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INTRODUCTION

The myelodysplastic syndromes (MDS) are a group of disorders characterized by one


or more peripheral blood cytopenias secondary to bone marrow dysfunction. The MDS
are diagnosed in slightly more than 10,000 people in the United States yearly for an
annual age-adjusted incidence of 3.4/100,000 people.The MDS are more common in
men and whites. The syndromes may arise de novo, or secondarily after treatment with
chemotherapy and/or radiation therapy for other diseases. Secondary myelodysplasia
usually has a poorer prognosis than does de novo myelodysplasia. Prognosis is directly
related to the number of bone marrow blast cells and to the amount of peripheral blood
cytopenias. The MDS transform to acute myeloid leukemia (AML) in about 30% of
patients after various intervals from diagnosis and at variable rates.

The acute leukemic transformation is much less responsive to chemotherapy than is de


novo AML. Prognosis is also related to the type of myelodysplastic syndrome.
Supportive care has been the mainstay of treatment. Judicious use of platelet and blood
transfusions and iron chelation may prevent or delay alloimmunization and iron overload
and favorably affect prognosis.

The MDS are characterized by abnormal bone marrow and blood cell morphology.
Megaloblastic erythroid hyperplasia with macrocytic anemia, which is associated with
normal vitamin B12 and folate levels, is frequently observed. Circulating granulocytes are
frequently severely reduced, often hypogranular or hypergranular, and may display the
acquired pseudo-Pelger-Hut abnormality. Early, abnormal myeloid progenitors are
identified in the marrow in varying percentages, depending on the type of
myelodysplastic syndrome. Abnormally small megakaryocytes (micromegakaryocytes)
may be seen in the marrow and hypogranular or giant platelets may appear in the
blood.

The MDS occur predominantly in older patients (usually >60 years), though patients as
young as 2 years have been reported. Anemia, bleeding, easy bruising, and fatigue are
common initial findings. Splenomegaly or hepatosplenomegaly may occasionally be
present in association with an overlapping myeloproliferative disorder. Approximately
50% of the patients have a detectable cytogenetic abnormality, most commonly a
deletion of all or part of chromosome 5 or 7, or trisomy 8.Although the bone marrow is
usually hypercellular at diagnosis, 15% to 20% of patients present with a hypoplastic
bone marrow.Hypoplastic myelodysplastic patients tend to have profound cytopenias
and may respond more frequently to immunosuppressive therapy.

A variety of risk classification systems have been developed to predict the overall
survival of patients with MDS and the evolution from MDS to AML. These classification
systems include the French-American-British classification, the Bournemouth score, the
Sanz score, the Lille score, and the World Health Organization classification. Clinical
variables in these systems have included bone marrow and blood myeloblast
percentage, specific cytopenias, age, lactate dehydrogenase level, and bone marrow
cytogenetic pattern.

An International MDS Risk Analysis Workshop was convened, and the clinical data from
816 patients with primary MDS from seven previously reported studies, which used
independent risk-based prognostic systems, were combined and collated.The combined
data were analyzed centrally, and a global analysis was performed, which formed the
basis of a new prognostic system called the International Prognostic Scoring System for
MDS. In multivariate analyses, significant predictors for both survival and AML evolution
included bone marrow blast percentage, number of peripheral blood cytopenias, and
cytogenetic subgroup. The data are used to assign MDS patients a score, which
stratifies patients into one of four risk groups: low risk, intermediate-1, intermediate-2,
and high risk. The time for the development of AML in the risk groups was 9.4 years, 3.3
years, 1.1 years, and 0.2 years, respectively. Median survival for the groups was 5.7
years, 3.5 years, 1.2 years, and 0.4 years, respectively. The system has been
incorporated into clinical trial design for MDS.
CLASSIFICATION

The myelodysplastic syndromes (MDS) are classified according to features of cellular


morphology, etiology, and clinical presentation. The morphological classification of the
MDS is largely based on the percent of myeloblasts in the bone marrow and blood, the
type and degree of myeloid dysplasia, and the presence of ringed sideroblasts. The
clinical classification of the MDS depends upon whether there is an identifiable etiology
and whether the MDS has been treated previously.

