Current Diagnosis

• Myelodysplastic syndromes are diseases of the elderly.

• Chronic unexplained cytopenias should be evaluated to rule out myelodysplastic syndromes.

• Bone marrow biopsy with cytogenetic testing is necessary to make the diagnosis.

• The international prognostic scoring system (IPSS) is an important tool for risk stratification and choice of therapy.

Current Therapy

• Myelodysplastic syndromes are broadly divided into two therapeutic categories per the IPSS: low-risk disease (encompassing low and intermediate-1 risk groups), and high-risk disease (encompassing Intermediate-2 and high risk groups).

• The IPSS-R defines 5 prognostic groups (very low, low, intermediate, high, and very high risk). Treatment options are also dependent on risk category.

• Patients with low-risk disease should receive supportive care and hematopoietic growth factors; those with deletion 5q abnormality should be treated with lenalidomide (Revlimid).

• Patients with high-risk disease should be treated with a hypomethylating agent and should be considered for allogeneic stem cell transplantation.


The myelodysplastic syndromes (MDS) represent a group of heterogeneous clonal stem cell disorders that affect the elderly. The reported annual incidence of approximately 4.4 per 100,000 of the general United States population is highest among whites and non- Hispanics. The onset of MDS before the age of 50 years is rare; the incidence rises with age such that in patients older than 70 years, the incidence exceeds 45 per 100,000 persons. Men are nearly twice as likely to be affected as women (5.8 vs. 3.3 per 100,000 per year).

Risk Factors

De novo or primary MDS refers to cases in which no prior toxic exposure can be documented. Therapy-related MDS, on the other hand, occurs in patients who have been previously treated with either chemotherapy, radiotherapy or both. Median onset of therapy-related MDS varies with the agents used and is usually 2 to 5 years after initial exposure and/or chemotherapy.

Tobacco use and occupational exposure to solvents and agricultural chemicals have also been associated with the development of MDS. A minority of MDS cases might have evolved from an antecedent hematologic disorder such as aplastic anemia or paroxysmal nocturnal hemoglobinuria. Several rare and inherited genetic disorders have been associated with a higher risk of developing MDS, such as

Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan syndrome, and Shwachman-Diamond syndrome.


A variety of pathophysiologic processes have been described in association with MDS, resulting in ineffective hematopoiesis and peripheral cytopenias. These processes include excessive apoptosis of myeloid progenitors, abnormal responses to cytokines and growth factors, epigenetic aberrations resulting in gene silencing, chromosomal abnormalities, and a defective bone marrow microenvironment. Recently, several somatic point mutations affecting multiple genes have been identified in up to 50% of MDS patients. However, the initiating event remains is unknown.

Clinical Manifestations

Some patients with MDS are asymptomatic, but the majority present with peripheral blood cytopenias of which anemia is the most common. Patients might complain of fatigue, weakness, and exercise intolerance. Those with significant neutropenia and thrombocytopenia can present with infections or bleeding. Systemic symptoms are less common, but when present, can herald disease progression. Similarly, the presence of Sweet’s syndrome (acute febrile neutrophilic dermatosis) can herald transformation to acute leukemia.

Organomegaly and lymphadenopathy are uncommon. Infection is the cause of death in approximately 20% to 35% of cases. Transformation to acute leukemia occurs in about 30% of all patients.


The diagnosis of MDS can be challenging, because its clinical and pathologic characteristics can overlap with other disorders such as aplastic anemia, myeloproliferative neoplasms, and acute leukemia.

A thorough history and physical examination should be performed on every patient with one or more peripheral blood cytopenias, along with basic laboratory tests such as iron studies, vitamin B12, and folic acid levels. However, many disorders can cause pancytopenia; therefore, consideration for a hematology referral should be entertained for the evaluation of pancytopenia or persistent otherwise-unexplained cytopenias, in which case a bone marrow biopsy may be necessary.

The diagnosis of MDS requires an evaluation of the peripheral blood smear, a bone marrow biopsy and aspirate to ascertain the presence of myeloid dysplasia; iron stains, which are necessary for the detection of ring sideroblasts; and cytogenetic studies to detect abnormal clones. Bone marrow dysplasia involving at least 10% of the cells of a specific myeloid lineage is the hallmark of MDS.

