Definition
Historically, the myelodysplastic syndromes (MDS) have been referred to as oligoblastic leukemia, refractory anemia, smoldering acute leukemia, or preleukemia. They represent a group of heterogeneous hematopoietic disorders derived from an abnormal multipotent progenitor cell, characterized by ineffective hematopoiesis, bone marrow failure, peripheral blood cytopenias, and reduced survival. MDS may be classified as indolent or aggressive (lower- or higher-risk), depending on life expectancy and likelihood of progression to acute myeloid leukemia (AML).
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Prevalence and Risk Factors
The precise incidence rate of MDS in the United States is still evolving. This may be in part due to the difficulty of defining MDS in the setting of changing classification systems. However, most studies report that MDS affects between 12,000 and 20,000 people in the United States each year. Surveillance, Epidemiology and End Results (SEER) and North American Association of Central Cancer Registries, Inc. (NAACCR) data report an incidence rate of 4.5 per 100,000 people in 2006. In general, MDS is a disease of older adults, with a median age at diagnosis of approximately 71 years with a male predominance. With the exception of treatment-induced MDS (MDS that develops following chemotherapy or radiation treatment for another cancer), age of onset prior to 50 is uncommon.
Risk factors for developing MDS include the following:
Age: Population studies in England have found that the crude yearly incidence rate increases from 0.5 per 100,000 people younger than 50 years to 89 per 100,000 people older than 80 years.
Genetic predisposition: Familial syndromes have been reported but are rare. Congenital syndromes that put a patient at risk for MDS include Down's syndrome, Fanconi Anemia, Dyskeratosis Congentia, Schwachman Diamond, and neurofibromatosis.
Environmental exposure: This includes particularly benzene and possibly other industrial solvents.
Prior therapy, including radiation treatment, alkylating agents (e.g., chlorambucil, cyclophosphamide, melphalan), and other chemotherapy agents.
For alkylating agents, the risk of developing a secondary MDS or AML starts with the end of therapy and peaks at four years, with a plateau at ten years.
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Pathophysiology and Natural History
In MDS, the hematopoietic stem cells that define the disease are clonally derived. Generally, MDS can be divided into two major subtypes–indolent (or lower-risk) MDS, in which pro-apoptotic, pro-inflammatory, and bone marrow microenvironment forces predominate, and aggressive (or higher-risk) MDS, in which proproliferative factors are more common. In indolent MDS, inhibitory cytokines, including tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β (TGF-β), and Fas ligand promote apoptosis. As genetic lesions accumulate, indolent MDS becomes proliferative MDS and eventually AML. This occurs as oncogenes are activated and tumor suppressor genes are inactivated. In the proliferative categories, ras, FMS, and p53 mutations are more common than inhibitory cytokines, and are believed to facilitate the transformation to AML. In general, bone marrow stem cells in MDS are less responsive to and produce fewer hematopoietic growth factors, including IL-3, IL-6, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. Peripheral blood cytopenias result from this process. Thus, there is the paradox of having a hypercellular bone marrow in patients requiring blood transfusions.
Cytogenetic abnormalities are found in approximately 50% of MDS patients using conventional karyotyping techniques, and in up to 80% using single nucleotide polymorphism array technology. Typically, trisomy 8 and monosomy 5 or 7 will be present. Findings of these abnormalities in patients with frank AML indicate probable evolution (which may be subclinical) from an antecedent MDS, which confers a worse prognosis. Therapy-related MDS can be associated with these same abnormalities in addition to translocations or rearrangements involving 11q23 or 21q22. Favorable abnormalities include del(5q), del(20q), -Y, or normal cytogenetics, whereas unfavorable abnormalities are found with complex cytogenetics (three or more cytogenetic abnormalities) or chromosome 7 abnormalities.
Deficiencies in hematopoiesis lead to cytopenias, which may be severe. Not surprisingly, morbidity and mortality result from anemia, bleeding, and infection, along with transformation to AML, which occurs in approximately one-third of patients.
