Myelodysplastic syndrome

Signs and symptoms

Signs and symptoms are nonspecific and generally related to the blood cytopenias:

Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:

Although there is some risk for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important fact in the person's medical history. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process.

Cause

Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. There may be a link between the development of MDS "in atomic bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bomb in Hiroshima and Nagasaki during World War II).

Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.

Pathophysiology

MDS may be caused by environmental exposures such as radiation and benzene; other risk factors have been inconsistently reported. However, definitive proof of specific causes cannot be determined. Secondary MDS occurs as a late toxicity of cancer treatment, usually with a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or the DNA topoisomerase inhibitors (latency 2 years). Both acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia can evolve into MDS.

MDS is thought to arise from mutations in the multi-potent bone marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and there is a significant increase in levels of apoptotic cell death in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.

While recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion, MDS patients rarely suffer injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload.

Genetics

The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the U.S. Food and Drug Administration (FDA) to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth, and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, and thereby restore normal blood counts and retard the progression of MDS to acute leukemia.

Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS.

5q- syndrome

Since at least 1974, it has been known that the deletion in the long arm of chromosome 5 is associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, it was recognized that lenalidomide, a chemotherapy drug, was effective in MDS patients with the 5q- syndrome, and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with 63 months median survival. Lenalidomide has dual action: by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion.

Splicing factor mutations

Mutations in splicing factors have been found in 40-80% of cases with myelodysplastic syndrome, particularly in those with ringed sideroblasts.

IDH1 and IDH2 mutations

Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10-20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state.

Diagnosis

MDS must be differentiated from anemia, thrombocytopenia and/or leukopenia. Usually, the elimination of other causes of these cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

A typical investigation includes:

The features generally used to define a MDS are: blood cytopenias; ineffective hematopoiesis; dyserythropoiesis; dysgranulopoiesis; dysmegakaropoiesis and increased myeloblasts.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:

Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy, high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

Differential diagnosis

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) has been recognized, Pearson's syndrome (sideroblastic anemia), Jordans anomaly - vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes and platelets or their progenitor cells, megakaryocytes).

French-American-British (FAB) classification

In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories:

(A table comparing these is available from the Cleveland Clinic.)

The best prognosis is seen with RA and RARS, where some non-transplant patients live more than a decade (the average is on the order of three to five years, although long-term remission is possible if a bone marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About one quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

World Health Organization

In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. Most recently, the WHO has evolved a new classification scheme (2008) which is based more on genetic findings. However, morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy is still the screening test used in order to decide which classification is best and which cytogenetic aberrations may be related.

The list of dysplastic syndromes under the new WHO system includes:

Not all physicians concur with this reclassification, because the underlying pathology of the diseases is not well understood.

Myelodysplastic syndrome unclassified

WHO-proposed criteria for diagnosis and classification of MDS apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features:

Management

The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia (AML).

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy. Supportive care with blood products and hematopoietic growth factors (e.g. erythropoietin) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document though.

Three agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS:

1. 5-azacytidine: 21 month median survival
2. Decitabine: Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with valproic acid.
3. Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS

Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome. In the United States, treatment of MDS with lenalidomide costs about US$9,200 per month.

Stem cell transplantation, particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.

Iron levels

Iron overload can develop in MDS as a result of the red blood cell (RBC) transfusions which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need in some cases, many MDS patients may not respond to these treatments and thus may develop iron overload from repeated RBC transfusions.

Patients requiring relatively large numbers of RBC transfusions can experience the adverse effect of chronic iron overload on their liver, heart, endocrine functions. The resulting organ dysfunction from transfusional iron overload might be a contributor to increased sickness and death in early stage MDS.

For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to < 1000 µg/L.

There are currently two iron chelators available in the US, deferoxamine for IV use and deferasirox for oral use. These options now provide potentially useful drugs for treating this iron overload problem. A third chelating agent is available in Europe, deferiprone for oral use, but not available in the US.

Clinical trials in the MDS are ongoing with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy have been shown.

Both the MDS Foundation and the National Comprehensive Cancer Network MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggest there is a potential value to iron chelation in patients who will undergo a stem cell transplant.

Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following post-marketing use of deferasirox, there were rare cases of acute kidney failure or liver failure, some resulting in death. Due to this, it is recommended that patients be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter.

Prognosis

The outlook in MDS is variable, with ~30% of patients progressing to refractory acute myeloid leukemia. The median survival rate varies from years to months, depending on type. Stem cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly.

Indicators of a good prognosis: Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in-vitro marrow culture with a non-leukemic growth pattern.

Indicators of a poor prognosis: Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20-29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes or complex marrow chromosome abnormalities and in-vitro bone marrow culture with a leukemic growth pattern.

karyotype prognostic factors:

The International Prognostic Scoring System (IPSS) is the most commonly used tool in MDS to predict long-term outcome.

Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype.

Genetic markers

Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased our understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival.

Epidemiology

The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 cases per 100,000 per year.

The average age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50; MDS diagnoses are rare in children. Males are slightly more commonly affected than females.

History

Since the early 20th century, it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped together with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

Notable cases