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Myelodysplastic Syndrome (MDS)


Ashkan Emadi

, MD, PhD, University of Maryland;

Jennie York Law

, MD, University of Maryland, School of Medicine

Last full review/revision May 2020
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The myelodysplastic syndrome (MDS) is group of disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular bone marrow, and a high risk of conversion to acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Acute Myeloid Leukemia (AML) . Symptoms are referable to the specific cell line most affected and may include fatigue, weakness, pallor (secondary to anemia), increased infections and fever (secondary to neutropenia), and increased bleeding and bruising (secondary to thrombocytopenia). Diagnosis is by blood count, peripheral smear, and bone marrow aspiration and biopsy. Treatment with azacitidine or decitabine may help; if acute myeloid leukemia supervenes, it is treated per the usual protocols.

The number of people diagnosed with myelodysplastic syndromes (MDS) in the United States each year is not known. Some estimates put this number at about 10,000, while other estimates have been much higher. MDS is most commonly diagnosed in people in their 70s.

Pathophysiology of MDS

Myelodysplastic syndromes are a group of clonal hematopoietic stem cell disorders unified by the presence of distinct mutations of hematopoietic stem cells, most frequently in genes involved in RNA splicing. Myelodysplastic syndromes are characterized by ineffective and dysplastic hematopoiesis and include the following:

  • Refractory anemia : Anemia with reticulocytopenia; normal or hypercellular marrow with erythroid hyperplasia, and dyserythropoiesis; blasts 5% of nucleated marrow cells

  • Refractory anemia with ringed sideroblasts: Same as refractory anemia with reticulocytopenia, except that ringed sideroblasts are > 15% of nucleated marrow cells

  • Refractory cytopenia with multilineage dysplasia: Cytopenia not restricted to red cells; prominent dysplasia of white cell precursors and megakaryocytes

  • Refractory cytopenia with multilineage dysplasia and ringed sideroblasts With ringed sideroblasts that are > 15% of nucleated marrow cells

  • Refractory anemia with excess blasts (RAEB): Cytopenia of 2 cell lines with morphologic abnormalities of hematopoietic cells; hypercellular marrow with dyserythropoiesis and dysgranulopoiesis; blasts 5 to 9% (RAEB-I) or 10 to 19% (RAEB-II) of nucleated marrow cells

  • Myelodysplastic syndrome, unclassified: MDS that does not fall into any defined category

  • MDS with isolated del(5q): Typically severe anemia and thrombocytosis, with deletion of the long arm of chromosome 5

  • Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML): Mixed myelodysplastic/myeloproliferative neoplasms; absolute monocytosis (> 1000/mcL [> 1/L]) in blood; significant increase in marrow monocyte precursors

  • Chronic neutrophilic leukemia: Characterized by neutrophilia and absence of the Philadelphia chromosome and the BCR-ABL1 fusion gene

The etiology of myelodysplastic syndrome is unknown. Risk increases with age due to the acquisition of somatic mutations that can promote clonal expansion and dominance of a particular hematopoietic stem cell, and possibly due to exposure to environmental toxins such as benzene, radiation, and chemotherapeutic agents (particularly long or intense regimens and those involving alkylating agents, hydroxyurea, and/or topoisomerase inhibitors). Chromosomal abnormalities (eg, deletions, duplications, structural abnormalities) are often present.

The bone marrow can be hypocellular or hypercellular. The ineffective hematopoiesis causes anemia (most common), neutropenia, thrombocytopenia, or a combination of these, even to the point of marrow aplasia. Patients with significant, refractory, or chronic anemia eventually develop iron overload due to transfusions and/or increased iron absorption from the gut.

The disordered cell production is also associated with morphologic cellular abnormalities in bone marrow and blood. Extramedullary hematopoiesis may occur, leading to hepatomegaly and splenomegaly. Myelofibrosis Primary Myelofibrosis Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells. Diagnosis... read more may develop during the course of MDS. Classification is by blood and bone marrow findings and also by karyotype and mutation. The MDS clone tends to progress to acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Acute Myeloid Leukemia (AML) .

Symptoms and Signs of MDS

Symptoms of myelodysplastic syndrome tend to reflect the most affected cell line and may include pallor, weakness, and fatigue (anemia); fever and infections (neutropenia); and increased bruising, petechiae, epistaxis, and mucosal bleeding (thrombocytopenia). Splenomegaly and hepatomegaly are not uncommon.

Diagnosis of MDS

  • Complete blood count (CBC)

  • Peripheral smear

  • Bone marrow examination

Myelodysplastic syndrome is suspected in patients (especially older patients) with refractory anemia, leukopenia Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to read more , or thrombocytopenia. Cytopenias secondary to autoimmune disorders Autoimmune Disorders In autoimmune disorders, the immune system produces antibodies to an endogenous antigen (autoantigen). The following hypersensitivity reactions may be involved: Type II: Antibody-coated cells... read more , vitamin B12 deficiencies Vitamin B12 Deficiency Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage... read more , folate deficiencies Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more , idiopathic aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more Aplastic Anemia , paroxysmal noctural hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria (PNH) Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder characterized by intravascular hemolysis and hemoglobinuria. Leukopenia, thrombocytopenia, arterial and venous thromboses... read more , copper deficiency Acquired Copper Deficiency Copper is a component of many body proteins; almost all of the body’s copper is bound to copper proteins. Copper deficiency may be acquired or inherited. (See also Overview of Mineral Deficiency... read more , zinc toxicity Zinc Toxicity Zinc (Zn) is contained mainly in bones, teeth, hair, skin, liver, muscle, leukocytes, and testes. Zinc is a component of several hundred enzymes, including many nicotinamide adenine dinucleotide... read more , or drug effects must be ruled out. The diagnosis is suggested by the finding of peripheral blood and bone marrow morphologic abnormalities in 10 to 20% of cells of a particular lineage but is established by demonstrating specific cytogenetic abnormalities and somatic mutations.

