Definition

Historically, disorders in the myelodysplastic syndrome (MDS) group have been referred to as oligoblastic leukemia, refractory anemia, smoldering acute leukemia, or preleukemia. They represent a collection of heterogeneous hematopoietic disorders derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis. MDS can be indolent or aggressive, depending on the subclassification (see later).

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Prevalence and risk factors

MDS is a disease of older adults, with more than 80% of patients older than 60 years. The precise incidence of new diagnoses has been difficult to define in the setting of changing classification systems and difficulty in establishing the diagnosis. In general, MDS affects between 12,000 and 20,000 people in the United States each year, or 22 to 45 per 100,000 people older than 70 years. The population prevalence is estimated to be between 30,000 and 40,000 people in the United States, with most of them having indolent (early) MDS, generally defined as fewer than 5% myeloblasts in the bone marrow. These numbers make it as prevalent as other common hematologic malignancies of older adults, such as multiple myeloma and chronic lymphocytic leukemia.

Risk factors for developing MDS include the following:

• Age: Population studies in England have found that the crude incidence 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.
• 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 (on a case report level).

For alkylating agents, the risk of developing a secondary MDS or acute myelogenous leukemia (AML) starts with the end of therapy and peaks at 4 years, with a plateau at 10 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 early) MDS, in which pro-apoptotic forces predominate, and aggressive (or advanced) 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 (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). 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 40% to 70% of primary and 80% to 90% of secondary MDS patients. 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 5q−, 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. 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). In addition, a subset of MDS, chronic myelomonocytic leukemia, which actually represents an overlap syndrome with myeloproliferative disorders, may cause splenomegaly and subsequent complaints of left upper quadrant abdominal pain and early satiety. Cytokine release (see earlier, “Pathophysiology and Natural History”) may result in constitutional symptoms, such as anorexia, weight loss, and even low-grade fevers.

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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, an “overlap syndrome” that can include features of a myelodysplastic syndrome, myeloproliferative disorder, or both.

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 (CMML) was also formally separated from the myelodysplastic syndromes, and a cytogenetically defined MDS subgroup, the 5q− syndrome—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, which does not differ substantially from the FAB classification, is gaining wider acceptance in clinical practice and in the literature.

A differential diagnosis includes the following:

• Anemia from other causes, such as vitamin deficiencies, iron deficiency from an inadequate diet or blood loss, another cancer with bone marrow involvement, rheumatologic disorders, or medication effect
• Thrombocytopenia resulting from idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or medication effect
• Leukopenia from other causes, such as infections (from human immunodeficiency virus (HIV), hepatitis, or parvovirus), rheumatologic disorders, or medication effect

If MDS is suspected, a bone marrow biopsy and aspirate should be performed. The diagnosis is made based on cell morphology, immunohistochemistry and, in the case of more advanced subtypes of MDS, flow cytometry. Obtaining a bone marrow aspirate sample for cytogenetics is crucial, because abnormalities may help in establishing the diagnosis and in risk stratification (see later).

Other laboratory tests that should be obtained to narrow the differential diagnosis include vitamin B₁₂, folate, and iron studies, including a ferritin level, serum erythropoietin level determination, certain rheumatologic studies (including antinuclear antibody or rheumatoid factor assay in certain patients), or monitoring for infectious causes, including HIV and hepatitis serologies. Although not specific, determination of the erythrocyte sedimentation rate and lactate dehydrogenase level can establish the presence of an acute process or rapid cell turnover.

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Summary

• MDS can be classified into five or eight subtypes, depending on the system (FAB or WHO) used. In general, MDS is indolent (early) or proliferative (advanced).
• In patients with cytopenias, rule out vitamin or iron deficiencies, rheumatologic, or infectious causes.
• Obtain a bone marrow biopsy and aspirate. Always carry out cytogenetic testing on the aspirate.

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Treatment

Options for the treatment of MDS range from supportive care, which includes blood product transfusions and the use of growth factors, to intensive therapy with allogeneic hematopoietic stem cell transplantation.

Patients with more indolent forms of MDS, without excess myeloblasts. who may be dependent on blood product transfusions, may derive some benefit from the use of growth factors. Often, recombinant human erythropoietin (epoetin alfa [EPO, Procrit, Epogen]) is used initially as a single agent, in escalating doses. G-CSF, filgrastim, GM-CSF, or sargramostim may be combined with epoetin alfa, and may result in higher response rates. Typical response rates, across a number of studies, are in the 15% to 40% range. Growth factor agents tend to be more effective in low-risk MDS patients with lower serum erythropoietin levels, less than 500 U/L, who do not already require frequent blood transfusions (defined as less than 2 units packed red blood cells per month). Darbepoetin alfa (Aranesp) has recently been used for the treatment of patients with MDS, although few clinical trials have supported its use.