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Signs and Symptoms
Recognition of this entity has increased over the past decade, and should be suspected in older adults with anemia, thrombocytopenia, leukopenia, or a combination of these abnormalities. MDS often manifests as a refractory cytopenia in an older adult who may be entirely asymptomatic. A macrocytic or normocytic anemia is found in almost all MDS patients, and frequently is accompanied by thrombocytopenia, leukopenia, or both. Typical symptoms reflect underlying cytopenias—patients with anemia frequently complain of fatigue, shortness of breath, loss of appetite, and even exacerbation of underlying cardiac symptoms; patients with thrombocytopenia may have spontaneous bruising, the appearance of petechiae (particularly in dependent areas, such as the shins, or in areas exposed to minor trauma, such as skin under elastic waistbands), or bleeding of mucosal surfaces (including the gums when brushing teeth); and patients with leukopenia may have recurrent infections, particularly of the skin, mucosal surfaces (especially the oral and rectal mucosa), and lungs.
MDS can be associated with paraneoplastic syndromes related to autoimmune processes, particularly when MDS overlaps with myeloproliferative neoplasms (such as chronic myelomonocytic leukemia, often associated with splenomegaly). These may be dermatologic (e.g., psoriasis or Sweet’s syndrome), rheumatologic (e.g., vasculitis), hematologic (e.g., hemolytic anemia or Glanzmann’s disease [an acquired glycoprotein IIB/IIIA inhibition resulting in abnormal platelet function]), or endocrinologic (e.g., hypothyroidism, diabetes insipidus). Cytokine release (see earlier, “Pathophysiology and Natural History”) may result in constitutional symptoms, such as anorexia, weight loss, and even low-grade fevers. Splenomegaly, seen in overlap disorders, may be associated with left upper quadrant pain.
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Diagnosis
MDS is diagnosed through a combination of abnormal findings in the peripheral blood and bone marrow. Morphologic abnormalities should be present in at least 10% of cells in a given lineage. In the peripheral blood, erythrocytes may be macrocytic, nucleated, or stippled, whereas neutrophils may be hyposegmented, hypogranular, or bilobed, with chromatin condensation (pseudo Pelger-Huët cells). In the bone marrow, erythrocyte precursors may have megaloblastoid changes, contain ringed sideroblasts, or include Howell-Jolly bodies. Myeloid maturation may be stunted, and megakaryocytes can be dysplastic.
Subtypes of MDS are defined using one of two classification systems. The French-American-British (FAB) system has been used widely since 1982 and is useful in predicting rates of survival and transformation to AML (Table 1). In the FAB system, MDS is divided into refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia, now considered an overlap syndrome that can include features of a myelodysplastic syndrome, myeloproliferative neoplasm, or both.
Table 1: French-American-British (FAB) Myelodysplastic Syndrome (MDS) Classification System
MDS Subtype Peripheral Blasts (%) Bone Marrow Blasts (%) AML Transformation Median Survival (months) MDS Diagnoses (%)
Refractory anemia (RA) ≤1 <5 10-20 30-65 10-40
Refractory anemia with ringed sideroblasts (RARS) ≤1 <5 10-35 34-83 10-35
Refractory anemia with excess blasts (RAEB) <5 5-20 >50 8-18 25-30
Refractory anemia with excess blasts in transformation (RAEB-T) ≥5 21-29 60-100 4-11 10-30
Chronic myelomonocytic leukemia (CMML) <5 ≤20 >40 15-32 10-20
AML, acute myelogenous leukemia.
Data from Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51:189–199.
In 1999, the World Health Organization (WHO) published its classification of hematopoietic and lymphoid neoplasms, and in 2002 published a clarification and rationale for differences between the FAB and WHO classifications (Table 2). The most important difference was the lowering of the blast threshold for the diagnosis of AML, from 30% to 20% blasts in the blood or bone marrow. Chronic myelomonocytic leukemia was also formally separated from the myelodysplastic syndromes, and a cytogenetically defined MDS subgroup, patients with an isolated del(5q) abnormality—which confers a good prognosis, is associated with normal or elevated platelet counts, and is found in 5% to 13% of patients—was identified. The WHO system was revised again in 2009, the most important changes being the recognition of patients with refractory cytopenia with unilineage dysplasia (which included refractory anemia, neutropenia, or thrombocytopenia) and refractory cytopenia with multilineage dysplasia (in which two or more cell lines are involved).