Myelodysplastic Syndrome

Hematology

Clinicals - History

Fact Explanation
Introduction Myelodysplasia is a heterogeneous group of hematopoietic stem cell disorder disease occurring due to the disordered development of blood cells in bone marrow causing failure of normal blood cell production, leading to low blood counts, giving the clinical features of anemia or, less commonly, bi- or pancytopenia. It is is usually diagnosed in elderly patients. The pathological hallmark of myelodysplastic syndrome is the marrow dysplasia. There is ineffective hematopoiesis and a varying risk of transformation to acute leukemia. Though the aetiology is not clear, evidence suggest the alterations in the oncogens underlies the pathogenesis. Minimally for diagnosis of myelodysplasia, there should be erythroid, granulocyte, or megakaryocyte dysplasia in 10% or more of informative cells. Introduction
Myelodysplasia is a heterogeneous group of hematopoietic stem cell disorder disease occurring due to the disordered development of blood cells in bone marrow causing failure of normal blood cell production, leading to low blood counts, giving the clinical features of anemia or, less commonly, bi- or pancytopenia. It is is usually diagnosed in elderly patients. The pathological hallmark of myelodysplastic syndrome is the marrow dysplasia. There is ineffective hematopoiesis and a varying risk of transformation to acute leukemia. Though the aetiology is not clear, evidence suggest the alterations in the oncogens underlies the pathogenesis. Minimally for diagnosis of myelodysplasia, there should be erythroid, granulocyte, or megakaryocyte dysplasia in 10% or more of informative cells.
Fatigue, lethargy, dizziness, All these features are due to the anaemia. Low blood haemoglobin causes less oxygen delivery to the tissues and reduced cellular energy production. Fatigue, lethargy, dizziness,
All these features are due to the anaemia. Low blood haemoglobin causes less oxygen delivery to the tissues and reduced cellular energy production.
Shortness of breath on exertion May be due to anaemia. Also the patients with pre existing cardiac disease may get aggravated cardiac failure due to the anaemia. Shortness of breath on exertion
May be due to anaemia. Also the patients with pre existing cardiac disease may get aggravated cardiac failure due to the anaemia.
Palpitations Due to the increased cardiac workload, this needed to maintain tissue oxygenation. Palpitations
Due to the increased cardiac workload, this needed to maintain tissue oxygenation.
Nose bleeds / gum bleeds, blood in the stool, heavy menstrual bleeding Bone marrow dysplasia causes thrombocytopenia and morphological abnormalities of the platelets. Platelet abnormalities may cause skin and mucosal bleeding. Nose bleeds / gum bleeds, blood in the stool, heavy menstrual bleeding
Bone marrow dysplasia causes thrombocytopenia and morphological abnormalities of the platelets. Platelet abnormalities may cause skin and mucosal bleeding.
Easy bruising and rashes Cutaneous bleeding can occur in thrombocytopenia. They can have petechiae/purpura, bruises, haemorrhagic spots in the skin and mucous membranes. Easy bruising and rashes
Cutaneous bleeding can occur in thrombocytopenia. They can have petechiae/purpura, bruises, haemorrhagic spots in the skin and mucous membranes.
Frequent infections There are changes in the leucocyte function such as leucopenia, defect in the phagocytic function, adheson and chemotaxis of the neutrophils that can lead to defects in the immune system, making individual vulnerable for infections. Cardiac iron overload may also make the person prone to get infections. Frequent infections
There are changes in the leucocyte function such as leucopenia, defect in the phagocytic function, adheson and chemotaxis of the neutrophils that can lead to defects in the immune system, making individual vulnerable for infections. Cardiac iron overload may also make the person prone to get infections.
Visual problems Iron overload and thrombocytopenia causing retinal hemorrhages are responsible for vision problems. Visual problems
Iron overload and thrombocytopenia causing retinal hemorrhages are responsible for vision problems.
Involvement of the other organs Excess iron deposits within the liver, pancreas, and heart of these patients after repeated blood transfusions and may cause cirrhosis, diabetes, and cardiomyopathy. Involvement of the other organs
Excess iron deposits within the liver, pancreas, and heart of these patients after repeated blood transfusions and may cause cirrhosis, diabetes, and cardiomyopathy.
Occupational history and past history of radiation/ cytotoxic drug exposure Occupational history to assess exposure to carcinogens and past history of radiation/ cytotoxic drug exposure is important to evaluate as an aetiological factors. Occupational history and past history of radiation/ cytotoxic drug exposure
Occupational history to assess exposure to carcinogens and past history of radiation/ cytotoxic drug exposure is important to evaluate as an aetiological factors.
Age Mostly seen in the middle aged to elderly population. Age
Mostly seen in the middle aged to elderly population.

