |
| | __NOTOC__ |
| Name = {{PAGENAME}} |
| | '''For patient information, click [[Myelodysplastic syndrome (patient information)|here]]''' |
| Image = |
| | {{Myelodysplastic syndrome}} |
| Caption = |
| | {{CMG}}; {{AE}} {{NM}} {{ADS}} |
| DiseasesDB = 8604|
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| ICD10 = {{ICD10|D|46||d|37}} |
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| ICD9 = {{ICD9|238.7}} |
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| ICDO = 9980/0-9989/3 |
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| OMIM = |
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| MedlinePlus = |
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| eMedicineSubj = med |
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| eMedicineTopic = 2695 |
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| eMedicine_mult = {{eMedicine2|ped|1527}} |
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| MeshID = D009190 |
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| }}
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| {{SI}} | |
| {{CMG}} | |
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| {{Editor Help}} | | {{SK}} Preleukemia syndrome; dysmyelopoietic syndrome; myelodysplasia; refractory anaemia; refractory anemia |
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| ==Overview== | | ==[[Myelodysplastic syndrome overview|Overview]]== |
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| The '''myelodysplastic syndromes''' (MDS, formerly known as "preleukemia") are a diverse collection of [[hematology|hematological]] conditions united by ineffective production of blood cells and varying risks of transformation to [[acute myelogenous leukemia]]. [[Anemia]] requiring chronic [[blood transfusion]] is frequently present. Although not truly [[cancer|malignant]], MDS is nevertheless classified within the [[Hematological malignancy|haematological neoplasms]].
| | ==[[Myelodysplastic syndrome historical perspective|Historical Perspective]]== |
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| Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.
| | ==[[Myelodysplastic syndrome classification|Classification]]== |
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| == Signs and symptoms == | | ==[[Myelodysplastic syndrome pathophysiology|Pathophysiology]]== |
| Abnormalities include:
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| * [[neutropenia]], [[anemia]] and [[thrombocytopenia]] (low cell counts of white and red blood cells, and platelets, respectively)
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| * abnormal granules in cells, abnormal nuclear shape and size
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| * [[chromosome|chromosomal]] abnormalities, including [[chromosomal translocation]]s and abnormal chromosome number.
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| Symptoms of myelodysplastic conditions:
| | ==[[Myelodysplastic syndrome causes|Causes]]== |
| * [[Anemia]]—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
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| * [[Neutropenia]] (low neutrophil count) —increased susceptibility to [[infection]]
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| * [[Thrombocytopenia]] (low platelet count) —increased susceptibility to [[bleeding]]
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| Although there is some risk for developing [[acute myelogenous leukemia]], about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.
| | ==[[Myelodysplastic syndrome differential diagnosis|Differentiating Myelodysplastic syndrome from other Diseases]]== |
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| ==Diagnosis== | | ==[[Myelodysplastic syndrome epidemiology and demographics|Epidemiology & Demographics]]== |
| Investigation:
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| * [[Full blood count]] and examination of [[blood film]]
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| * [[Bone marrow examination]] by an experienced [[hematopathologist]]
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| * [[Cytogenetics]] or chromosomal studies. This is performed on the bone marrow aspirate.
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| ==Diagnosistic Workup==
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| The differential diagnosis is that of [[anemia]], [[thrombocytopenia]], and/or [[leukopenia]]. Usually, the elimination of known [[etiologies]] of [[cytopenias]], along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.
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| Investigation:
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| * [[Full blood count]] and examination of [[blood film]]. The [[blood film]] morphology can provide clues about [[hemolytic anemia]], clumping of the [[platelets]] leading to spurious [[thrombocytopenia]], or [[leukemia]].
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| * Blood tests to eliminate other common causes of [[cytopenias]], such as [[lupus]], [[hepatitis]], [[B12]], [[folate]], or other [[vitamin]] deficiencies, [[renal failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]. Age-appropriate cancer screening should be considered for all [[anemic]] patients.
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| * [[Bone marrow examination]] by an experienced [[hematopathologist]]. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
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| * [[Cytogenetics]] or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter [[metaphase]] to enhance [[chromosomal]] staining.
