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MYELODYSPLASTIC SYNDROMES

Babak Tamizi Far MD.Assistant professor of internal medicineAl-zahra university hospital,Isfahan university of medical sciences

Key FeaturesESSENTIALS OF DIAGNOSIS

• Cytopenias with hypercellular bonemarrow

• Morphologic abnormalities in two ormore hematopoietic cell lines

• Cytopenias with hypercellular bonemarrow

• Morphologic abnormalities in two ormore hematopoietic cell lines

Causes

– Idiopathic (most common)– May be seen after cytotoxic chemotherapy

• May evolve into acute myeloid leukemia(AML); had been termed "preleukemia" inthe past

– Idiopathic (most common)– May be seen after cytotoxic chemotherapy

• May evolve into acute myeloid leukemia(AML); had been termed "preleukemia" inthe past

Myelodysplasia encompasses severalheterogeneous syndromes

– Refractory anemia (with or without ringedsideroblasts): no excess bone marrowblasts

– Refractory anemia with excess blasts(RAEB): 5–19% blasts

– Chronic myelomonocytic leukemia (CMML):a proliferative syndrome, includingperipheral blood monocytosis > 1000/mcL

– Refractory anemia (with or without ringedsideroblasts): no excess bone marrowblasts

– Refractory anemia with excess blasts(RAEB): 5–19% blasts

– Chronic myelomonocytic leukemia (CMML):a proliferative syndrome, includingperipheral blood monocytosis > 1000/mcL

GENERAL CONSIDERATIONS

• Group of acquired clonal disorders ofthe hematopoietic stem cell,characterized by cytopenias, usuallyhypercellular marrow, and morphologicand cytogenetic abnormalities

• No specific chromosomal abnormality isseen, but abnormalities inchromosomes 5 and 7 are common

• Group of acquired clonal disorders ofthe hematopoietic stem cell,characterized by cytopenias, usuallyhypercellular marrow, and morphologicand cytogenetic abnormalities

• No specific chromosomal abnormality isseen, but abnormalities inchromosomes 5 and 7 are common

DEMOGRAPHICS

• Occurs most often in patientsaged > 60

Clinical FindingsSYMPTOMS AND SIGNS

• Asymptomatic, with incidentally foundcytopenias

• Fatigue, infection, or bleeding is related to bonemarrow failure

• Wasting, fever, weight loss• Splenomegaly• Pallor• Bleeding• Signs of infection

• Asymptomatic, with incidentally foundcytopenias

• Fatigue, infection, or bleeding is related to bonemarrow failure

• Wasting, fever, weight loss• Splenomegaly• Pallor• Bleeding• Signs of infection

DIFFERENTIAL DIAGNOSIS

• AML ( 20% blasts)• Aplastic anemia• Anemic of chronic disease• Vitamin B12 or folate deficiency

• AML ( 20% blasts)• Aplastic anemia• Anemic of chronic disease• Vitamin B12 or folate deficiency

DiagnosisLABORATORY TESTS

• Anemia may be marked• Mean cell volume is normal or increased• Peripheral blood smear may show macro-ovalocytes• White blood cell count usually normal or reduced;

neutropenia is common• Neutrophils may exhibit morphologic abnormalities,

including deficient numbers of granules, or bilobed nucleus(Pelger-Huet anomaly)

• Myeloid series may be left shifted with small numbers ofpromyelocytes or blasts

• Platelet count is normal or reduced; hypogranular plateletsmay be present

• Anemia may be marked• Mean cell volume is normal or increased• Peripheral blood smear may show macro-ovalocytes• White blood cell count usually normal or reduced;

neutropenia is common• Neutrophils may exhibit morphologic abnormalities,

including deficient numbers of granules, or bilobed nucleus(Pelger-Huet anomaly)

• Myeloid series may be left shifted with small numbers ofpromyelocytes or blasts

• Platelet count is normal or reduced; hypogranular plateletsmay be present

IMAGING STUDIES

• Radiographic findings are variable– Stage I: hilar adenopathy alone– Stage II: hilar adenopathy with parenchymal

involvement– Stage III: parenchymal involvement alone

• Parenchymal involvement usuallymanifests as diffuse reticular infiltrates,but focal infiltrates, acinar shadows,nodules, and rare cavitation are seen

• Pleural effusion occurs in < 10% ofpatients

• Radiographic findings are variable– Stage I: hilar adenopathy alone– Stage II: hilar adenopathy with parenchymal

involvement– Stage III: parenchymal involvement alone

• Parenchymal involvement usuallymanifests as diffuse reticular infiltrates,but focal infiltrates, acinar shadows,nodules, and rare cavitation are seen

• Pleural effusion occurs in < 10% ofpatients

DIAGNOSTIC PROCEDURES

• ECG may show conduction disturbancesand dysrhythmias

• Biopsy demonstrating noncaseatinggranulomas is required for diagnosis

• Easily accessible biopsy sites includelymph nodes, skin lesions, and salivaryglands

• ECG may show conduction disturbancesand dysrhythmias

• Biopsy demonstrating noncaseatinggranulomas is required for diagnosis

• Easily accessible biopsy sites includelymph nodes, skin lesions, and salivaryglands