Clinicals - Examination

Fact Explanation
Pallor without signs of nutritional deficiency Due to anemia. As the patient do not have the features of nutritional deficiency, it helps in distinguishing this anaemia from the other causes. Pallor without signs of nutritional deficiency
Due to anemia. As the patient do not have the features of nutritional deficiency, it helps in distinguishing this anaemia from the other causes.
Dyspnoea Anemia causes low Hb and at the lung gas exchange site that will lead to reduced oxygen supply to the body. There is a decreased capacity to increase the extraction of O2 due to the anaemia. Dyspnoea
Anemia causes low Hb and at the lung gas exchange site that will lead to reduced oxygen supply to the body. There is a decreased capacity to increase the extraction of O2 due to the anaemia.
Cardiovascular system: Tachycardia, arrhythmias, and systoloc murmer and other features of heart failure; Third heart sound, Elevated jugular venous pressure, Hepatomegaly Anemia can cause flow murmurs, due to increased flow of blood through the aortic valve as the cardiac output increases. Tachycardia may result due to the increased work load on the heart. Other features of heart failure are due to aggravated heart failure. Iron overload may also cause cardiomyopathy. Cardiovascular system: Tachycardia, arrhythmias, and systoloc murmer and other features of heart failure; Third heart sound, Elevated jugular venous pressure, Hepatomegaly
Anemia can cause flow murmurs, due to increased flow of blood through the aortic valve as the cardiac output increases. Tachycardia may result due to the increased work load on the heart. Other features of heart failure are due to aggravated heart failure. Iron overload may also cause cardiomyopathy.
Ankle oedema Low concentration of haemoglobin in patients with anaemia leads to reduced inhibition of basal endothelium-derived relaxing factor activity, that results in generalised vasodilatation. Reduced peripheral resistance and low blood pressure may lead to sympathetic activation via baroreceptors with neurohormonal activation of renin angiotensinogen aldesterone mechanism by juxtaglomerular cells. Aldesterone causes retention of sodium and water inside the body causing oedema.
On the other hand heart failure occurs due to the increase work load on heart, causing increased venous pooling with the hydrostatic pressure inside the veins of the lower limbs to exceed the compensation by the oncotic pressure (according to the starling forces) leading to ankle oedema by fluid extravasation in to the interstitium.
Ankle oedema
Low concentration of haemoglobin in patients with anaemia leads to reduced inhibition of basal endothelium-derived relaxing factor activity, that results in generalised vasodilatation. Reduced peripheral resistance and low blood pressure may lead to sympathetic activation via baroreceptors with neurohormonal activation of renin angiotensinogen aldesterone mechanism by juxtaglomerular cells. Aldesterone causes retention of sodium and water inside the body causing oedema.
On the other hand heart failure occurs due to the increase work load on heart, causing increased venous pooling with the hydrostatic pressure inside the veins of the lower limbs to exceed the compensation by the oncotic pressure (according to the starling forces) leading to ankle oedema by fluid extravasation in to the interstitium.
Petechiae/Purpura, bruises, haemorrhagic spots in the skin and mucous membrane Due to the thrombocytopenia. Petechiae/Purpura, bruises, haemorrhagic spots in the skin and mucous membrane
Due to the thrombocytopenia.
Febrile Recurrent infections due to leucopenia may be a cause. Immediate fever and chills may occur as a common side effects of drug therapy particularly after antithymocyte globulin administration. Febrile
Recurrent infections due to leucopenia may be a cause. Immediate fever and chills may occur as a common side effects of drug therapy particularly after antithymocyte globulin administration.
Signs of infections (eg:- lung crepitations, skin infections, urinary tract infections) Recurrent infections may be associated with reduced immunity due to leukopenia. Neutropenia is the main predisposing factor, but there are other immune defects including impaired neutrophil function, B-, T- and NK-cell defects and the possible consequences of iron overload due to red blood cell transfusions responsible for the infections. Signs of infections (eg:- lung crepitations, skin infections, urinary tract infections)
Recurrent infections may be associated with reduced immunity due to leukopenia. Neutropenia is the main predisposing factor, but there are other immune defects including impaired neutrophil function, B-, T- and NK-cell defects and the possible consequences of iron overload due to red blood cell transfusions responsible for the infections.

