Published: April 2014
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).
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:
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.
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.
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.
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.
| 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).
| MDS Subtype | Blood Findings | Bone Marrow Findings |
|---|---|---|
| Refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia (RA), refractory neutropenia (RN), refractory thrombocytopenia (RT) | Unicytopenia or bicytopenia* No or rare blasts (<1%)† |
Unilineage dysplasia: ≥10% of the cells in one myeloid lineage <5% blasts <15% of erythroid precursors are ring sideroblasts |
| Refractory anemia with ring sideroblasts (RARS) | Anemia No blasts |
≥15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts |
| Refractory cytopenia with multilineage dysplasia (RCMD) | Cytopenia(s) No or rare blasts (<1%)† No Auer rods <1 x 109/L monocytes |
Dysplasia in ≥10% of the cells in ≥2 myeloid lineage (neutrophil and/or erythroid precursors and/or megakaryocytes) <5% blasts in marrow No Auer rods ±15% ring sideroblasts |
| Refractory anemia with excess blasts-1 (RAEB-1) | Cytopenia(s) <5% blasts† No Auer rods <1 x 109/L monocytes |
Unilineage or multilineage dysplasia 5% to 9% blasts† No Auer rods |
| Refractory anemia with excess blasts-2 (RAEB-2) | Cytopenia(s) 5% to 19% blasts‡ ±Auer rods‡ <1 x 109/L monocytes |
Unilineage or multilineage dysplasia 10% to 19% blasts‡ ±Auer rods‡ |
| Myelodysplastic syndrome - unclassified (MDS-U) | Cytopenias <1% Blasts† |
Unequivocal dysplasia in <10% of cells in one or more myeloid lineage when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts |
| MDS associated with isolated del(5q) | Anemia Usually normal or increased platelet count No or rare blasts (<1%) |
Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del(5q) cytogenetic abnormality No Auer rods |
MDS, myelodysplastic syndrome.
* Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.
† If the marrow myeloblast percentage is <5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U.
‡ Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB-2. Although the finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of RAEB-2 may have <5% blasts in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both. Similarly, cases of RAEB-2 may have <10% blasts in the marrow but may be diagnosed by the other two findings, Auer rod + and/or 5% to 19% blasts in the blood.
Republished with permission of The American Society of Hematology (Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization [WHO] classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937–951); permission conveyed through Copyright Clearance Center, Inc.
A differential diagnosis includes the following:
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 (Tables 3, 4, 5, and 6).
| Score |
|||||
|---|---|---|---|---|---|
| Prognostic variable | 0 | 0.5 | 1.0 | 1.5 | 2.0 |
| Bone marrow blasts (%) | <5 | 5 - 10 | 11 - 20 | 21 - 30 | |
| Cytogenetics | Good | Intermediate | Poor | ||
| Cytopenias | 0/1 | 2/3 | |||
Republished with permission of The American Society of Hematology (Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079–2088); permission conveyed through Copyright Clearance Center, Inc.
| Prognostic Subgroup | Abnormality | Median Survival (months) | Median AML Transformation (months) |
|---|---|---|---|
| Very good | del(11q), -Y | 60.8 | NR |
| Good | normal, del(20q), del(5q) alone and double, del(12p) | 48.6 | NR |
| Intermediate | del(7q), +8, i(17q), +19, any other single or double | 26.0 | 78.0 |
| Poor | inv(3)/t(3q)/del(3q), -7, double including 7q-, complex (3 abnormalities) | 15.8 | 21.0 |
| Very poor | complex (>3 abnormalities) | 5.9 | 8.2 |
AML, acute myeloid leukemia; NR, not reached.
Data from Schanz J, Tüchler H, Solé F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 2012; 30:820–829.
| Score |
|||||||
|---|---|---|---|---|---|---|---|
| Prognostic variable | 0 | 0.5 | 1.0 | 1.5 | 2.0 | 3.0 | 4.0 |
| Cytogenetics | Very good | Good | Intermediate | Poor | Very poor | ||
| Bone marrow blasts (%) | ≤2 | >2 - <5 | 5 - 10 | >10 | |||
| Hemoglobin | ≥10 | 8 - <10 | <8 | ||||
| Platelets | ≥100 | 50 - <100 | <50 | ||||
| Absolute neutrophil count | ≥0.8 | <0.8 | |||||
Republished with permission of The American Society of Hematology (Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454–2465); permission conveyed through Copyright Clearance Center, Inc.
| Risk Score | IPSS-R Subgroup | Patients (%) 7,012 Total | Survival, All (years) | Hazard Ratio [95% CI] | Patients (%) 6,485 Total | AML/25% (years) | Hazard Ratio [95% CI] |
|---|---|---|---|---|---|---|---|
| ≤1.5 | Very low | 19% | 8.8 (7.8-9.9) | 0.5 (0.46-0.59) | 19% | NR (14.5-NR) | 0.5 (0.4-0.6) |
| >1.5 - 3 | Low | 38% | 5.3 (5.1-5.7) | 1.0 (0.93-1.1) | 37% | 10.8 (9.2-NR) | 1.0 (0.86-1.2) |
| >3 - 4.5 | Intermediate | 20% | 3.0 (2.7-3.3) | 2.0 (1.8-2.1) | 20% | 3.2 (2.8-4.4) | 3.0 (2.7-3.5) |
| >4.5 - 6 | High | 13% | 1.6 (1.5-1.7) | 3.2 (2.9-3.5) | 13% | 1.4 (1.1-1.7) | 6.2 (5.4-7.2) |
| >6 | Very high | 10% | 0.76 (0.7-0.8) | 8.0 (7.2-8.8) | 11% | 0.73 (0.7-0.9) | 12.7 (10.6-15.2) |
IPSS-R, Revised International Prognostic Scoring System; NR, not reached.
