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Norman DjamaludinDivision of Haematology and Medical Oncology Department of Internal Medicine Faculty of Medicine University of Sriwijaya Myelodysplastic Syndromes
Definition of MyelodysplasiaClonal disorderStable cytopenias for 2-6 weeksMorphologic evidence of dysplastic changes in at least 2 hematopoietic cell linesHypercellular or normocellular bone marrowPropensity to transform into AML in 20%
Pathogenesis of MyelodysplasiaIneffective erythropoiesis due to increased apoptosis (programmed cell death)Impaired cellular maturation due to intrinsic defects in cells of neoplastic cloneAltered responses to regulatory hormones
Presentation of Myelodysplasia
Most over age 60Slight male predominanceHx of acquired or congenital risk factorsradiation, chemotherapy (alkylating agents, topoisomerase inhibitors)Hodgkins disease, non-Hodgkins lymphoma, multiple myelomaovarian CA, breast CANH3, diesel, benzeneaplastic anemia, paroxysmal nocturnal hemoglobinuriaFanconis anemia, Downs syndrome, Turners syndrome, Blooms syndrome
DyserythropoiesisMacrocytosisLow reticulocyte countRinged sideroblastsNuclear-cytoplasmic asynchronyBizarre nuclear configurationsAbnormal Fe metabolism
Macrocytosis, biphenotypic populationRinged sideroblastDysmorphic nucleated rbcsIncreased iron stores
DysmyelopoiesisHypogranulationNuclear-cytoplasmic asynchronyPseudo-Pelger-Huet anomalyDefective adhesion, phagocytosis, and bacterial killing
Hypogranulation, nuclear-cytoplasmic asynchronyPseudo-Pelger-Huet anomalyStodtmeister cellAberrant granulation
DysmegakaryocytopoiesisGiant, agranular plateletsMicromegakaryocytes and mononuclear megakaryocytesAbnormal platelet function
Hypogranular plateletsCirculating micromegakaryocyteAbnormal megakaryocyteMononuclear megakaryocyte
Other Manifestations of MDSRheumatologic - vasculitis, arthritis, lupus-like syndromesNeurologic - peripheral neuropathyMetabolic - abnormal LFTsDermatologic - urticaria pigmentosa, chloroma, Sweets syndrome
ChloromaGranulocytic Sarcoma1. Extramedullary aggregates of blast cells2. Greenish color on sectioning due to myeloperoxidase3. AML (M2 with 8;21 translocation), MDS
Sweets SyndromeAcute neutrophilic dermatosis1. Tender red plaques and nodules2. Benign infiltration of PMNs in lower dermis3. AML, MDS, NHL, idiopathic4. Rx - systemic steroids
FAB Classification of MDS
Chronic Myelomonocytic LeukemiaFeatures of myeloproliferative disorder (leukocytosis, splenomegaly)Trilineage dysplasia, classical chromosomal abnormalitiesRisk of transformation to AML correlated with number of bone marrow blasts
Cytogenetics of MDSAbnormalities seen in 40-60% with primary MDSAbnormalities seen in > 80% with secondary MDSValuable in prognosticationnormal, Y-, 5q-> 2 years+81-2 years-7, -5, others< 1 year
Deletion of Chromosome 7Cytogenetic Analysis1. Metaphase cells2. Can screen for any obvious cytogenetic abnormalityFluorescent In-situ Hybridization (FISH)1. Interphase cells2. Allows for computerized analysis3. Restricted to well-established cytogenetic abnormality
Prognostic Factors of AMLGood PrognosisIncreased erythroid activityYounger ageFemale sexHigh percentage of ringed sideroblastsBad PrognosisHigh M:E ratio
Older ageMale sexTrilineage dysplasia, increased blasts
International Prognostic Scoring SystemPercentage of blasts 2.5Median survival 0.4 yrs
Treatment of MyelodysplasiaSupportive careHormonal and immunosuppressive therapyHematopoietic growth factorsDifferentiating agentsChemotherapyBone marrow transplantation
Supportive care of MDSRBC and platelet transfusionsDeferoxamine (Desferal)AntibioticsAvoidance of myelotoxic medicationsPyridoxine 200 mg QD
Growth Factors in MDSGM-CSFG-CSFErythropoietinIL-3IL-6IL-11Thrombopoietin
Differentiating Agents in MDSRetinoidsCholecalciferolsHexamethylene bisacetamide5-aza-2-deoxycytidine - inhibits DNA methylationAmifostine - cytoprotective agent
Chemotherapy in MDSSingle agentsLow-dose cytarabine (LoDAC)High-dose cytarabine (HiDAC)HomoharringtonineTopotecanCombination therapyStandard AML induction therapyFludarabine, cytarabine, idarubicinCyclophosphamide, cytarabine, topotecan
Bone Marrow Transplantation in Myelodysplastic SyndromeAllogeneic BMTBest results withyoung patients (DFS 75%)marrow blasts counts < 5%absence of marrow fibrosisinterval to BMT < 5 yearsmatched sibling donorTreatment-related mortality 34-55%Disease-free survival 26-45%Relapse 19-34%Autologous BMTHigher relapse rate25%42%33%
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