Investigations - Diagnosis

Fact Explanation
Complete blood count with red cell indices There may be isolated cytopenia (leucopenia, thrombocytopenia, anaemia) or bicytopenia involving two cell lines or pancytopenia involving all the three cell lines. Leukocyte count is often <4000/μL, platelet count is often <100 000/μL and hemoglobin often <12 g/dL. Thrombocytopenia may present in nearly 50% of patients at the presentation. Low haemoglobin level in the blood may be found due to anaemia. Increased mean corpuscular volume, and increased red cell distribution width is found in these patients. Complete blood count with red cell indices
There may be isolated cytopenia (leucopenia, thrombocytopenia, anaemia) or bicytopenia involving two cell lines or pancytopenia involving all the three cell lines. Leukocyte count is often <4000/μL, platelet count is often <100 000/μL and hemoglobin often <12 g/dL. Thrombocytopenia may present in nearly 50% of patients at the presentation. Low haemoglobin level in the blood may be found due to anaemia. Increased mean corpuscular volume, and increased red cell distribution width is found in these patients.
Blood picture There are macrocytic (mean cell volume of >100 fL) cells usually with a dimorphic blood picture involving hypochromic microcytic population or normocytic picture. Anisosytosis, poikilocytosis, basophilic stippling, megaloblastoid nucleated erythrocytes and some ring sideroblasts may be seen. Granulocytes may have reduced segmentation and absent granulation. Blood picture
There are macrocytic (mean cell volume of >100 fL) cells usually with a dimorphic blood picture involving hypochromic microcytic population or normocytic picture. Anisosytosis, poikilocytosis, basophilic stippling, megaloblastoid nucleated erythrocytes and some ring sideroblasts may be seen. Granulocytes may have reduced segmentation and absent granulation.
Reticulocyte count Reticulocyte count response may be very low due to dysplasia of bone marrow. Reticulocyte count
Reticulocyte count response may be very low due to dysplasia of bone marrow.
Bone marrow examination Impaired myeloid maturation with with increased granulocyte precursor percentage and maturation arrest is seen. Platelets abnormalities such as giant hypogranular with megakaryocyte fragments, micromegakaryocytes, and mononuclear forms are also common. Bone marrow examination
Impaired myeloid maturation with with increased granulocyte precursor percentage and maturation arrest is seen. Platelets abnormalities such as giant hypogranular with megakaryocyte fragments, micromegakaryocytes, and mononuclear forms are also common.
Cytogenetic techniques-Polymerase chain reaction (PCR) assay or fluorescent in-situ hybridization (FISH) There are mutations in clonal cell lines, with abnormal chromosomes. Chromosomal abnormalities consists of 5q-, monosomy 7 /7q-, trisomy 8 (+8), and numerous other abnormalities which are less frequent. Cytogenetic techniques-Polymerase chain reaction (PCR) assay or fluorescent in-situ hybridization (FISH)
There are mutations in clonal cell lines, with abnormal chromosomes. Chromosomal abnormalities consists of 5q-, monosomy 7 /7q-, trisomy 8 (+8), and numerous other abnormalities which are less frequent.
Flow cytometry Flow cytometry immunophenotyping shows cardinal parameters like blasts, B-cell progenitors, myeloblast CD45 expression, and channel number of side scatter where the maximum number of granulocytes occurs and is used for quantitatification and qualitative evaluation of hematopoietic cells. Flow cytometry
Flow cytometry immunophenotyping shows cardinal parameters like blasts, B-cell progenitors, myeloblast CD45 expression, and channel number of side scatter where the maximum number of granulocytes occurs and is used for quantitatification and qualitative evaluation of hematopoietic cells.
Neutrophil myeloperoxidase activity Is increased in some patients. Neutrophil myeloperoxidase activity
Is increased in some patients.
Lactate dehydrogenase level If increased taht indicates a poor prognosis. Lactate dehydrogenase level
If increased taht indicates a poor prognosis.