IPSS-R, Revised International Prognostic Scoring System; NR, not reached. Republished with permission of The American Society of Hematology (Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454–2465); permission conveyed through Copyright Clearance Center, Inc.
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 select patients), or monitoring for infectious causes, including human immunodeficiency virus 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.
MDS is a heterogeneous disease, with varied options for the treatment. These range from supportive care, which includes blood product transfusions and the use of growth factors, to intensive therapy with allogeneic hematopoietic stem cell transplantation (HSCT). Treatment selection should be based on the patient's age, performance status, and Myelodysplastic Syndrome International Prognostic Scoring System (IPSS) and Revised International Prognostic Scoring System (IPSS-R) subgroup classification. The main goal of MDS therapy is to provide symptom control and to improve quality of life for lower-risk subtypes, and to extend survival and delay transformation to AML in higher-risk groups. Treatment is indicated for lower-risk MDS if there is symptomatic anemia, thrombocytopenia, or recurrent infections in the setting of neutropenia, and for higher-risk MDS under most circumstances regardless of blood counts or symptoms. At this time, there is no evidence that treatment of asymptomatic patients improves overall survival. Additionally, the only curative option for MDS is allogeneic HSCT.
Patients with lower-risk 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], at doses of 60,000 to 80,000 U weekly) or darbepoietin (Aranesp, at a dose of 500 mcg every 2 to 3 weeks) is used initially as a single agent, in escalating doses. Either increases hemoglobin levels and/or decreases transfusion needs in approximately 40% of lower-risk patients. Growth factor agents tend to be more effective in lower-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).
In patients who are transfusion dependent, or who are unlikely to respond to growth factors, disease-modifying therapy may be initiated. Less intensive (midrange) therapeutic options for patients with lower-risk MDS include the use of lenalidomide (Revlimid) or immunosuppressive therapy. Lenalidomide, a derivative of thalidomide, purportedly works through inhibition of halpodeficient phosphatase activity in the common deleted region that plays a key role in cell cycle regulation, and through a defect in the ribosomal protein function. It has been investigated in two large phase II trials and in one phase III study in patients with a del(5q) cytogenetic abnormality and in patients with non-del(5q) lower-risk MDS. Response rates, defined as transfusion independence, in patients with the del(5q) abnormality are approximately two-thirds, with 44% of patients attaining a cytogenetic remission. In patients with lower-risk MDS who lack the del(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 del(5q) abnormality.
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 MDS that resembles aplastic anemia, with a hypocellular bone marrow, or in those with other autoimmune stigmata. Improved hematologic counts and transfusion independence may be achieved in up to 30% to 40% of appropriately selected patients.
For patients with higher-risk MDS, two drugs approved for use in MDS by the FDA deserve mention, azacitidine (5-AZA, Vidaza), and decitabine (Dacogen). These hypomethylating agents purportedly work by reactivating tumor suppressor genes and through direct cytotoxic mechanisms, and may induce hematopoietic progenitor cell differentiation. In a recent phase III trial in higher-risk patients, responses occurred in approximately 50% of patients, and survival was doubled at 2 years of follow-up in patients receiving azacitidine, compared to those treated with conventional care, including best supportive care or chemotherapy. 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%, though no overall survival advantage has been demonstrated compared to best supportive care.
Allogeneic HSCT, the only potentially curative approach to MDS, is a realistic option for only about 5% to 10% of patients, due to advanced patient age at time of MDS diagnosis, co-morbidities, advanced age of potential sibling donors, and patient preference. Conditioning regimens typically consist of busulfan (Myleran) and cyclophosphamide (Cytoxan) or fludarabine, and long-term (often 2-year) disease-free survival approaches 40%, although studies using fully myeloablative regimens have often included younger MDS patients (with a median age between 30 and 45 years). 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 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 higher-risk subtypes of MDS, but can be delayed in patients with lower-risk MDS.
The most widely used prognostic classification system for MDS is the IPSS (Tables 3 and 7). The first IPSS was derived from a study published in 1997. This study was based on survival data of 816 patients with primary MDS based upon the FAB classification system and treated in general with supportive care only. The IPSS separates patients into four distinct subgroups based solely on the percentage of bone marrow blasts, cytogenetics, and the number of cytopenias. Due to several limitations of the first IPSS, new cytogenetic categories were developed for a revised IPSS (IPSS-R) in 2012. The IPSS-R was based on data from over 7,000 patients with primary MDS diagnosed using the FAB or WHO classifications and validated in an independent cohort. The IPSS-R changes include: a larger number of cytogenetic abnormalities which are given more weight than previously, different cut-offs for blast percentage, and sensitivity to degrees of cytopenias. Patients with fewer bone marrow blasts and cytopenias and with better cytogenetic profiles (Y-, del(11q), normal, del(5q), del(20q), del(12p)) have a prolonged median survival, whereas those with more blasts and cytopenias and complex cytogenetic profiles have a shorter survival.
| Score | IPSS Subgroup | Median Survival (years) |
|---|---|---|
| 0 | Low | 5.7 |
| 0.5-1.0 | Intermediate 1 | 3.5 |
| 1.5-2.0 | Intermediate 2 | 1.2 |
| >2.5 | High | 0.4 |
IPSS, International Prognostic Scoring System.
Data from Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079–2088.