Cellular Classification

Work on the French-American-British (FAB) classification scheme for the MDS began in
the late 1970s under the direction of the French-American-British Cooperative Group
(see table below). The version published in 1982 was the first diagnostic classification
scheme to clearly and reproducibly distinguish MDS from acute myelogenous leukemia
(AML). According to the FAB scheme, the percentage of bone marrow blasts required
for the diagnosis of MDS ranges from less than 5% to as much as 29%. The FAB
scheme is still frequently used by clinicians to categorize the MDS.

Several weaknesses were identified in the FAB classification of MDS. The inclusion of
chronic myelomonocytic leukemia (CMML) was problematic; CMML is a disease that
combines features of both MDS and chronic myeloproliferative disorders. In addition,
the FAB classification did not take cytogenetic findings into account. For example, the
cytogenetically defined MDS subtype del(5q) represents a distinct clinical entity.

In 1997, under the auspices of the World Health Organization (WHO), a working group
of pathologists and clinicians from around the world agreed to a new cellular
classification scheme for hematopoietic and lymphoid malignancies. Significant changes
to the FAB classification of these malignancies were made. For the classification of
MDS, the new WHO classification lowered the threshold to 20% for the number of
myeloblasts required to make the diagnosis of AML. This arbitrary threshold value for
blast percentage eliminated the cellular type, refractory anemia with excess blasts in
transformation (RAEB-t), found in the FAB classification scheme. In the WHO cellular
classification scheme, RAEB-t is no longer considered a distinct clinicopathologic entity;
instead, RAEB-t is included within the broader category, AML with multilineage
dysplasia, and identified as AML with multilineage dysplasia following a myelodysplastic
syndrome.

The elimination of RAEB-t from the WHO cellular classification scheme met some
resistance. Some have argued that the biology of RAEB-t is distinct from AML and
should be retained as a diagnostic category of MDS. Others have emphasized the
similar prognoses and responses to treatment for RAEB-t and AML with trilineage
dysplasia.The diagnosis of AML, which is based upon a threshold of 20% bone marrow
or peripheral blood myeloblasts, does not represent a therapeutic mandate. The
decision to treat must include other factors, such as patient age, prior history of MDS,
clinical findings, disease progression, and most importantly, patient preference, in
addition to the blast count. The same factors influence treatment options for patients
with 30% or more myeloblasts in the blood or marrow.

The addition of refractory cytopenia with multilineage dysplasia (RCMD),


myelodysplastic syndrome, unclassifiable (MDS-U), and the myelodysplastic syndrome
associated with an isolated del(5q) chromosome abnormality completes the WHO
cellular classification scheme for MDS. Finally, the WHO classification of MDS removed
CMML from MDS and placed it in a new category, myelodysplastic syndromes and
myeloproliferative diseases (MDS and MPD).

Myelodysplastic Syndromes:
Comparison of the FAB and WHO
Classifications WHO (1997)
Enlarge
FAB (1982)

Myelodysplastic Syndromes Myelodysplastic Syndromes


Myelodysplastic Syndromes:
Comparison of the FAB and WHO
Classifications WHO (1997)
Enlarge
FAB (1982)

Refractory anemia Refractory anemia

Refractory cytopenia with multilineage dysplasia

Refractory anemia with ringed Refractory anemia with ringed sideroblasts


sideroblasts

Refractory anemia with excess blasts Refractory anemia with excess blasts

Myelodysplastic syndrome, unclassifiable

Myelodysplastic syndrome associated with


del(5q)

Reclassified from MDS to:

Refractory anemia with excess blasts Acute Myeloid Leukemia identified as, AML
in transformation with multilineage dysplasia following a
myelodysplastic syndrome

Chronic myelomonocytic leukemia Myelodysplastic and Myeloproliferative


Diseases

MDS cellular types and subtypes in either cellular classification scheme have different
degrees of disordered hematopoiesis, frequencies of transformation to acute leukemia,
and prognoses. All WHO cellular types and subtypes and the FAB cellular type, RAEB-t,
are described in detail below.

