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

Immunotherapy in MDSAntithymocyte globulin +/- cyclosporineComplete remissions in hypoplastic MDSEliminated transfusion requirement in 44% with normocellular and hypercellular MDSMonoclonal antibody against CD33Disproportionately expressed on blast cellsEffective in those with

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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