Myelodysplastic Syndrome 

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.^[1]

All 3 cell lineages in myeloid hematopoiesis can be involved, including erythrocytic, granulocytic, and megakaryocytic cell lines. Although clonal, MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myelogenous leukemia (AML) when additional genetic abnormalities are acquired.

See the following image depicting MDS.

Patients with MDS may present with clinical manifestations of anemia, thrombocytopenia, and/or neutropenia (see Clinical). The workup in patients with possible MDS includes a complete blood count with differential, peripheral blood smear, and bone marrow studies (see Workup).

Standard care for MDS is constantly changing, but it typically includes supportive therapy, including transfusions, and may include bone marrow stimulation and cytotoxic chemotherapy. Bone marrow transplantation has a limited role. (See Treatment.)

MDS develops when a clonal mutation predominates in the bone marrow, suppressing healthy stem cells. The clonal mutation may result from genetic predisposition or from hematopoietic stem cell injury caused by exposure to any of the following:

• Cytotoxic chemotherapy
• Radiation
• Viral infection
• Genotoxic chemicals (eg, benzene)

MDS can be classified as primary (no known exposure) or secondary to aggressive treatment of other cancers, with exposure to radiation, alkylating agents, or topoisomerase II inhibitors; it also occurs in heavily pretreated patients with autologous bone marrow transplants.

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

Cytogenetically, patients with MDS or AML fall into 3 groups:

• Normal karyotype
• Balanced chromosomal abnormality causing the generation of fusion oncogenes
• Complex karyotypes (usually >3 abnormalities)

Patients with complex karyotypes constitute 30% of primary MDS cases (only 20% of de novo AML) and up to 50% of therapy-related MDS and AML cases. These patients have a worse prognosis and response to treatment.

Balanced translocation abnormalities lead to the generation of fusion oncogenes such as Bcr-Abl in chronic myelogenous leukemia (CML) and PML-Rar alpha in acute promyelocytic leukemia (APL). Unbalanced recurrent aberrations, most commonly -5, 5q-,-7, 7q-, +8, 11q-, 13q-, and 20q-, suggest that genes within these regions have a role in the pathogenesis of MDS or myeloproliferative disorder (MPD), which is based on loss of tumor suppressor genes or haploinsufficiency of genes necessary for normal myelopoiesis.

Approximately 60-70% of patients with MDS do not have an obvious exposure or cause for MDS. In these cases, the disorder is classified as primary or idiopathic MDS.

Secondary MDS describes the development of MDS or acute leukemia 10-15 years after known exposure to sources of chromosomal damage. Patients who survive cancer treatment with alkylating agents, with or without radiotherapy, have a high risk of developing MDS or secondary acute leukemia. These drugs are associated with a high prevalence of chromosomal abnormalities in bone marrow.

MDS may also develop after exposure to certain chemicals (eg, benzene). Insecticides, weed killers, and fungicides are also possible causes of MDS and secondary leukemia.^[2] Viral infections have also been implicated. Less evidence supports genetic predisposition, but familial incidences have been described.

A study by Kristinsson et al found that chronic immune stimulation is a trigger for acute leukemia and MDS development. The underlying mechanisms may also be caused by a genetic predisposition or treatment for infections or autoimmune conditions.^[3]

The actual incidence of MDS in the United States is unknown. MDS was first considered a separate disease in 1976, and its 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. Statistics from 1999 show that 13,000 new cases occur annually (approximately 1000 cases each year in children), surpassing chronic lymphocytic leukemia as the most common form of leukemia in the Western Hemisphere.

The incidence of MDS has appeared to be increasing; however, this perception may have arisen because of improvements in recognition and criteria for the diagnosis.

Although MDS may occur in persons of any age, including children, MDS primarily affects elderly people, with the median onset in the seventh decade of life. Data from 2001 through 2003 of the first National Cancer Institute's Surveillance, Epidemiology & End Reports (SEER) indicate 86% of MDS cases were diagnosed in individuals who were 60 years of age or older (median age: 76y).

Other data from SEER also show that the estimated incidence of MDS increases significantly with age, ranging from 0.7 per 100,000 population during the fourth decade of life to 20.8-36.3/100,000 after age 70 years. There is a fivefold difference in risk between age 60 and ≥80 years.