Refractory anemia (RA)


In patients with RA, the myeloid and megakaryocytic series in the bone marrow appear
normal, but megaloblastoid erythroid hyperplasia is present. Dysplasia is usually
minimal. Marrow blasts are less than 5%, and no peripheral blasts are present.
Macrocytic anemia with reticulocytopenia is present in the blood. Transformation to
acute leukemia is rare, and median survival varies from 2 years to 5 years in most
series. RA accounts for 20% to 30% of all patients with MDS.

Refractory anemia with ringed sideroblasts (RARS)

In patients with RARS, the blood and marrow are identical to those in patients with RA,
except that at least 15% of marrow red cell precursors are ringed sideroblasts.
Approximately 10% to 12% of patients present with this type, and prognosis is identical
to that of RA. Approximately 1% to 2% of RARS evolve to AML.

Refractory anemia with excess blasts (RAEB)

In patients with RAEB, there is significant evidence of disordered myelopoiesis and


megakaryocytopoiesis in addition to abnormal erythropoiesis. Because of differences in
prognosis related to progression to a frank AML, this cellular classification is comprised
of two categories, refractory anemia with excess blasts-1 (RAEB-1) and refractory
anemia with excess blasts-2 (RAEB-2). Combined, the two categories account for
approximately 40% of all patients with MDS. RAEB-1 is characterized by 5% to 9%
blasts in the bone marrow and less than 5% blasts in the blood. Approximately 25% of
cases of RAEB-1 progress to AML. Median survival is approximately 18 months. RAEB-
2 is characterized by 10% to 19% blasts in the bone marrow. Approximately 33% of
cases of RAEB-2 progress to AML. Median survival for RAEB-2 is approximately 10
months.

Refractory anemia with excess blasts in transformation (RAEB-t)


In the FAB classification, RAEB-t represents a panmyelosis in which 20% to 30% of
marrow cells are blasts, and more than 5% blasts are seen in the blood. Auer rods may
be seen. Sixty percent to 75% of patients develop overt acute leukemia, and median
survival is 6 months or less. Approximately 25% of patients present with RAEB-t. In the
WHO classification, RAEB-t is not a distinct clinical entity; rather, it is included within the
broader category, AML with multilineage dysplasia, and identified as AML with
multilineage dysplasia following a myelodysplastic syndrome.

Refractory cytopenia with multilineage dysplasia (RCMD)

In patients with RCMD, bicytopenia or pancytopenia is present. In addition, dysplastic


changes are present in 10% or more of the cells in two or more myeloid cell lines. There
are less than 1% blasts in the blood and less than 5% blasts in the bone marrow. Auer
rods are not present. Monocytes in the blood are less than 1 10 9. RCMD accounts for
approximately 24% of cases of MDS. The frequency of evolution to acute leukemia is
11%. The overall median survival is 33 months. Refractory cytopenia with multilineage
dysplasia and ringed sideroblasts (RCMD-RS) represents another category of RMDS. In
RCMD-RS, features of RCMD are present, and more than 15% of erythroid precursors
in the bone marrow are ringed sideroblasts. RCMD-RS accounts for approximately 15%
of cases of MDS. Survival in RCMD-RS is similar to that in primary RCMD.

Unclassifiable myelodysplastic syndrome (MDS-U)

The cellular subtype, MDS-U, lacks findings appropriate for classification as RA, RARS,
RCMD or RAEB. Blasts in the blood and bone marrow are not increased.

Myelodysplastic syndrome associated with an isolated del(5q) chromosome


abnormality

This MDS cellular subtype, the 5q- syndrome, is associated with an isolated del(5q)
cytogenetic abnormality. Blasts in both blood and bone marrow are less than 5%. This
subtype is associated with a long survival. Karyotypic evolution is uncommon. Additional
cytogenetic abnormalities may be associated with a more aggressive MDS cellular
subtype or may evolve to acute myeloid leukemia.

Clinical Classification

The clinical classification of MDS is used to determine disease prognosis and treatment
strategy, and to define entry requirements for many MDS clinical trials.

De novo myelodysplastic syndrome

Most MDS cases occur de novo with no known cause.

Secondary myelodysplastic syndrome

The risk of developing MDS may be increased by exposure to a variety of agents


including:

Tobacco smoke.
Ionizing radiation.