Investigations - Management

Fact Explanation
Complete blood count Persistent cytopenia will be helpful in differentiating myelodyaplasiafrom other disorders. It is important to check the blood cell counts during the follow up to assess the response to therapy and the side effects of the treatment. Complete blood count
Persistent cytopenia will be helpful in differentiating myelodyaplasiafrom other disorders. It is important to check the blood cell counts during the follow up to assess the response to therapy and the side effects of the treatment.
Renal functions, liver functions, These are necessary as a baseline and then weekly for the first month of treatment, monthly for the next 5 months and bimonthly thereafter during the iron chelation therapy. Renal functions, liver functions,
These are necessary as a baseline and then weekly for the first month of treatment, monthly for the next 5 months and bimonthly thereafter during the iron chelation therapy.
2DEchocardiography Cardiomyopathy may occur as a result of iron overload. 2DEchocardiography
Cardiomyopathy may occur as a result of iron overload.
Funduscopy Examination of the ocular fundus is done as a baseline and then every 6 months. Funduscopy
Examination of the ocular fundus is done as a baseline and then every 6 months.
Complete blood count Bone marrow dysplasia may cause anaemia with low haemoglobin. Usually transfusion is done when the hemoglobin values below 8 to 9 g/dL. Complete blood count
Bone marrow dysplasia may cause anaemia with low haemoglobin. Usually transfusion is done when the hemoglobin values below 8 to 9 g/dL.
Renal functions (serum creatinine, 24-h creatinine excretion and creatinine clearance using the Cockcroft-Gault and Modification of Diet in Renal Disease formulae) and hepatic function (serum transaminases, bilirubin, alkaline phosphatase and γ-glutamyl transpeptidase) Chronically transfused MDS patients, will develop severe organ failure kidney which may involve and liver. Acute tumor lysis syndrome is associated with occurrence of acute kidney injury (AKI), metabolic acidosis and electrolyte disturbances which include hyperuricemia, hyperphosphatemia, hyperkalemia and hypocalcemia commonly from treatment of malignancies, and patient may present with oliguria. Renal functions (serum creatinine, 24-h creatinine excretion and creatinine clearance using the Cockcroft-Gault and Modification of Diet in Renal Disease formulae) and hepatic function (serum transaminases, bilirubin, alkaline phosphatase and γ-glutamyl transpeptidase)
Chronically transfused MDS patients, will develop severe organ failure kidney which may involve and liver. Acute tumor lysis syndrome is associated with occurrence of acute kidney injury (AKI), metabolic acidosis and electrolyte disturbances which include hyperuricemia, hyperphosphatemia, hyperkalemia and hypocalcemia commonly from treatment of malignancies, and patient may present with oliguria.
International Prognostic Scoring System (IPSS) for staging MDS Depending on the percentage of bone marrow blasts, karyotyping studies and degree of cytopenia IPSS score gives a total value as follows which can be categorized as low: 0, intermediate 1: 0.5-1, intermediate 2: 1.5-2 and high: ≥ 2.5. Revised IPSS (IPSS-R) used five parameters (cytogenetics, BM blast percentage, hemoglobin, platelet count, and neutrophil count), and generated five prognostic classes instead of the original four (very low, low, intermediate, high, and very high) International Prognostic Scoring System (IPSS) for staging MDS
Depending on the percentage of bone marrow blasts, karyotyping studies and degree of cytopenia IPSS score gives a total value as follows which can be categorized as low: 0, intermediate 1: 0.5-1, intermediate 2: 1.5-2 and high: ≥ 2.5. Revised IPSS (IPSS-R) used five parameters (cytogenetics, BM blast percentage, hemoglobin, platelet count, and neutrophil count), and generated five prognostic classes instead of the original four (very low, low, intermediate, high, and very high)
WHO Classification-Based Prognostic Scoring System (WPSS), MD Anderson Prognostic Schemes These are other systems used to assess the prognosis. WHO Classification-Based Prognostic Scoring System (WPSS), MD Anderson Prognostic Schemes
These are other systems used to assess the prognosis.
Subtyping the disease French American British Cooperative Group has devided the MDS into subtypes as follows.
Refractory anemia, Excess blasts with refractory anemia,Excess blasts in transition to Acute myelogenous leukemia with refractory anemia, Ringed sideroblasts with refractory anemia, and
Chronic myelomonocytic leukemia.
Subtyping the disease
French American British Cooperative Group has devided the MDS into subtypes as follows.
Refractory anemia, Excess blasts with refractory anemia,Excess blasts in transition to Acute myelogenous leukemia with refractory anemia, Ringed sideroblasts with refractory anemia, and
Chronic myelomonocytic leukemia.
Fluorescent in-situ hybridization (FISH) Supports the diagnosis as well as contributes to determining the prognosis of MDS. Fluorescent in-situ hybridization (FISH)
Supports the diagnosis as well as contributes to determining the prognosis of MDS.

