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Myelodysplastic Syndromes

Definition of MDS.
Classification of MDS.
Differentiation of MDS from acute Leukemia.
Cytogenetics of MDS.
Pathogenesis and Pathophysiology of MDS.
Clinical features and presentation of MDS.
Laboratory findings in MDS.
Prognosis and management of MDS.

Definition of Myelodysplastic Syndromes:

Myelodysplastic Syndromes (MDS) are a heterogeneous group of acquired neoplastic  hematological disorders of the bone marrow (1) , resulting from clonal proliferation of abnormal stem cells (2) .  These disorders are characterized by the presence of the following: peripheral blood cytopenias due to dyshematopoiesis in the three cell lines (red cells, monocytes/granulocytes and platelets), anaemia and hypercellular bone marrow (3) . In general, MDS is grouped into: several forms of refractory anaemia and a form of chronic leukemia (2) .  Abnormalities in these disorders are both functional and morphological expressed in the three cell lines mentioned earlier, with the abnormal clones being coexisting with the normal cells (1) .  In general, MDS is a disease of the male elderly (over 50 years).  About 50% of the patients are over 70 and less than 25% are less than 50 years old.  However, younger people are not an exception, since prolonged exposure to cytotoxic drugs such as the alkylating agents, radiotherapy and toxic chemicals such as benzene may predispose them to MDS (5) .  In the elderly, spontaneous mutations are the cause of MDS occurrence (4) .  All the previous were causes, but the presence of a cause is not always the case.  When a cause is not present, MDS may be arising from aplastic anaemia or paroxysmal nocturnal hemoglobinuria (6) .  MDS in most cases precedes the occurrence of acute myelogenous or lymphosytic leukemias, that’s why preleukemia was the term given to this group of disorders (7) .  However, MDS is the most proper term given to describe this group of disorders.

Classification of MDS:

According to the French-American-British group (FAB), MDS consists of five clinical syndromes (3) .  The classification is based upon blood and bone marrow morphology.  The morphological criteria of subdividing MDS into the five syndromes are 1) the number of myelocytes and ringed sideroblasts in the bone marrow, 2) the number of blasts and monocytes in the peripheral blood, and 3) the presence of Auer rods (4) .  The five subtypes of MDS according to FAB are:

1) Refractory Anaemia (RA) with bone marrow myeloblasts less than 5% of the hematopoietic cells, and peripheral blood blasts less than 1%.  Ringed sideroblasts may or may not be present in the bone marrow (5) .

2) Refractory Anaemia with ringed sideroblasts (RARS) with RA presenting with ringed sideroblasts making up 15% or more of the erythroid precursors (5) .

3) Refractory Anaemia with excess blasts (RAEB) with 5 – 20 % of the bone marrow cells is made up of myeloblasts.  Peripheral blood blasts are less than 5%. (3)   Here, the number of ringed sideroblasts doesn’ t makes a difference.  Moreover, there is a risk of transformation into leukemia (5) .

4) Refractory Anaemia with excess blasts in transformation (RAEB-t) with about 20 – 30% of the bone marrow cells is made up of myeloblasts and the peripheral blood blasts being less than 5% (4) .  Auer Rods are usually present. The number of ringed sideroblast doesn’t make a difference (6) .

5) Chronic Myelomonocytic leukemia (CMML) with monocytes’ count greater than 109/L with any of the subtypes presented earlier (5) .

It is worth saying that the prognosis is better in patients with the marrow blasts being less than 5% (6) .  The FAB system of classifying MDS into its five major subtypes is useful since it is easily applied and allows for uniformity of reporting.  However, this system remains imperfect, since the morphologic subtypes do not group patients with closely similar clinical course .  Moreover, the prognostic outcomes are just the same in different groups.  In addition, no consideration is given for the biologic characteristics of involved cells such as the mutations or their effect, which is the main cause.  Finally, this method of classification groups different disorders into phenotypically similar groups (7) .

Differentiation of MDS from Acute Luekemia:

 The major criteria of differentiation between MDS and acute luekemia is the number of blast cells in the bone marrow.  The need to differentiate between MDS and acute leukemia arised when a subgroup of MDS which is RAEBt was recognized (8) .  When the blasts of the bone marrow make up less than 30% of the total WBCs count, MDS is the disorder of concern.  In fact, according to blasts count, MDS can be either low grade with blasts being less than 5%, or high risk with blasts count usually between 20% and 30% of bone marrow WBCs count.  When the blasts count is more than 30%, acute leukemia has taken place (8) .  Acute leukemia is caused by accumulation of abnormal WBCs in the bone marrow and this results in bone marrow failure presenting in  pancytopenia.  MDS is caused by trilineage dysplasia due to defective stem cells.  Moreover,  MDS can arise from AML treatment, while AML can arise from MDS through transformation.