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| * [[Flow cytometry]] is helpful to establish the presence of any [[lymphoproliferative]] disorder in the [[marrow]]
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| ==Genetics== | |
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| {| class="wikitable"
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| |-
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| ! Abnormality
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| ! Frequency in MDS
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| |-
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| | -5/del(5q)
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| | 10-20%
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| |-
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| | +8
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| | 10%
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| |-
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| | -7/del(7q)
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| | 5-10%
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| |-
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| | -Y
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| |10%
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| |-
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| | 17p-
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| | 7%
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| |-
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| | del(20q)
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| | 5-6%
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| |-
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| | t(11q23)
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| | 5-6%
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| |-
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| | complex karyotype
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| | 10-20%
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| |}
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| Overall, the mutations in the RUNX1/AML1 are the most common point mutations described in MDS to date but RUNX1/AML1 mutations have no distinct hematologic phenotype and are most commonly associated with previous radiation exposure and with a higher risk disease (especially with excess blasts).
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| Hypermethylation leading to silencing of the p151NK-4b gene is also common in MDS. This phenomenon occurs in up to 80% of the cases with advanced MDS. The silencing of this gene can be reversed by the uyse of demethylating agents such as 5-azacytidine. These agents are pyrimidine analogues that inhibit DNA methyltransferase activity and could improve MDS hematopoiesis by reversing aberrant gene methylation and permitting cellular differentiation.
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| A number of studies suggest that erythropoietin (EPO) signaling and STAT5 activation is abnormal in MDS. The SOCS1 gene is hypermethylated in 31% of MDS patients which is associated with increased activity of the JAK/STAT pathway.
| | ==[[Myelodysplastic syndrome risk factors|Risk Factors]]== |
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| Microsatellite instability involving defects in the DNA mismatch repair system has been identified in some MDS patients, especially those with therapy-related disease.
| | ==[[Myelodysplastic syndrome screening|Screening]]== |
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| The TP53 tumor suppressor gene, which regulates cell cycle progression, DNA repair and apoptosis is mutated in 5-10% of MDS cases. Inactivation of the TP53 gene may contribute to the leukemic progression from MDS.
| | ==[[Myelodysplastic syndrome natural history, complications and prognosis|Natural History, Complications & Prognosis]]== |
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| ==Pathophysiology==
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| MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]]. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).
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| While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).
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| The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]]. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].
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| Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>
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| ==Types and classification==
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| ===French-American-British (FAB) classification===
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| In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This [[French-American-British classification | French-American-British (FAB) classification]] was published in 1976 and revised in 1982. Cases were classified into 5 categories: ([[ICD-O]] codes are provided where available)
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| * ({{ICDO|9980|3}}) '''Refractory [[anemia]]''' (RA) - characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
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| * ({{ICDO|9982|3}}) '''Refractory anemia with ringed sideroblasts''' (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
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| * ({{ICDO|9983|3}}) '''Refractory anemia with excess blasts''' (RAEB) - characterized by 5-19% myeloblasts in the marrow;
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| * ({{ICDO|9984|3}}) '''Refractory anemia with excess blasts in transformation''' (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
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| * ({{ICDO|9945|3}}) '''Chronic myelomonocytic leukemia''' (CMML) - not to be confused with [[chronic myelogenous leukemia]] or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 10<sup>9</sup>/uL monocytes (a type of white blood cell) circulating in the peripheral blood.
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| A table comparing these is available from the [http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm Cleveland Clinic].
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| The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.
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| The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.
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| ===WHO classification===
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| In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.
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| One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.
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| The list of dysplastic syndromes under the new WHO system includes:
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| # Refractory anemia (RA)
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| # Refractory anemia with ringed sideroblasts (RARS)
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| # Refractory cytopenia with multilineage dysplasia (RCMD)
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| # Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
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| # Refractory anemia with excess blasts I and II
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| # [[5q- syndrome]]
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| # Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)
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| RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).
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| 5q- syndrome, typically seen in older women was added to the classification. The diagnosis of 5q minus syndrome requires that 5q minus MUST be an isolated abnormality. Clinical manifestations include a tendency towards a hypercellular bone marrow, macrocytosis/RA, normal or high platelet counts and hypolobulated megakaryocytes. It carries a good prognosis, with a median survival > 5 years, a low risk of AML and a benign course. 14(RPS4) is the underlying genetic defect of 5q minus syndrome. Haploinsufficiency of the ribosomal gene 14(RPS4)occurs here; it is required for the maturation of the 40s ribosomal subunit and it maps to the deleted region on 5q minus. 67% of patients with 5q minus achieve transfusion independence with the administration of Lenalidomide. Lenalidomide in 5q minus causes a response by decreasing Cdc25c and PP2A mRNA expression. Lenalidomide has such high clinical activity for this type of MDS that it is almost comparable to teh track record of imatinib in CML.