Management - Supportive

Fact Explanation
Patient education Patient should be educated about the nature of disease, potential complications and available treatment strategies. Patient education
Patient should be educated about the nature of disease, potential complications and available treatment strategies.
Supportive management Fever, pain like constitutional symptoms require attention. Nutritional support may also needed specially in anaemic patients. Psychological support is important in alleviating the anxiety, depression associated with chronic disease. Supportive management
Fever, pain like constitutional symptoms require attention. Nutritional support may also needed specially in anaemic patients. Psychological support is important in alleviating the anxiety, depression associated with chronic disease.
Iron chelation therapy Chronically transfused patients, will develop iron overload and may need to be treated with iron chelation therapy. Patients who have received more than 20 units of RBCs are at high risk for transfusion-associated iron overload. Iron chelation therapy is given with subcutaneously administered desferoxamine once the serum ferritin is 1000 ng/mL. Iron chelation therapy
Chronically transfused patients, will develop iron overload and may need to be treated with iron chelation therapy. Patients who have received more than 20 units of RBCs are at high risk for transfusion-associated iron overload. Iron chelation therapy is given with subcutaneously administered desferoxamine once the serum ferritin is 1000 ng/mL.

Management - Specific

Fact Explanation
Multidisciplivary approach and targets of treatment Various specialities should be involved in the management of these patients. Hematologist is the key person. Nutritional problems, infections, psychological problems like other areas need specific attention. For low-risk patients, the priority is maintenance or restoration of quality of life, and for high-risk patients, treatment is targeted foe prolonging life expectancy. Multidisciplivary approach and targets of treatment
Various specialities should be involved in the management of these patients. Hematologist is the key person. Nutritional problems, infections, psychological problems like other areas need specific attention. For low-risk patients, the priority is maintenance or restoration of quality of life, and for high-risk patients, treatment is targeted foe prolonging life expectancy.
Cytotoxic chemotherapy Azacitidine is a pyrimidine nucleoside analog which has the cytotoxicity as a consequence of its incorporation into RNA as well as DNA. Patients are treated with single dose of azacitidine 75 mg/m2 either subcutaneously or intravenously with a minimum of 7 days and maximum of 28 days inbetween treatments. Lower dose of azacitidine (15 mg/m2 per day for 14 days can be used as a maintenance treatment. Immunomodulatory drugs such as lenalidomide are target the pathogenesis of MDS at the sites of that fosters increased angiogenesis, overproduction of proinflammatory cytokines, accelerated apoptosis of hematopoietic progenitors, and autocrine stimulation by vascular endothelial growth factor. Antithymocyte globulin (ATG) is an immune globulin that has shown to destroy lymphocytes and improve blood counts in some MDS patients. Cytotoxic chemotherapy
Azacitidine is a pyrimidine nucleoside analog which has the cytotoxicity as a consequence of its incorporation into RNA as well as DNA. Patients are treated with single dose of azacitidine 75 mg/m2 either subcutaneously or intravenously with a minimum of 7 days and maximum of 28 days inbetween treatments. Lower dose of azacitidine (15 mg/m2 per day for 14 days can be used as a maintenance treatment. Immunomodulatory drugs such as lenalidomide are target the pathogenesis of MDS at the sites of that fosters increased angiogenesis, overproduction of proinflammatory cytokines, accelerated apoptosis of hematopoietic progenitors, and autocrine stimulation by vascular endothelial growth factor. Antithymocyte globulin (ATG) is an immune globulin that has shown to destroy lymphocytes and improve blood counts in some MDS patients.