At all ages, MDS is more common in males than in females. In SEER data from 2001-2003, the incidence rate was significantly higher in men than in women (4.5 vs 2.7 per 100,000 population).^[4]

The prevalence of MDS is currently estimated to be 35,000 to 55,000 cases in the US.^{[5, 6]} The apparently increasing number is believed to reflect the increase in the elderly population.

MDS is found worldwide and is similar in characteristics throughout the world. Data based mainly on European numbers from Germany and Sweden were very similar to the US numbers.

In some patients, MDS is an indolent disease. In others, the disease follows an aggressive course and converts into an acute form of leukemia.

Risk classification systems to estimate prognosis in patients with MDS have been developed by the French-American-British (FAB) Cooperative Group, the World Health Organization (WHO), and the MDS Risk Analysis Workshop.

The FAB system classifies MDS into the following 5 subgroups, differentiating them from acute myeloid leukemia^[7] :

• Refractory anemia (RA)
• RA with ringed sideroblasts (RARS)
• RA with excess blasts (RAEB; 6-20% myeloblasts)
• RAEB in transition to AML (RAEB-T; 21-30% myeloblasts)
• Chronic myelomonocytic leukemia (CMML)

An underlying trilineage dysplastic change in the bone marrow cells is found in all subtypes.

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

RAEB and RAEB-T (see the image below) are characterized by greater than 5% myeloblasts. The higher the percentage of myeloblasts present, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia.

Transition from early to more advanced stages may occur, which indicates that these subtypes are merely stages of disease rather than distinct entities. Elderly patients with MDS who progress to acute leukemia are often considered to have a poor prognosis because their disease response to chemotherapy is worse than that of de novo acute myeloid leukemia patients.

The 1999 WHO classification proposed including all cases of RAEB-T in the category of acute leukemia because these patients have similar prognostic outcomes.^[8] However, the response to therapy is worse than in patients with de novo or more typical AML or acute nonlymphocytic leukemia.

The fifth type of MDS, CMML, is the most difficult to classify. This subtype can have any percentage of myeloblasts but manifests as a monocytosis of 1000/μL or more, a total white blood cell (WBC) count of less than 13,000/μL, and trilineage dysplasia.

CMML may be associated with splenomegaly. This subtype overlaps with myeloproliferative disease (MPD) and may have an intermediate clinical course. CMML must be differentiated from classic chronic myelocytic leukemia, which is characterized by a negative Ph chromosome.

The 2008 WHO classification proposed that juvenile myelomonocytic leukemia and CMML be listed as separate entities within a group of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. WHO criteria for these forms of CMML include splenomegaly and a WBC count greater than 13,000/μL.

WHO Classification

The WHO classification scheme for MDS was published in 1999. Updates to the scheme were published in 2008. Under the revised scheme, single-lineage dysplasia is considered a valid criterion for diagnosis of MDS. As well, refractory cytopenia with unilineage dysplasia (RCUD) became an official entity under the new WHO classification.

The 2008 WHO classification of MDS is as follows^[9] :

• Refractory cytopenia with unilineage dysplasia – this includes refractory anemia, refractory neutropenia, or refractory thrombocytopenia
• RARS
• RAEB
• Refractory cytopenia with multilineage dysplasia
• MDS with isolated deletion of 5q
• MDS, unclassifiable
• Childhood MDS

The WHO classification also includes a provisional entity: refractory cytopenia of childhood.

International Prognostic Scoring System

To improve prognostic classification, the MDS Risk Analysis Workshop developed the Myelodysplastic Syndrome International Prognostic Scoring System (IPSS). The IPSS score is calculated on the basis of 3 variables:

• Number of cytopenias
• Karyotype
• Percentage of bone marrow blasts

The IPSS score is used to stratify patients into 4 risk groups, as shown in Table 1, below:

Table 1. International Prognostic Scoring System Risk Groups and Prognosis^[10] (Open Table in a new window)

Mean survival is 18-24 months or longer in patients with the following features:

• Single or mild cytopenias
• Normal chromosomes or a single chromosomal abnormality (except those involving chromosome 7)
• Fewer than 10% myeloblasts in the bone marrow

Mean survival is 6-12 months in patients with the following features:

• Pancytopenia requiring red blood cell or platelet transfusions
• Chromosome 7 abnormalities or multiple chromosomal abnormalities
• Greater than 10% myeloblasts