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| CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.
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| ==Diagnosis== | | ==Diagnosis== |
| | [[Myelodysplastic syndrome history and symptoms|History and Symptoms]] | [[Myelodysplastic syndrome physical examination|Physical Examination]] | [[Myelodysplastic syndrome laboratory findings|Laboratory Findings]] | [[Myelodysplastic syndrome electrocardiogram|Electrocardiogram]] | [[Myelodysplastic syndrome chest x ray|Chest X Ray]] | [[Myelodysplastic syndrome CT|CT]] | [[Myelodysplastic syndrome MRI|MRI]] | [[Myelodysplastic syndrome other imaging findings|Other Imaging Findings]] | [[Myelodysplastic syndrome other diagnostic studies|Other Diagnostic Studies]] |
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| Differential Diagnosis (for dysplasia)
| | ==Treatment== |
| * Arsenic, Lead, Benzene, Xylene, petroleum, Agent Orange (Vietnam Veterans).
| | [[Myelodysplastic syndrome medical therapy|Medical Therapy]] | [[Myelodysplastic syndrome surgery|Surgery]] | [[Myelodysplastic syndrome primary prevention|Primary Prevention]] | [[Myelodysplastic syndrome secondary prevention|Secondary Prevention]] | [[Myelodysplastic syndrome cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Myelodysplastic syndrome future or investigational therapies|Future or Investigational Therapies]] |
| * Congenital Dyserythropoietic anemia
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| * HIV
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| * Vitamin B12 / folate
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| * Parvovirus
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| * Alcohol abuse
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| * Prior chemotherapy (eg. melphalan, mustard, chlorambucil, busulfan, cyclophosphamide).
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| * Radiation (with or without chemotherapy).
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| Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
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| *Granulocytic series
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| *# Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
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| *# Hyposegmented neutrophils (Pseudo-Pelger Huet)
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| *# Hypogranular neutrophils or pseudo Chediak Higashi large granules
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| *# Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
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| * Erythroid series
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| *# Binucleated erythroid percursors and karyorrhexis
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| *# Erythroid nuclear budding
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| *# Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
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| *# PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
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| *# Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
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| * Megakaryocytic series (can be the most subjective)
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| *# Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
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| *# Hypersegmented (osteoclastic appearing) megakaryocytes
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| *# Ballooning of the platelets (seen with interference contrast microscopy)
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| Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.
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| MDS can appear a lot like megaloblastic anemia however megaloblastic anemia has cell lysis thereby causing an increase in the bilirubin and LDH whereas, in MDS, these aren't elevated.
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| On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells/(blasts) clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.
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| Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.
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| Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.
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| Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, [[vitamin]] deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, [[Sideroblastic anemia|Pearson's syndrome (sideroblastic anemia)]], Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.
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| All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood ([[red blood cell|red cell]]s, [[white blood cell|white cell]]s other than [[lymphocyte]]s and [[platelets]] or their progenitor cells, [[megakaryocyte]]s).
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| ==Epidemiology==
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| The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the [[United States]] alone. The incidence is probably increasing as the age of the population increases
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| ==Therapy==
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| The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to [[acute myelogenous leukemia]].
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| The IPSS scoring system can help triage patients for more aggressive treatment (i.e. [[bone marrow transplant]]) as well as help determine the best timing of this therapy.<ref>{{cite journal | author=Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J | volume=89 | issue=6 | id=PMID 9058730}}</ref> <ref>{{cite journal | author=Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title=A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. | journal=Blood | year=2004 | pages=579-85 | volume=104 | issue=2 | id=PMID 15039286}}</ref> Supportive care with blood product support and hematopoeitic growth factors (e.g. [[erythropoietin]]) is the mainstay of therapy. The regulatory environment for the use of [[erythropoietin]]s is evolving, according to a recent [[Medicare (United States)|US Medicare]] National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.<ref>{{cite web |url=http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203 |title=Centers for Medicare & Medicaid Services |accessdate=2007-10-29 |format= |work=}}</ref>
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| The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.