Hematopoietic growth factors Patients with neutropenia, will respond to granulocyte colony-stimulating factor (G-CSF) and patients with anemia and neutropenia, will respond to erythropoietin and G-CSF for their neutropenia. Although majority of patients who need transfusion requirements (2 units of red blood cells per month) or elevated erythropoietin levels are unlikely to respond to this treatment. Hematopoietic growth factors
Patients with neutropenia, will respond to granulocyte colony-stimulating factor (G-CSF) and patients with anemia and neutropenia, will respond to erythropoietin and G-CSF for their neutropenia. Although majority of patients who need transfusion requirements (2 units of red blood cells per month) or elevated erythropoietin levels are unlikely to respond to this treatment.
Bone marrow transplantation Allogenic blood stem cell transplantation is the only therapeutic measure that has the potential cure to appropriate patients. This is appropriate for patients aged up to 70 years without relevant comorbidities. Bone marrow transplantation
Allogenic blood stem cell transplantation is the only therapeutic measure that has the potential cure to appropriate patients. This is appropriate for patients aged up to 70 years without relevant comorbidities.
Management of anaemia Usually transfusion is done when the hemoglobin values below 8 to 9 g/dL, but it should be according to individual need. Transfusion-related complications can be reduced by using leukocyte-depleted blood products. Complications can be either infectious or non infectious and hemolytic transfusion reactions and transfusion-related acute lung injury (TRALI) are the most common non infectious complications. Transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and transfusion-related immunomodulation may cause lung injury. Thrombotic complications , allergic reactions, post-transfusion purpura, transfusion-related acute kidney injury, ransfusion-associated graft-versus-host disease may also occur. Management of anaemia
Usually transfusion is done when the hemoglobin values below 8 to 9 g/dL, but it should be according to individual need. Transfusion-related complications can be reduced by using leukocyte-depleted blood products. Complications can be either infectious or non infectious and hemolytic transfusion reactions and transfusion-related acute lung injury (TRALI) are the most common non infectious complications. Transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and transfusion-related immunomodulation may cause lung injury. Thrombotic complications , allergic reactions, post-transfusion purpura, transfusion-related acute kidney injury, ransfusion-associated graft-versus-host disease may also occur.
Management of thrombocytopenia Tranexamic acid is given for patients with marked thrombocytopenia and bleeding diathesis. Platelets, are a “high-plasma” component with donor-derived antibodies, which has a 6-fold increased risk of transfusion-related acute lung injury. Leukoreduction will prevent complications of blood transfusion such as febrile non-hemolytic transfusion-reactions, platelet refractoriness due to human leukocyte antigen alloimmunization transmission of cytomegalovirus. Management of thrombocytopenia
Tranexamic acid is given for patients with marked thrombocytopenia and bleeding diathesis. Platelets, are a “high-plasma” component with donor-derived antibodies, which has a 6-fold increased risk of transfusion-related acute lung injury. Leukoreduction will prevent complications of blood transfusion such as febrile non-hemolytic transfusion-reactions, platelet refractoriness due to human leukocyte antigen alloimmunization transmission of cytomegalovirus.

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