In patients who are transfusion dependent, or who are unlikely to respond to growth factors, non–growth factor therapy, such as chemotherapy, may be initiated. Less intensive (midrange) therapeutic options for patients with indolent MDS include the use of thalidomide (Thalomid), lenalidomide (Revlimid), arsenic trioxide (Trisenox), or immunosuppressive therapy. Thalidomide, whose effects may be mediated through the inhibition of TNF-α, TGF-β and a decrease in microvessel density, appears to be more effective in patients without excess myeloblasts, in whom the response rate—defined as hematologic improvement, improvement in blood product transfusion requirements, or both—may be as high as 19%. Many patients are intolerant of the medication's side effects, which include gastrointestinal toxicity, particularly constipation, somnolence, and neurotoxicity. A thalidomide derivative, lenalidomide, has been investigated in two large phase II trials in patients with the 5q− syndrome and in patients with non-5q− early MDS. Response rates, defined as transfusion independence, in patients with the 5q− abnormality are approximately two thirds, with 44% of patient attaining a cytogenetic remission. In patients with early MDS who lack the 5q− abnormality, the transfusion independence response rate is lower, approximately 25%. Lenalidomide has been approved by the U.S. Food and Drug Administration (FDA) for use in transfusion-dependent patients with early MDS who have the 5q− abnormality.

Arsenic trioxide works through both prodifferentiation and proapoptotic mechanisms and, as a single agent, can yield response rates—defined as improvement in hematologic parameters—of 25% to 30%. This drug can also be used in patients with advanced MDS. Immunosuppressive therapy (which includes the use of antithymocyte globulin (ATG, Atgam) and cyclosporine A (Neoral, Sandimmune)) takes advantage of the immune-mediated aspects of MDS and may be effective in the subset of patients with hypoplastic MDS, MDS that resembles aplastic anemia, with a hypocellular bone marrow. Improved hematologic counts and transfusion independence may be achieved in up to 33% of appropriately treated patients.

For patients with advanced MDS, two drugs approved for use in MDS by the FDA deserve mention, 5-azacitidine (azacitidine; 5-AZA, Vidaza), and decitabine (Dacogen). These hypomethylating agents induce hematopoietic progenitor cell differentiation. In a recent phase III trial, responses occurred in 60% of patients treated with 5-azacitidine compared with 5% of patients receiving supportive care, including 23% complete or partial remissions. Median survival, transformation to AML, and even quality of life were better for patients receiving 5-azacitidine than for those receiving supportive care. Decitabine has been investigated in a multicenter phase III study, in which responses were achieved in 30% of patients, with a complete and partial remission rate in 17%.

Allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative approach to MDS, is a realistic option for only about 5% to 10% of patients because MDS is usually diagnosed in patients in their seventh or eighth decade of life. Conditioning regimens typically consist of busulfan (Myleran) and cyclophosphamide (Cytoxan), and long-term (often 2-year) disease-free survival approaches 40%, although studies have often included younger MDS patients (with a median age between 30 and 45 years) in earlier stages of MDS. Treatment-related mortality may be as high as 40% to 50%. Newer approaches take advantage of nonmyeloablative (“mini”) conditioning regimens in an effort to reduce treatment-related mortality and to include older patients with MDS. This type of transplantation is still considered experimental, but can be offered to patients up to 70 years of age who otherwise are in good health. Allogeneic HSCT should be considered as up-front therapy in patients with advanced subtypes of MDS, but can be delayed in patients with early MDS.

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Summary

• Determine whether the patient has early or advanced MDS.
• For early MDS, growth factors may be initiated once patients are almost or completely transfusion-dependent.
• Once growth factors fail, or in patients less likely to respond to growth factors, non-growth factor approaches lead to responses in 15% to 66% of patients.
• For advanced MDS, HSCT or therapy with hypomethylating agents should be initiated immediately.

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Outcomes

One of the most widely used prognostic systems for MDS patients is the International Prognostic Scoring System (IPSS; Tables 3 and 4). The IPSS separates patients into four distinct subgroups based solely on the percentage of bone marrow blasts, cytogenetics, and the number of cytopenias. Patients with fewer bone marrow blasts and cytopenias and with better cytogenetic profiles (normal, 5q−, 20q−, Y−) have a prolonged median survival, whereas those with more blasts and cytopenias and worse cytogenetic profiles (complex, or with abnormalities of chromosome 7) have a shorter survival.

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Suggested Readings

• Aul C, Gattermann N, Schneider W. Age-related incidence and other epidemiological aspects of myelodysplastic syndromes. Br J Haematol. 1992, 82: 358-367.
• Allampallam K, Shetty V, Mundle S, et al: Biological significance of proliferation, apoptosis, cytokines, and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. Int J Hematol. 2002, 75: 289-297.
• Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982, 51: 189-199.
• Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic syndromes. Semin Hematol. 1996, 33: 127-138.
• Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997, 89: 2079-2088.
• Kernan NA, Bartsch G, Ash RC, et al: Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med. 1993, 328: 593-602.
• List A, Kurtin S, Rose D, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005, 352: 549-557.
• Molldrem JJ, Caples M, Mavroudis D, et al: Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997, 99: 699-705.
• Negrin RS, Stein R, Doherty K, et al: Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: Evidence for in vivo synergy. Blood. 1996, 87: 4076-4081.
• Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol. 2002, 20: 2429-2440.
• Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002, 100: 2292-2302.