Myelodysplastic syndrome

Myelodysplastic syndrome
ICD-10	D46
ICD-9	238.7
ICD-O:	9980/0-9989/3
DiseasesDB	8604
eMedicine	med/2695  ped/1527
MeSH	D009190

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

The myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of hematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia. Anemia requiring chronic blood transfusion is frequently present. Although not truly malignant, MDS is nevertheless classified within the haematological neoplasms.

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 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.

Signs and symptoms

Abnormalities include:

• neutropenia, anemia and thrombocytopenia (low cell counts of white and red blood cells, and platelets, respectively)
• abnormal granules in cells, abnormal nuclear shape and size
• chromosomal abnormalities, including chromosomal translocations and abnormal chromosome number.

Symptoms of myelodysplastic conditions:

• Anemia—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
• Neutropenia (low neutrophil count) —increased susceptibility to infection
• Thrombocytopenia (low platelet count) —increased susceptibility to bleeding

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

Diagnosis

Investigation:

• Full blood count and examination of blood film
• Bone marrow examination by an experienced hematopathologist
• Cytogenetics or chromosomal studies. This is performed on the bone marrow aspirate.

Differential Diagnosis and Workup

The differential diagnosis is that of anemia, thrombocytopenia, and/or leukopenia. Usually, the elimination of known etiologies of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

Investigation:

• Full blood count and examination of blood film. The blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia.
• Blood tests to eliminate other common causes of cytopenias, such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, renal failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy. Age-appropriate cancer screening should be considered for all anemic patients.
• Bone marrow examination by an experienced hematopathologist. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
• Cytogenetics or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter metaphase to enhance chromosomal staining.
• Flow cytometry is helpful to establish the presence of any lymphoproliferative disorder in the marrow

Genetics

Abnormality	Frequency in MDS
-5/del(5q)	10-20%
+8	10%
-7/del(7q)	5-10%
-Y	10%
17p-	7%
del(20q)	5-6%
t(11q23)	5-6%
complex karyotype	10-20%

Overall, the mutations in the RUNX1/AML1 are the most common point mutations described in MDS to date but RUNX1/AML1 mutations have no distinct hematologic phenotype and are most commonly associated with previous radiation exposure and with a higher risk disease (especially with excess blasts).

Hypermethylation leading to silencing of the p151NK-4b gene is also common in MDS. This phenomenon occurs in up to 80% of the cases with advanced MDS. The silencing of this gene can be reversed by the uyse of demethylating agents such as 5-azacytidine. These agents are pyrimidine analogues that inhibit DNA methyltransferase activity and could improve MDS hematopoiesis by reversing aberrant gene methylation and permitting cellular differentiation.

A number of studies suggest that erythropoietin (EPO) signaling and STAT5 activation is abnormal in MDS. The SOCS1 gene is hypermethylated in 31% of MDS patients which is associated with increased activity of the JAK/STAT pathway.

Microsatellite instability involving defects in the DNA mismatch repair system has been identified in some MDS patients, especially those with therapy-related disease.

The TP53 tumor suppressor gene, which regulates cell cycle progression, DNA repair and apoptosis is mutated in 5-10% of MDS cases. Inactivation of the TP53 gene may contribute to the leukemic progression from MDS.

Pathophysiology

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 cell death apoptosis 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 blasts rises over a particular cutoff (20% for WHO and 30% for FAB) then transformation to leukemia (specifically acute myelogenous leukemia or AML) is said to have occurred. The progression of MDS to leukemia 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. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).

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. However, if an MDS patient is fortunate enough to suffer nothing more than anemia over several years, they then risk iron overload. 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).

The recognition of epigenetic changes in DNA structure in MDS has explained the success of two of three commercially available medications approved by the US 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.

Types and classification

French-American-British (FAB) classification

In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This French-American-British (FAB) classification was published in 1976 and revised in 1982. Cases were classified into 5 categories: (ICD-O codes are provided where available)

• (Template:ICDO) Refractory anemia (RA) - characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
• (Template:ICDO) Refractory anemia with ringed sideroblasts (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
• (Template:ICDO) Refractory anemia with excess blasts (RAEB) - characterized by 5-19% myeloblasts in the marrow;
• (Template:ICDO) Refractory anemia with excess blasts in transformation (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
• (Template:ICDO) Chronic myelomonocytic leukemia (CMML) - not to be confused with chronic myelogenous leukemia or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 10⁹/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the Cleveland Clinic.

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 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. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.

The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.

WHO classification

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.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

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

1. Refractory anemia (RA)
2. Refractory anemia with ringed sideroblasts (RARS)
3. Refractory cytopenia with multilineage dysplasia (RCMD)
4. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
5. Refractory anemia with excess blasts I and II
6. 5q- syndrome
7. Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).

5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

Diagnosis

The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, mustard, 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. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS.

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:

• Granulocytic series
  1. Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
  2. Hyposegmented neutrophils (Pseudo-Pelger Huet)
  3. Hypogranular neutrophils or pseudo Chediak Higashi large granules
  4. Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
• Erythroid series
  1. Binucleated erythroid percursors and karyorrhexis
  2. Erythroid nuclear budding
  3. Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
  4. PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
  5. Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
• Megakaryocytic series (can be the most subjective)
  1. Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
  2. Hypersegmented (osteoclastic appearing) megakaryocytes
  3. Ballooning of the platelets (seen with interference contrast microscopy)

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 cells/(blasts) clustering together. This morphology can be difficult to recognize 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. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.

Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.

Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.

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 dyserthropoietic anemia (CDA I through IV) has been recognized, Pearson's syndrome (sideroblastic anemia), Jacobson's 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).

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 incidence is probably increasing as the age of the population increases

Therapy

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

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 product support and hematopoeitic 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.

The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.

Survival and AML evolution score

Prognostic Variable	0	0.5	1	1.5	2
Bone marrow blasts (%)	<5	5-10	X	11-20	21-30
Karyotype *	good	intermediate	poor	X	X
Cytopenias **	0 or 1	2 or 3	X	X	X

• Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.

Intermediate = other abnormalities. Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.

• • Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.

IPSS Risk Category	Low	Intermediate 1	Intermediate 2	High
Combined score	0	0.5-1	1.5-2	>/=2.5
AML evolution	19%	30%	33%	45%
Median time to AML (years)	9.4	3.3	1.1	0.2
Median survival (years)	5.7	3.5	1.2	0.4

Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)

Three agents have been approved by the US FDA for the treatment of MDS:

Name	Comment	References
5-azacytidine	21 month median survival similar to that of decitabine
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.
Lenalidomide	Most effective in reducing red cell transfusion requirement

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. It was approved in July, 2006 for use in multiple myeloma. The retail price of lenalidomide is estimated at $7,000 per month .

Stem cell transplantation, particularly in younger patients (ie less than 40 years of age), 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.

Additional Readings

• Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189. PMID 6952920.
• Block M, Jacobson LO, Bethard WF. Preleukemic acute human leukemia. JAMA 1953;152:1018-28. PMID 13052490.
• Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835-49. PMID 10577857.
• Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
• Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
• Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.

External links

• Cancer Medicine. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
• Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families
• Website of MDS-Foundation with a lot of helpful materials
• Myelodysplastic syndromes. Comprehensive article from MayoClinic.com.
• Myelodysplastic syndrome (MDS). article from virtualcancercentre.com.
• [3] Agent Orange and MDS, 100% service connected.

See also

• Myeloproliferative syndrome
• Acute myeloid leukemia
• Chloroma

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