Conventional karyotyping can detect cytogenetic abnormalities in 50% of patients with de novo MDS and in 95% of patients with therapy- related MDS. The presence of certain cytogenetic abnormalities can aid in making the diagnosis of MDS, particularly when dysplastic features are not prominent. It should be noted that the presence of +8,-Y, or del(20q) is not considered to be MDS-defining in that setting.

Recently, next generation sequencing (NGS) has allowed for the identification of point mutations in the majority of patients with MDS. These mutations involve genes encoding for splicing factors, epigenetic modifiers, and transcription factors among others. NGS is increasingly utilized in this patient population to assist in making the diagnosis (.SF3B1 in MDS-RS), or to provide important prognostic information (TP53 in del 5 MDS).

Differential Diagnosis

MDS should be distinguished from a broad number of disorders including megaloblastic anemia, aplastic anemia, large granular lymphocyte leukemia, myelofibrosis, copper deficiency, and HIV infection, which can cause anemia and dysplastic features in the bone marrow. Exposure to certain drugs and toxins can result in marrow dysplasia. These include mycophenolate mofetil (Cellcept), ganciclovir (Cytovene), lead, and excess zinc. Such changes are reversible once the offending agent is discontinued. The diagnosis of MDS can be made by performing a bone marrow biopsy to detect dysplasia and rule out other disorders that can also cause pancytopenia. Every effort should be made to rule out other reactive causes of dysplasia prior to making a diagnosis of MDS.

Classification and Risk Stratification

Since 1982, there have been various proposals for the classification and risk stratification of MDS. The French-American-British (FAB) classification scheme was the first attempt developed to address the broad range of morphologic features and clinical outcomes in MDS. It identified five subtypes based on morphology and percentage of marrow blasts: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). This classification allowed MDS to be separated into distinct subsets relative to survival and acute leukemia evolution.

The World Health Organization (WHO) revised the FAB system to further refine MDS subsets by adding a category of refractory cytopenia with multilineage dysplasia, recognizing 5q-deletion syndrome as a separate clinical and pathologic entity, and lowering the blast percentage from 30% to 20% to diagnose acute myelogenous leukemia (AML). The WHO system was revised in 2008 and again in 2016. The most recent revision eliminated reference to refractory anemia and modified the terminology to identify 6 general MDS categories based on presence of single or multilineage dysplasia, ring sideroblasts, blast percentage and del(5q) (Table 1).

Table 1

WHO 2008 Classification of Myelodysplastic Syndromes


* Bicytopenia is occasionally observed. Cases with pancytopenia should be classified as MDS- U.

† If the marrow myeloblast percentage is <5% but there are 2%–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.

The International Prognostic Scoring System (IPSS) was introduced in 1997 to address the variability in prognosis within FAB subtypes. It predicts survival and risk of evolution to acute leukemia. The IPSS is calculated by adding scores assigned to three variables: blast cell count, cytogenetics, and number of cytopenias (Table 2). The IPSS was revised in 2012 (IPSS-R) to incorporate 5 cytogenetic categories and to account for the depth of cytopenias in MDS (Table 3). The IPSS/IPSS-R are widely utilized to predict the prognosis and clinical behavior of patients with various forms of MDS and to guide choice of therapy.

Table 2

International Prognostic Scoring System (IPSS) for MDS

* Cytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex (≥3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. This excludes karyotypes t(8;21), inv16 and t(15;17), which are considered to be AML, not  MDS.

†  Cytopenias: neutrophil count <1800/μL, platelets <100,000/μL, Hb <10  g/dL.

Table 3

Survival and Progression by IPSS Risk Category

Abbreviation: IPSS = International Prognostic Scoring  System.


A variety of therapeutic options exist for the treatment of MDS patients spanning the spectrum from supportive care to allogeneic stem cell transplantation. Choice of therapy should take into account the patient’s age, comorbidities, and the IPSS/IPSS-R score.