MDS cytogenetics:

 MDS is divided into two main groups, which are primary and secondary MDS (1) .  Chromosomal abnormalities are commonly seen in secondary MDS, but not that common in primary MDS.  In general, chromosomal abnormalities are seen in about 50% of MDS patients (4) .  These abnormalities are mainly quantitative in which chromosomal material is gained of lost.  The commonest abnormalities are those of chromosomes 5, 7, Y and 8 (5) .  One type of abnormality or another is not necessarily confined to a specific subtype of MDS or MDS in general, since their occurrence in another disorder such as ANLL is possible (7) .  Other chromosomal abnormalities that can be seen in MDS but less commonly are 11q-, 12q-, 20q- and iso 17q (4) .  The clinical features of an MDS caused by a chromosomal abnormality may not be affected by the chromosomal abnormality, except in 5q-, -7 and 11q- in which the chromosomal abnormality may contribute to the occurrence of some clinical features (5) .  A single or several chromosomal abnormalities may be present in a single patient.  When several chromosomal abnormalities are present, then the prognosis becomes poor (6) .  Moreover, the more the bone marrow cells that have normal cytogenitics, the higher the chance to have a good prognosis and the lower the chance to have leukemic transformation and the vice versa (5) .

5q- Syndrome: corresponds to the loss of band q13 to q33 of chromosome 5 in the elderly females (3) .  Usually Refractory macrocytic anaemia is present (4) .  This is accompanied by normal or raised platelet count and micro megakaryocytes, which are hypolobulated or unilobulated (5) .  The clinical features in a patient with 5q- Syndrome are consistent.  The clinical course is long with no major events, except when occasional transfusion is needed (4) .  About 50% of the patients experience splenomegaly.  Moderate dyserythropoiesis may be present and the granulocyte differentiation is well (3) .  5q- Syndrome patients do not develop leukemia and the prognosis of this disorder is good (5) .

Monosomy 7: Found in patients who were previously subjected to chemotherapy, and is always accompanied by another chromosomal abnormality.  Children with MDS usually have such chromosomal abnormality (6) .  In such abnormality, anaemia is present, but nuetropenia and thrombocytopenia are variable.  Hepatosplenomegaly is found with increased susceptibility to infections, especially in children.  Moreover, defective chemotaxis of neutrophils and monocytes is found in children and adult (3) .  Monocytosis is present in about ¼ of the patients with Monosomy 7.  The prognosis of such disorder is not good since the development of acute leukemia is very predictable (5) .

11q-:  MDS patients with deletion of the long arm of chromosome 11 usually have ringed sideroblasts with increased iron deposits.  11q- is usually accompanied by other chromosomal abnormalities and is found in patients with RAEB or RARS (4) .

Pathogenesis and Pathophysiology of MDS:

 The pathogenesis of MDS is not yet known.  The chromosomal abnormalities may or may not be a basis for the mechanisms responsible for the development of MDS, since the occurrence of cytogenetic abnormalities is not always accompanied by the occurrence of phenotypic expression of the disease (6) . In addition, highly diverse chromosomal abnormalities are accompanied by phenotypically indistinguishable disorders.  Moreover, the occurrence of MDS or the procession to leukemic transformation is not always caused by a specific chromosomal abnormality (5) .  If present, the role of the chromosomal abnormalities in the pathogenesis of MDS is not also certain (6) .  Mutations targeted against ras and fms genes may make the picture clearer.  Point mutations resulting in the substitution of one amino acid at codons 12, 13 and 61 of ras gene were found in 30% of MDS patients.  The product of the mutant ras gene could stimulate continuos signal transduction, which may result in malignant transformation (5) .  Ras oncogene plays a critical role in terminal differentiation and this function is certainly disturbed if the responsible gene is defected (4) .  Cells may also experience increased resistance to toxic chemicals with mutated ras oncogene due to the expression of mdr-1 and glutathione-S transferase genes (6) .   Although all the previous facts about mutated ras oncogen seem to be important in the occurrence of MDS, mutated ras oncogen can be presenting in normal subjects.  Therefore, mutations of ras oncogen may occur and remain latent until other triggering factors take place to make it possible for MDS to evolute (5) .  Moreover, the possibility of transformation of MDS into acute leukemia with patients with mutated ras oncogene is higher than those without the mutated gene (4) .  Mutations of fms gene result in higher than normal rates of  production of M-CSF receptor and the result is more activity in the myelogenous lineage (6) .  Such mutations were found in 20% of patients with CMML.  It is worth mentioning that ras and fms genes mutations, if they take place, are early events that contribute in an unknown manner to the development of MDS (4) .  The pathophysiologies of the cytopenias occurring in MDS are also of limited certainty.  Ineffective hematopoiesis is said to be the cause (3) .  Demonstration of cytopenia occurring because of excessive intramedullay destruction of precursor cells has not yet been established .  Another approach to explain the pathophysiology of MDS is to assume the failure of differentiation.  This concept was proved since colony formation in cultures of multipotent progenitors from bone marrow of patients MDS as well as colony growth of committed progenitors are absent or reduced (4) .  Moreover, maturation defects often are seen in the progenitors of one or two lineages resulting in the cytopenias (5) .  The production of hematopoietic growth factors including GM-CSF, M-CSF, G-CSF, IL-3 and IL-6 may also be reduced in MDS.  Due to the importance of these factors in the regulation of the myeloid maturation sequence, reduced amounts of the factors certainly result in defective differntiation in MDS (6) .

