MDS is 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:

Etiology is often 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 and/or epipodophyllotoxins). 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 anemia can develop iron overload from 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 may develop during the course of MDS. Classification is by blood and bone marrow findings (see Table: Myelodysplastic Syndrome Bone Marrow Findings and Survival) and also by karyotype and mutation. The MDS clone is unstable and tends to progress to acute myelogenous leukemia.

Symptoms 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 common.

Symptoms may also be referable to other underlying disorders; eg, in elderly patients with preexisting cardiovascular disorders, anemia from MDS may exacerbate anginal pain or heart failure.

MDS is suspected in patients (especially the elderly) with refractory anemia, leukopenia, or thrombocytopenia. Cytopenias secondary to autoimmune disorders, vitamin deficiencies, idiopathic aplastic anemia, paroxysmal noctural hemoglobinuria, 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 MCV and RBC distribution width.

Some degree of thrombocytopenia is usual; on peripheral smear, platelets vary in size, and some appear hypogranular.

The WBC count may be normal, increased, or decreased. Neutrophil cytoplasmic granularity is abnormal, 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 myelomonocytic leukemia subgroup, 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 5q- syndrome is a unique form of MDS, occurring primarily in women in whom macrocytic anemia and thrombocytosis are typically present; this form is very responsive to lenalidomide.

Prognosis depends greatly on classification and on any associated disorder. Patients with the 5q- syndrome, refractory anemia, or refractory anemia with ringed sideroblasts are less likely to progress to the more aggressive forms and may die of unrelated causes.

Azacitidine relieves symptoms, decreases the rate of transformation to leukemia and the need for transfusions, and improves survival. Other therapy is supportive, including RBC transfusions as indicated, platelet transfusions for bleeding, and antibiotic therapy for bacterial infection. Deoxyazacitidine, a hypomethylating agent, is sometimes effective, even in patients who do not respond to azacitidine.

Drugs that provide hematopoietic support can improve cytopenias in some patients but have not increased survival:

Thrombopoietin may also improve marrow function in general.

Combination therapy with azacitidine or decitabine plus an immune modulator such as lenalidomide is currently under investigation. Lenalidomide alone is particularly useful in patients with the 5q- syndrome and also appears to be effective in 25% of anemic MDS patients who do not have the 5q- syndrome. In patients with hypoplastic MDS, cyclosporine with or without ATG has been successful.

Allogeneic stem cell transplantation is the treatment of choice for young patients, and nonablative allogeneic bone marrow transplantations are now being studied for patients > 50 yr. Response of MDS to chemotherapy, typically regimens similar to those used for AML, is similar to that of AML after age and karyotype are considered.