The treating physician should consider the ultimate goal of therapy and whether it is intended to cure, extend survival, or merely palliate symptoms. In the first decade of the 21st century, several novel therapeutic options for MDS have emerged. Clinical trials evaluating novel agents are being conducted to help identify effective agents for patients who have relapsed or failed to respond to standard therapies.

Supportive Care

Supportive care has been the cornerstone of MDS therapy for decades; it includes red blood cell transfusion for symptomatic anemia, platelet transfusion to reduce the risk of or to treat bleeding, and use of hematopoietic growth factors such as erythropoiesis stimulating agents (ESA) and colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF) (Filgrastim [Neupogen])1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Sargramostim [Leukine]).1

There are two currently available ESAs: a recombinant human erythropoietin (rhu-EPO; epoetin alfa [Epogen, Procrit])1 and a super- sialylated form of EPO (darbepoetin alfa [Aranesp]).1 These are considered the standard of care for the treatment of anemia in patients with low-risk MDS. A predictive model for response to such treatment has been developed by the Nordic MDS study group to guide patient selection. In general, patients with a serum EPO level less than 500 mU/mL and low transfusion burden are likely to respond by improving their hemoglobin level and reducing their need for transfusions.

Immunomodulatory Drugs

The novel class of immunomodulatory drugs includes thalidomide (Thalomid)1 and lenalidomide (Revlimid). Thalidomide was investigated initially with some success in patients with low-risk disease. However, its use was compromised because of poor tolerability. Lenalidomide has been approved for the treatment of patients with low-risk MDS who harbor deletion 5q abnormality, because it was shown in clinical trials to result in transfusion independence in about two thirds of such patients.

Hypomethylating Agents

Currently, two hypomethylating agents are approved for the treatment of MDS: 5-azacitidine (Vidaza) and decitabine (Dacogen). These agents are cytosine analogues known to inhibit and deplete DNA methyltransferase, which adds a methyl group to cytosine residues in newly formed DNA, resulting in the formation of a hypomethylated DNA in vitro. The exact mechanism of action in vivo has not yet been identified.

Results of randomized clinical trials comparing these agents to best supportive care in patients with MDS have demonstrated a statistically significant improvement in response rate and hematologic improvement. It has been shown for the first time that treatment with 5-azacitidine was reported to result in prolongation of survival in patients with Int-2 and high-risk. Both drugs have myelosuppressive properties and comparable response rates.

Immunosuppressive Therapy

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)1 or cyclosporine (Neoral)1 (or both) was evaluated in several clinical trials and was shown to result in durable hematological responses in a subset of MDS patients, specifically, younger patients with low-risk disease, hypocellular marrows, PNH clone, human leukocyte antigen (HLA)-DR 15 phenotype, and low transfusion need.

Hematopoietic Stem Cell Transplantation

Allogeneic stem cell transplantation is the only curative therapy for MDS patients; this option is feasible for a small subset: typically, younger patients with good performance status and an available HLA-matched donor. Approximately 40% of patients can be cured with this modality. The recent introduction of reduced-intensity conditioning regimens and nonmyeloablative transplants has resulted in expanding the age limit for performing the procedure, reducing transplant-related complications and mortality. However it has been associated with a higher risk of relapse. Because stem cell transplantation is associated with a high rate of treatment-related death—estimated at 39% at 1 year—and the development of acute and chronic graft versus host disease, such treatment is recommended to patients with high-risk disease. Patients with low-risk MDS may be considered for transplant at disease progression.

Conclusion and Future Direction

MDS is a chronic disease characterized by features reminiscent of bone marrow failure states with a variable propensity for leukemic evolution. It is curable only by allogeneic stem cell transplantation, which is feasible in only a small subset of patients. For all others, the treatment goal is aimed at improving quality of life and prolonging survival. A variety of ongoing clinical trials are evaluating novel agents and combinations of drugs to further optimize the outcome of patients with this disease. Meanwhile, a great deal of research is focused on understanding the molecular underpinning of this disease to enhance our understanding of the biology of this heterogenous disorder.


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1  Not FDA approved for this  indication

1  Not FDA approved for this  indication.

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