Clinical features and presentation of MDS:

 The diagnostic criteria of MDS are not strongly defined (1) .  The presence of the triad of chronic cytopenia, bone marrow hyperplasia and dysmyelopoietic abnormalities are enough to confirm the presence of MDS (3) .  However, megaloblastic anaemia resulting from folate of vitamin B12 deficiency, the consequences of cytotoxic therapy, myelofibrosis or ANLL may make the diagnosis more difficult (5) .  Other difficulties can be the presence of normocytic anaemia, hypoblastic bone marrow and the non-recognizable morphologic abnormalities (4) .  Nevertheless, the characteristic cytogenetic abnormalities may be helpful findings (3) .  The evolution of the disease is usually slow, and the discovery of the disease may happen accidentally when the patient’s blood is tested for other unrelated reasons.  There are no specific features discriminating MDS from other hematological disorders and they are similar to those of anaemia of gradual onset.  These include fatigue and weakness in about 30% of the patients (4) .  In the elderly, aggravation of already present heart disease may also take place.  Recurrent infections, easy bruising and abnormal bleeding also happen due to leukopenia and thrombocytopnia (5) .  Arthralgias are common findings.  In addition, fever and weight loss are occasional findings (3) . Sweet’s Syndrome presenting as cutaneous vasculitis may also be found in MDS patients.  Slight marrow fibrosis is another common finding in MDS.  Severe myelofibrosis either presenting at the time of diagnosis or developing later during the disease course can be another finding (6) .  Cytopenia discovered accidentally is another finding since 50% of the patients are asymptomatic.  Hepatosplenomegaly and lymphadenopathy are common findings especially in CMML patients (3) .  Pallor and ecchymoses may be present (4) .

Laboratory findings in MDS:

 The laboratory findings in one subtype of MDS differ in a way or another from the findings in another subtype (3) . Generally,  dysplasia in the three cell lines is present in all subtypes.  Dyserythropoiesis presents as qualitative erythroid abnormalities of blood and marrow.  Islands of erythroid hyperplasia with erythroblastic deformities (4) .  In addition, megaloblastoid changes and nuclear-cytoplasmic dyssynchrony can occur with abnormal nuclear morphology (5) .  Dysgranulopoiesis presenting as abnormalities of the myeloid series and these are more subtle than those of dyserythropoiesis.  Blood and marrow neutrophils seem to be  agranular or hypogranular.  Secondary granules in marrow myelocytes may be lacking with basophilic cell cytoplasm due to increased ribosomes number (6) .  Primay granules in promyelocytes may be lacking or increased.  Dysmegakaryopoiesis presents in the form of diminished or deranged megakaryocyte populations which may be smaller than normal with several seperated nuclei (7) .  The platelets produced by these abnormal cells are larger than normal.  Moreover, blast cells found in MDS are of two types, blasts I and II. which differ in their cytoplasmic features.  Type I blasts range from being normal-appearing myeloblasts to undifferentiated forms with uncondensed nuclear chromatin, large nucleoli and agranular cytoplasm.  TypeII  blasts have abundant cytoplasm with few primary granules (3) .  The following are the major laboratory findings of peripheral blood and bone marrow of each subtype of MDS.