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| Survival and AML evolution score
| | ==Case Studies== |
| {| class="wikitable"
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| |-
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| ! Prognostic Variable
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| ! 0
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| ! 0.5
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| ! 1
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| ! 1.5
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| ! 2
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| |-
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| | Bone marrow blasts (%)
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| | <5
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| | 5-10
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| | X
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| | 11-20
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| | 21-30
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| |-
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| | Karyotype *
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| | good
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| | intermediate
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| | poor
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| | X
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| | X
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| |-
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| | Cytopenias **
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| | 0 or 1
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| | 2 or 3
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| | X
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| | X
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| | X
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| |}
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|
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| *Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.
| | [[Myelodysplastic syndrome case study one|Case #1]] |
| Intermediate = other abnormalities.
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| Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.
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| ** Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.
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| | | ==Related chapters== |
| {| class="wikitable"
| | *[[Myelodysplastic syndrome genetics]] |
| |-
| | *[[Myelodysplastic syndrome staging]] |
| ! IPSS Risk Category
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| ! Low
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| ! Intermediate 1
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| ! Intermediate 2
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| ! High
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| |-
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| | Combined score
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| | 0
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| | 0.5-1
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| | 1.5-2
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| | >/=2.5
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| |-
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| | AML evolution
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| | 19%
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| | 30%
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| | 33%
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| | 45%
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| |-
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| | Median time to AML (years)
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| | 9.4
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| | 3.3
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| | 1.1
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| | 0.2
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| |-
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| | Median survival (years)
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| | 5.7
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| | 3.5
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| | 1.2
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| | 0.4
| |
| |}
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| Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)
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| Since 2004 3 medications have been approved for MDS; 5-azacytidine and decitabine are hypomethylating agents, lenalidomide is immunomodulatory. Lenalidomide is especially useful in the treatment of 5q minus syndrome; for these patients the medication not only improves counts but it also has a high complete response rate in the bone marrow and a high remission rate for the chromosome. For non-5q deletion, low-risk MDS patients treatment options include lenalidomide and demethylating agents.
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| DNA-methyltransferase inhibitors; normally methylation of cytosine in gene promoters causes them to become silent; they would otherwise cause terminal differentiation. There is survival benefit with the hypomethylating agents (Decitabine & Azacitadine)in higher-risk disease (intermediate-2 or high risk disease).Azacitidine and Decitabine are different chemically and patients whose disease doesn't respond or becomes refractory to one may respond to the other. The recommendation is to proceed until progression; sometimes stopping allows the disease to relapse or it relapses as it is resistant disease. The major toxicities are nausea, vomiting, diarrhea, cytopenias and fatigue.
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| <ref name="pmid10694544">{{cite journal |author=Wijermans P, Lübbert M, Verhoef G, ''et al'' |title=Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients |journal=J. Clin. Oncol. |volume=18 |issue=5 |pages=956–62 |year=2000 |pmid=10694544 |doi=}}</ref><ref name="pmid11529854">{{cite journal |author=Lübbert M, Wijermans P, Kunzmann R, ''et al'' |title=Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine |journal=Br. J. Haematol. |volume=114 |issue=2 |pages=349–57 |year=2001 |pmid=11529854 |doi=}}</ref><ref name="pmid12011120">{{cite journal |author=Silverman LR, Demakos EP, Peterson BL, ''et al'' |title=Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B |journal=J. Clin. Oncol. |volume=20 |issue=10 |pages=2429–40 |year=2002 |pmid=12011120 |doi=}}</ref><ref name="pmid16921040">{{cite journal |author=Silverman LR, McKenzie DR, Peterson BL, ''et al'' |title=Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B |journal=J. Clin. Oncol. |volume=24 |issue=24 |pages=3895–903 |year=2006 |pmid=16921040 |doi=10.1200/JCO.2005.05.4346}}</ref>
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| <ref name="pmid17133405">{{cite journal |author=Kantarjian HM, O'Brien S, Shan J, ''et al'' |title=Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome |journal=Cancer |volume=109 |issue=2 |pages=265–73 |year=2007 |pmid=17133405 |doi=10.1002/cncr.22376}}</ref><ref name="pmid16532500">{{cite journal |author=Kantarjian H, Issa JP, Rosenfeld CS, ''et al'' |title=Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study |journal=Cancer |volume=106 |issue=8 |pages=1794–803 |year=2006 |pmid=16532500 |doi=10.1002/cncr.21792}}</ref><ref name="pmid16882708">{{cite journal |author=Kantarjian H, Oki Y, Garcia-Manero G, ''et al'' |title=Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia |journal=Blood |volume=109 |issue=1 |pages=52–7 |year=2007 |pmid=16882708 |doi=10.1182/blood-2006-05-021162}}</ref><ref name="pmid17679729">{{cite journal |author=Blum W, Klisovic RB, Hackanson B, ''et al'' |title=Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3884–91 |year=2007 |pmid=17679729 |doi=10.1200/JCO.2006.09.4169}}</ref>
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| IMiDS, such as Lenalidomide are for erythroid failure such as in transfusion-dependent del(5q). The response rate (~67%)is independent of the karyoptype. Treatment can give a positive cytopgenetic response, the patient becomes transfusion-free and would no longer require Erythropoietin. With treatment there is a transient decrease in the leukocytes and platelets. It has been known to be useful in paients without the 5q deletion with ~25% of patients experiencing a significant response in hemoglobin levels.