Anemia is the most common feature, associated usually with macrocytosis and anisocytosis. With automatic cell counters, these changes are indicated by an increased mean corpuscular volume and red blood cell distribution width.

Some degree of thrombocytopenia is usual; on peripheral smear, platelets vary in size, and some appear hypogranular. Patients with refractory sideroblastic anemia may have thrombocytosis in combination with the JAK2 V617F mutation.

The white blood cell count may be normal, increased, or decreased. Neutrophil cytoplasmic granularity is decreased, with anisocytosis and variable numbers of granules. Eosinophils also may have abnormal granularity. Pseudo Pelger-Huët cells (hyposegmented neutrophils) may be seen.

Monocytosis is characteristic of the chronic and juvenile myelomonocytic leukemia subgroups, and immature myeloid cells may occur in the less well differentiated subgroups. The cytogenetic pattern is usually abnormal, with one or more clonal cytogenetic abnormalities often involving chromosomes 5 or 7.

The deletion 5q syndrome is a unique form of myelodysplastic syndrome, occurring primarily in women in whom macrocytic anemia and thrombocytosis are typically present. Anemia in deletion 5q syndrome appears to be responsive to lenalidomide.

Prognosis for MDS

Prognosis of myelodysplastic syndrome depends greatly on classification and on any associated disorders. Patients with the deletion 5q syndrome, refractory anemia, or refractory anemia with ringed sideroblasts are less likely to progress to the more aggressive forms.

The Revised International Prognostic Scoring System (IPSS-R) in MDS predicts the outcome of patients with MDS. The IPSS-R considers the following risk factors:

  • Cytogenetics: Worst prognosis associated with high-risk or multiple abnormalities

  • Percentage of bone marrow blasts: Worst prognosis associated with increasing numbers of (particularly >10%) blasts

  • Degree of cytopenia: Worst prognosis is associated with hemoglobin < 8 g/dL (< 80 g/L), platelet count < 50,000/mcL (< 50 × 109/L) )and absolute neutrophil count (ANC) < 800/mcL (0.8 × 109/L)

Outcome is worse with an increasing number of risk factors. Patients in the highest risk group have a median overall survival of 0.8 year. Patients in the lowest risk group have a median overall survival of about 8 years.

Treatment of MDS

  • Symptom amelioration and supportive care

  • Chemotherapy

  • Stem cell transplantation

In general, treatment is reserved for symptomatic patients.

Erythrocyte-stimulating agents (ESA) decrease the severity of anemia in 15 to 20% of patients with MDS, particularly in anemic patients who are not dependent on transfusions and have a serum erythropoietin level < 500 mIU/mL (< 500 IU/L). Treatment with both erythrocyte stimulating agents and granulocyte colony-stimulating factor (G-CSF) may increase the erythroid response rate to nearly 40% in refractory anemia with ringed sideroblasts. However, in all forms of MDS, treatment with growth factors (ESA + G-CSF) does not improve survival and/or reduce risk of transformation to AML.

Drugs used to treat MDS include

  • Azacitidine

  • Decitabine

  • Lenalidomide

Azacitidine is a pyrimidine nucleoside analog. Azacitidine prolongs overall survival compared with supportive care and conventional chemotherapy. Median survival in patients with all subgroups of MDS treated with azacitidine is 21 months. Patients should be treated for at least of 4 to 6 cycles and continue for as long as the patient continues to benefit.

Decitabine is also a pyrimidine nucleoside analog. It induces remission in as many as 43% of patients with MDS. It is indicated for treatment of patients with MDS of all subtypes.

Azacitidine and decitabine are epigenetic modulators that hypomethylate DNA. Hypermethylation of certain regions of DNA appears to impair tumor suppressor genes and play a role in oncogenesis in MDS.

Lenalidomide is an immunomodulator that is effective in reducing red blood cell transfusion requirements in patients with MDS with deletion 5q syndrome

In patients with hypoplastic MDS, immunosuppression with cyclosporine with or without antithymocyte globulin (ATG) has been effective, as evidenced by cell count improvement and decreased need for transfusion.

Key Points

  • Myelodysplastic syndrome is a disorder of hematopoietic cell production involving clonal proliferation of an abnormal hematopoietic stem cell.

  • Patients usually present with a deficiency of red cells (most common), white cells, and/or platelets.

  • Transformation to acute myeloid leukemia is common.

  • Azacitidine and decitabine may ameliorate symptoms and decrease the rate of transformation to acute leukemia.

  • Stem cell transplantation is the only curative treatment and is the treatment of choice in younger, medically fit patients.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

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