1) Refractory Anaemia: It is found mainly in patients over 50 years of age and anaemia that is resistant to treatment is the major presenting symptom.  The peripheral blood is characterized by the presence of reticulocytopenia with normal monocyte level and decreased RBCs count (6) .  There is also variable dyserythropoiesis.  Dysgranulopoiesis may also be presenting.  Blast cells are not usually seen in peripheral blood, and when seen they constitute no more than 1% of the WBCs count which may be normal or decreased (4) .    The bone marrow shows normal or hypercellularity.  There is also erythroid hyperplasia and/or dyserythropoiesis. The granulocytic and megakaryocytic series are normal (5) .  A major finding is the blast count being less than 5% of WBCs.  Moreover, neutropenia and thrombocytopenia are rare.  Ringed sideroblasts make up less than 3% of total erythroblasts (3) .  15% of cases may terminate in ANLL (6) .

2) Refractory anaemia with ringed sideroblasts (RARS) is characterized by a bone marrow that contain ringed sideroblasts that make up more than 15% of nucleated cells (4) .  The rest of the findings are just the same to those of refractory anaemia in peripheral blood and bone marrow.  About 15% of the cases may terminate in ANLL (6) .

3) Refractory anaemia with excess blasts (RAEB) occurs mainly in individuals who are over 50 years of age.  It is characterized by a hypercellular bone marrow with varying degrees of granulocytic or erythroid hyperplasia.  Cytopenia occurs in two or more of the bone marrow series and these could present as dysgranulopoiesis, dyserythropoiesis and dysmegakaryocytopoiesis.  Ringed sideroblasts may be present.  Blast cells account for more than 5% usually up to 20% of WBCs count.  The peripheral blood of RAEB patients shows abnormalities in all three cell lines.  Dysgranulopoiesis is a common blood finding.  Blast cells account for less than 5% of the total WBCs count which is decreased. About 30% of RAEB patients terminate in ANLL.

4) Chronic myelomonocytic leukemia (CMML) has monocytosis as its defining feature.  Monocytes count is more than 109/L.  Mature granulocytes count is also increased.  Dysgranulopoiesis may be present in the forms of hypogranular and Pelger forms.  The peripheral blood contains blasts that make up less than 5% of WBCs the count, which may be increased or decreased.  The bone marrow shows the same findings of RAEB with increase in monocytes precursors.  The blasts make up 5 – 20% of the WBCs count.  About 40% of CMML patients terminate in ANLL.

5) Refractory anaemia with excess blasts in transformation (RAEBt) affects virtually any age and it is characterized by general cytopenia with hematological findings similar to those of RAEB.  The peripheral blood shows blasts that make up more than 5% of the total WBCs count, which is decreased.  The bone marrow blast’s type I and II count is 20 – 30 % of WBC.  The presence of Auer Rods in granulocyte precursors is a defining feature of RAEBt.  100% of RAEBt patients terminate in ANLL.

Prognosis and management of MDS:

 Not all MDS patients need treatment because no treatment has been found to normalize haemopoieses and if treatment was tried, it may worsen the situation. About 75% of MDS patients do not terminate in leukemia during their lifetime and about 30% of the patients die of bleeding or infectious complications of the MDS.  In addition, many patients never have symptoms related to MDS and die of unrelated causes although they have the disease.  The median survival of patients with MDS is about 20 months.   MDS can be either low-grade or high risk MDS.  Low-grade MDS is managed by red cell and platelets transfusion with antibiotics.  Careful treatment with growth factors such as IL-3 and GM-CSF is used to improve bone marrow function.  High-grade MDS patients need a treatment plan that will improve the overall prognosis.  The first step is general support care only and this is the most suitable management that could be given to the elderly with other major medical problems.  This includes red cell and platelets transfusions along with antibiotics and antifungals.  The second step is the treatment with low-dose cytotoxic drugs such as cytosine arabinoside, which is used to reduce the number of blast cells and to induce the differentiation in the myeloid series.  The third step is the use of single agent oral chemotherapy in such as Hydroxyurea, especially in patients with CMML, RAEB and RAEBt.  The fourth step is the use of intensive chemotherapy in patients under 60 years with bad-risk.  Bone marrow transplantation is the fifth option and this is used in younger patients who are under 55 years of age. An HLA matching donor is needed and complete cure is of great chance of occurrence.
Evolution to ANLL occurs in only 20% to 25% of MDS patients.  Predesposition to leukemic transformation occurs mainly in MDS patients with severe cytopenias, more overt qualitative disorders of cells, complex chromosomal abnormalities and abnormalities of marrow cell colony growth in culture either increased or decreased.  In these leukemic patients, treatment is needed to control or eliminate the abnormal clone and to correct bone marrow failure as well as replacing the deficient blood cells.