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| <ref name="pmid17021321">{{cite journal |author=List A, Dewald G, Bennett J, ''et al'' |title=Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion |journal=N. Engl. J. Med. |volume=355 |issue=14 |pages=1456–65 |year=2006 |pmid=17021321 |doi=10.1056/NEJMoa061292}}</ref>
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| <ref name="pmid16625140">{{cite journal |author= |title=Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome |journal=The Medical letter on drugs and therapeutics |volume=48 |issue=1232 |pages=31–2 |year=2006 |pmid=16625140 |doi=}}</ref>.
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| [[Stem cell transplantation]], particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.<ref>{{cite journal |author=Oosterveld M, Wittebol S, Lemmens W, Kiemeney B, Catik A, Muus P, Schattenberg A, de Witte T |title=The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups |journal=Br J Haematol |volume=123 |issue=1 |pages=81-9 |year=2003 |pmid=14510946}}</ref>
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| ==References==
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| {{Reflist|2}}
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| ==Additional Readings==
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| * Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. ''Proposals for the classification of the myelodysplastic syndromes.'' Br J Haematol 1982;51:189. PMID 6952920.
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| * Block M, Jacobson LO, Bethard WF. ''Preleukemic acute human leukemia.'' [[Journal of the American Medical Association|JAMA]] 1953;152:1018-28. PMID 13052490. | |
| * Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. ''World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.'' J Clin Oncol 1999;17:3835-49. PMID 10577857.
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| * Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
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| * Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
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| * Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.
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| * List A, Dewald G, Bennett J, Giagnounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Store R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R. "Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion." NEJM 2006;355(14):1456-1465. PMID 17021321.
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| * Fenaux P, Mufti GJ, Lindberg EH, Santini V, Finelli C, Giagounidis A, Schoch R, Gatterman N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrum J, Zimmerman JF, McKenzie D, Beach CL, Silverman LR. "Efficacy of Azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised open-label phase III study." Lancet Oncology 2009;10(3):223-232. PMID 19230772.
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| ==External links==
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| * ''[http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?rid=cmed.chapter.32804 Cancer Medicine]''. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
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| * [http://www.aamds.org Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families]
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| *[http://www.mds-foundation.org Website of MDS-Foundation with a lot of helpful materials]
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| * [http://www.mayoclinic.com/print/myelodysplastic-syndromes/DS00596/DSECTION=all&METHOD=print Myelodysplastic syndromes]. Comprehensive article from MayoClinic.com. | |
| * [http://www.virtualcancercentre.com/diseases.asp?did=68 Myelodysplastic syndrome (MDS)]. article from virtualcancercentre.com.
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| * [http://www.va.gov/vetapp04/files4/0434293.txt] Agent Orange and MDS, 100% service connected.
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| ==See also==
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| *[[Myeloproliferative syndrome]] | | *[[Myeloproliferative syndrome]] |
| *[[Acute myeloid leukemia]] | | *[[Acute myeloid leukemia]] |
| *[[Chloroma]] | | *[[Chloroma]] |
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| {{Hematology}}
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| {{Hematological malignancy histology}}
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| [[de:Myelodysplastisches Syndrom]] | | [[de:Myelodysplastisches Syndrom]] |
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