Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular marrow with impaired morphology and maturation (dysmyelopoiesis) and peripheral blood cytopenias, resulting from ineffective blood cell production. All 3 cell lineages in myeloid hematopoiesis can be involved, including erythrocytic, granulocytic, and megakaryocytic cell lines. Although clonal, it is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML) when additional genetic abnormalities are acquired.

Pathophysiology: MDS can be classified as primary (no known exposure) or secondary as a complication of aggressive treatment of other cancers with exposure to radiation, alkylating agents, or topoisomerase II inhibitors and heavily pretreated patients with autologous bone marrow transplants.

The initial hematopoietic stem cell injury can be from cytotoxic chemotherapy, radiation exposure, viral infection, chemical exposure to genotoxins like benzene, or genetic predisposition. A clonal mutation predominates over bone marrow, suppressing healthy stem cells.

In early stages, the main cause of cytopenias is increased apoptosis (programmed cell death). As the disease progresses and converts into leukemia, a rare gene mutation occurs and a proliferation of leukemic cells overwhelms the healthy marrow.

Frequency:

—      In the US: The actual incidence is unknown. MDS was first considered a separate disease in 1976, and occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder. The perception that the incidence is increasing may be due to improvements in recognition and criteria for diagnosis. Statistics from 1999 show that 13,000 new cases occur per year (approximately 1000 cases each year in children), surpassing chronic lymphocytic leukemia as the most common form of leukemia in the Western Hemisphere.

—      Internationally: The disease is found worldwide and is similar in characteristics throughout the world.

Mortality/Morbidity: The disease course differs, with some patients having an indolent disease and others having aggressive disease with a very short clinical course that converts into an acute form of leukemia.

Because the diagnostic criteria are new, an international group of hematologists, the French-American-British (FAB) Cooperative Group, classified these disorders into 5 subgroups, differentiating them from acute myeloid leukemia. An underlying trilineage dysplastic change in the bone marrow cells of the patients is found in all subtypes.

—      The 2 subgroups of refractory anemia (RA) characterized by 5% or less myeloblasts in bone marrow are (1) RA and (2) RA with ringed sideroblasts (RARS), defined morphologically as having 15% erythroid cells with abnormal ringed sideroblasts, reflecting an abnormal iron accumulation in the mitochondria. Both have a prolonged clinical course and a low prevalence of progression to acute leukemia.

—      The 2 subgroups of RAs with greater than 5% myeloblasts are (1) RA with excess blasts (RAEB), defined as 6-20% myeloblasts, and (2) RAEB in transformation (RAEB-T), with 21-30% myeloblasts. The higher the percent of myeloblasts, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia.

Patient transition from early to more advanced stages indicates these subtypes are merely stages of disease rather than distinct entities. Elderly patients with MDS with trilineage dysplasia and greater than 30% myeloblasts who progress to acute leukemia are often considered to have poor prognoses because their response to chemotherapy is worse than de novo acute myeloid leukemia patients. The 1999 World Health Organization (WHO) classification proposes to include all cases of RAEB-T (patients with >20% myeloblasts) in the category of acute leukemia because these patients have similar prognostic outcomes. However, their response to therapy is worse than patients with the de novo or more typical acute myelogenous leukemia or acute nonlymphocytic leukemia.

—      The fifth type of MDS, the most difficult to classify, is called chronic myelomonocytic leukemia (CMML). This subtype can have any percent of myeloblasts but manifests as a monocytosis of 1000/mL or more. It may be associated with splenomegaly. This subtype overlaps with a myeloproliferative disorder (MPD) and may have an intermediate clinical course. CMML must be differentiated from the classic chronic myelocytic leukemia, which is characterized by a negative Ph chromosome. The 1999 WHO classification proposes that juvenile and proliferative CMML be listed separately from the FAB classification under MDS/MPD with splenomegaly and greater than 13,000/mL total WBC count. CMML in the FAB classification under MDS is limited to monocytosis, has less than 13,000/mL total leukocytes, and requires trilineage dysplasia.

Sex: A slight male predominance is noted in all age groups.

Age: MDS primarily affects elderly people, with the median onset in the seventh decade of life.

—      The median age of these patients is 65 years, with ages ranging from the early third decade of life to older than 80 years.

—      The syndrome may occur in persons of any age group, including the pediatric population.