Organic chemicals (e.g., benzene, toluene, xylene, and chloramphenicol).

Heavy metals.

Herbicides.

Pesticides.

Fertilizers.

Stone and cereal dusts.

Exhaust gases.

Nitro-organic explosives.

Petroleum and diesel derivatives.

Alkylating agents.
Marrow-damaging agents used in cancer chemotherapy.

Patients with documented exposure to such agents are referred to as having secondary
MDS or treatment-related MDS and constitute as many as 30% of all patients with MDS.
Secondary MDS typically has a poorer prognosis than does de novo MDS.

Previously treated myelodysplastic syndrome

Previously treated MDS are de novo or secondary cases of MDS that have progressed
despite previous treatment and, in many cases, are receiving additional treatment.

SYMPTOMS OF MYELODYSPLASIA

The list of signs and symptoms mentioned in various sources for Myelodysplastic
syndromes includes the 26 symptoms listed below:

Fatigue
Lightheadedness
Fever
Bruising
Splenomegaly
Angina pain
Shortness of breath
Epistaxis
Cytopenia
Bleeding
Frequent infections
Anemia
Fatigue
Exertional dyspnea
Low blood platelet level
Petechiae
Mucosal bleeding
Gastrointestinal bleeding
Enlarged spleen
Thrombocytopenia
Leucopenia
Poikilocytosis
Breathlessness
Reduced white blood cell level
Cytopenia
Low blood cell count

DIAGNOSIS

The following tests and procedures may be used:

Physical exam and history: An exam of the body to check general signs of health,
including checking for signs of disease, such as lumps or anything else that seems
unusual. A history of the patients health habits and past illnesses and treatments
will also be taken.
Complete blood count (CBC) with differential: A procedure in which a sample of
blood is drawn and checked for the following:

The number of red blood cells and platelets.

The number and type of white blood cells.


The amount of hemoglobin (the protein that carries oxygen) in the red
blood cells.

The portion of the blood sample made up of red blood cells.

Enlarge

Complete blood count (CBC). Blood is


collected by inserting a needle into a
vein and allowing the blood to flow into
a tube. The blood sample is sent to the
laboratory and the red blood cells, white
blood cells, and platelets are counted.
The CBC is used to test for, diagnose,
and monitor many different conditions.
Peripheral blood smear: A procedure in which a sample of blood is checked for
changes in the number, type, shape, and size of blood cells and for too much iron
in the red blood cells.

Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow


are viewed under a microscope to look for certain changes in the chromosomes.

Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a
small piece of bone by inserting a hollow needle into the hipbone or breastbone. A
pathologist views the bone marrow, blood, and bone under a microscope to look for
abnormal cells.
Bone marrow aspiration and biopsy.
After a small area of skin is numbed, a
Jamshidi needle (a long, hollow needle)
is inserted into the patients hip bone.
Samples of blood, bone, and bone
marrow are removed for examination
under a microscope.

Myelodysplastic syndromes are diagnosed based on certain changes in the blood


cells and bone marrow.

Refractory anemia: There are too few red blood cells in the blood and the
patient has anemia. The number of white blood cells and platelets is normal.

Refractory anemia with ringed sideroblasts: There are too few red blood cells
in the blood and the patient has anemia. The red blood cells have too much iron.
The number of white blood cells and platelets is normal.

Refractory anemia with excess blasts: There are too few red blood cells in the
blood and the patient has anemia. Five percent to 19% of the cells in the bone
marrow are blasts and there are a normal number of blasts found in the blood.
There also may be changes to the white blood cells and platelets. Refractory
anemia with excess blasts may progress to acute myeloid leukemia.
Refractory anemia with excess blasts in transformation: There are too few
red blood cells, white blood cells, and platelets in the blood and the patient has
anemia. Twenty percent to 30% of the cells in the bone marrow are blasts and
more than 5% of the cells in the blood are blasts. Refractory anemia with excess
blasts in transformation is sometimes called acute myeloid leukemia.

Refractory cytopenia with multilineage dysplasia: There are too few of at


least two types of blood cells. Less than 5% of the cells in the bone marrow are
blasts and less than 1% of the cells in the blood are blasts. If red blood cells are
affected, they may have extra iron. Refractory cytopenia may progress to acute
leukemia.