DIAGNOSTIC PROCEDURES

• Bone marrow aspirate and biopsy arecharacteristically hypercellular, but it maybe hypocellular

• Signs of abnormal erythropoiesis include– Megaloblastic features– Nuclear budding– Multinucleated erythroid precursors

• Bone marrow aspirate and biopsy arecharacteristically hypercellular, but it maybe hypocellular

• Signs of abnormal erythropoiesis include– Megaloblastic features– Nuclear budding– Multinucleated erythroid precursors

DIAGNOSTIC PROCEDURES

• Prussian blue stain may demonstrateringed sideroblasts

• Myeloid series is often left shifted withvariable increases in blasts

• Deficient or abnormal myeloid granulesmay be seen

• A characteristic abnormality is dwarfmegakaryocytes with unilobed nucleus

• Cytogenetics may be abnormal

• Prussian blue stain may demonstrateringed sideroblasts

• Myeloid series is often left shifted withvariable increases in blasts

• Deficient or abnormal myeloid granulesmay be seen

• A characteristic abnormality is dwarfmegakaryocytes with unilobed nucleus

• Cytogenetics may be abnormal

TreatmentMEDICATIONS

• Erythropoietin, 30,000 unitssubcutaneously weekly, reduces redblood cell transfusion requirement in20%

• The combination of high-doseerythropoietin and myeloid growthfactors produces higher response rate,but the cost is very high

• Erythropoietin, 30,000 unitssubcutaneously weekly, reduces redblood cell transfusion requirement in20%

• The combination of high-doseerythropoietin and myeloid growthfactors produces higher response rate,but the cost is very high

MEDICATIONSOral deferasirox (20 mg/kg/d)

• Used as iron chelation therapy• Prevents serious iron overload in

patients who depend on red blood celltransfusion and who do not haveimmediately life-threatening disease

• Used as iron chelation therapy• Prevents serious iron overload in

patients who depend on red blood celltransfusion and who do not haveimmediately life-threatening disease

Lenalidomide– Recommended initial dose is 10 mg orally

daily– Approved for treatment of transfusion-

dependent anemia due to myelodysplasia– Effective in patients with the 5q-cytogenetic

abnormality– Most common side effects are neutropenia

and thrombocytopenia, but venousthrombosis is also seen and warrants aspirinprophylaxis

– Cost is extremely high, and it is not effectiveeither for cell lines other than red blood cellsor for patients with increased blasts

– Recommended initial dose is 10 mg orallydaily

– Approved for treatment of transfusion-dependent anemia due to myelodysplasia

– Effective in patients with the 5q-cytogeneticabnormality

– Most common side effects are neutropeniaand thrombocytopenia, but venousthrombosis is also seen and warrants aspirinprophylaxis

– Cost is extremely high, and it is not effectiveeither for cell lines other than red blood cellsor for patients with increased blasts

MEDICATIONS

• Patients affected primarily with severeneutropenia may benefit from the use ofmyeloid growth factors such as G-CSF

• Azacitidine improves both symptoms andblood counts and prolongs survival and timeto conversion to acute leukemia

• Decitabine can produce similar responses

• Patients affected primarily with severeneutropenia may benefit from the use ofmyeloid growth factors such as G-CSF

• Azacitidine improves both symptoms andblood counts and prolongs survival and timeto conversion to acute leukemia

• Decitabine can produce similar responses

THERAPEUTIC PROCEDURES

• Red blood cell transfusions areindicated for severe anemia

• Allogeneic stem cell transplantation– Only curative therapy for myelodysplasia– Role is limited by advanced age of many

patients and indolent course of disease

• Red blood cell transfusions areindicated for severe anemia

• Allogeneic stem cell transplantation– Only curative therapy for myelodysplasia– Role is limited by advanced age of many

patients and indolent course of disease

OutcomeCOMPLICATIONS

• Infection and bleeding

PROGNOSIS

• Myelodysplasia is ultimately fatal, mostcommonly because of infections or bleeding

• Risk of transformation to AML depends on thepercentage of blasts in bone marrow

• Patients with refractory anemia without excessblasts may survive many years, with low risk ofleukemia (< 10%)

• Patients with excess blasts or CMML have shortsurvivals (usually < 2 years) and higher (20–50%) risk of developing acute leukemia

• Myelodysplasia is ultimately fatal, mostcommonly because of infections or bleeding

• Risk of transformation to AML depends on thepercentage of blasts in bone marrow

• Patients with refractory anemia without excessblasts may survive many years, with low risk ofleukemia (< 10%)

• Patients with excess blasts or CMML have shortsurvivals (usually < 2 years) and higher (20–50%) risk of developing acute leukemia

PROGNOSIS

• Deletions of chromosomes 5 and 7associated with poor prognosis

• Cure rates of allogeneic transplantationare 30–60%, depending on risk statusof disease

• Deletions of chromosomes 5 and 7associated with poor prognosis

• Cure rates of allogeneic transplantationare 30–60%, depending on risk statusof disease

• WHEN TO REFER– All patients should be referred to a

hematologist

• WHEN TO ADMIT– Hospitalization is needed only for specific

complications, such as severe infection

• WHEN TO REFER– All patients should be referred to a

hematologist

• WHEN TO ADMIT– Hospitalization is needed only for specific

complications, such as severe infection