Myelodysplastic syndrome associated with an isolated del(5q)


chromosome abnormality: There are too few red blood cells in the blood and the
patient has anemia. Less than 5% of the cells in the bone marrow and blood are
blasts. There is a specific change in the chromosome.

Unclassifiable myelodysplastic syndrome: There are too few of one type of


blood cell in the blood. The number of blasts in the bone marrow and blood is
normal, and the disease is not one of the other myelodysplastic syndromes .

TREATMENT
There are different types of treatment for patients with myelodysplastic
syndromes.

Different types of treatments are available for patients with myelodysplastic syndromes.
Some treatments are standard (the currently used treatment), and some are being
tested in clinical trials. A treatment clinical trial is a research study meant to help
improve current treatments or obtain information on new treatments for patients with a
myelodysplastic syndrome. When clinical trials show that a new treatment is better than
the standard treatment, the new treatment may become the standard treatment.
Patients may want to think about taking part in a clinical trial. Some clinical trials are
open only to patients who have not started treatment.

Treatment for myelodysplastic syndromes aims to relieve symptoms, slow


progression, and improve quality of life.

Treatment options for patients with myelodysplastic syndromes range from supportive
care that helps relieve symptoms to aggressive treatment that may slow or prevent
progression of the disease.

Problems caused by low blood cell counts, such as fatigue and infections, may be
treated with transfusions of blood products or the use of growth factors.

Chemotherapy may be used to delay progression of the disease. Other drug therapy
may be used to lessen the need for transfusions. Certain patients may benefit from
aggressive treatment with chemotherapy followed by stem cell transplant using stem
cells from a donor.

Three types of standard treatment are used:


Chemotherapy

In myelodysplastic syndromes, chemotherapy is a treatment that uses drugs to stop the


growth of immature blood cells, either by killing the cells or by stopping them from
dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the
drugs enter the bloodstream and can reach cancer cells throughout the body (systemic
chemotherapy). When chemotherapy is placed directly into the spinal column, an organ,
or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those
areas (regional chemotherapy). The way the chemotherapy is given depends on the
disease being treated.

Supportive care

Supportive care is given to lessen the problems caused by the disease or its treatment.
Supportive care may include the following:

Transfusion therapy

Transfusion therapy (blood transfusion) is a method of giving red blood cells, white
blood cells, or platelets to replace blood cells destroyed by disease or treatment.
Patients who receive frequent red blood cell transfusions may have their tissues
and organs damaged from the buildup of extra iron. Iron chelation therapy is a
treatment that uses drugs that attach to the extra iron. The drug and the iron are
removed from the body in the urine.

Platelet transfusions are usually given when the patient is bleeding or is having a
procedure that may cause bleeding.

Growth factor therapy


Erythropoietin may be given to increase the number of red blood cells and lessen
the effects of anemia. Sometimes granulocyte colony-stimulating factor (G-CSF) is
given with erythropoietin to help the treatment work better.

Drug therapy

Deferoxamine may be used to treat the build-up of too much iron in the blood of
patients receiving blood transfusions. It is sometimes given with vitamin C.

Lenalidomide may be used to lessen the need for transfusions in patients who have
myelodysplastic syndrome caused by a specific chromosome change.

Antithymocyte globulin (ATG) may also be used to lessen the need for transfusions
in patients with a certain form of myelodysplastic syndrome.

Antibiotics may be given to fight infections.

Chemotherapy with stem cell transplant

Stem cell transplant is a method of giving chemotherapy and replacing blood-forming


cells destroyed by the treatment. Stem cells (immature blood cells) are removed from
the blood or bone marrow of a donor and are frozen for storage. After the chemotherapy
is completed, the stored stem cells are thawed and given back to the patient through an
infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
REFERENCES

1. http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/HealthProfess
ional/page2

2. http://www.wrongdiagnosis.com/medical/myelodysplasia.htm

3. http://www.wrongdiagnosis.com/m/myelodysplastic_syndromes/symptoms.htm

4. http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/Patient/page3

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