Myelodysplastic syndrome by dr narmada
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  • An interplay between the malignant clone and the bone marrow microenvironment Innate stem cell lesion Chromosomal rearrangements Gene silencing (hypermethylation) Gene mutations Cellular and cytokine mediated stromal defects Increased angiogenesis Immunologic derangements Silverman, LR. The Oncologist. 2001;6(suppl 5):8-14 .
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Myelodysplastic syndrome by dr narmada Myelodysplastic syndrome by dr narmada Presentation Transcript

  • MODERATOR – Prof. DR. - ANIL KAPOOR
  • What Is Myelodysplastic Syndrome?The myelodysplastic syndromes are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction. In MDS the bone marrow cannot produce blood cells effectively, and many of the blood cells formed are defective.These abnormal blood cells are usually destroyed before they leave the bone marrow or shortly after entering the bloodstream.As a result, patients have shortages of blood cells, which are reflected in their low blood
  • CharacteristicsVarying degree of tri-lineage cytopenia ( red blood cells, white blood cells and platelets).DysplasiaNormocellular or hypercellular B.M.May progress to acute leukaemia
  • Incidence1- Disease of elderly.2- Median age is 65 years.3- <10% are younger than 50 years.4- Incidence rates 1/100,000 pop./ years.5- Incidence rise to 1/1000 / years in > 60 years old.6- Male slightly higher than female
  • MDS EtiologyTwo etiologic categories of MDS:1.) De Novo: Associated with: -benzene exposure (gasoline) -cigarette smoking -viruses -Fanconi’s anemia2.) Therapy related: Associated with: -alkylating agent chemotherapy -radiation
  • Aetiological Agents Tobacco smoke. Ionizing radiation. Organic chemicals (such as benzene, toluene, xylene, and chloramphenicol). Heavy metals. Herbicides. Pesticides. Fertilizers. Stone and cereal dusts. Exhaust gases. Nitro-organic explosives. Petroleum and diesel derivatives. Alkylating agents. Marrow-damaging agents used in cancer chemotherapy.
  • Pathophysiology: Contributing Factors Immune Apoptosis dysfunction Stem cell Stem Cell dysfunction Epigenetic Dysfunction Environmental changes direct toxicity /Stromal /Mutations angiogenic factors MDS DNA damage. With Permission of J. Maciejewski, M.DTaussig Cancer Center/ Cleveland Clinic Foundation
  • Myelodysplastic SyndromeDyserythropoiesisDysmyelopoiesisDysmegakaryopoiesisRing SideroblastType I and II blasts
  • Dyserythropoiesis Anemia Normocytic or macro-ovalocytes Low retic count NRBC Megaloblastic changes Ringed sideroblast Pappenheimer bodies Basophilic stippling
  • Dyserythropoiesis Ringed sideroblast
  • DysmyelopoiesisNeutropeniaMonocytosisPseudo Pelger-HuetHypogranular PMN<20% blasts in BMType I and type II blasts
  • Blasts in MDS Type I blasts Promyelocyte No granules Many 1o granules Prominent Less prominent nucleoli nucleoli Central nucleus Eccentric nucleus Type II and III blasts Few 1o granules Prominent nucleoli Central nucleus
  • Type I Blast Type III Blast
  • DysmegakaryopoiesisLow platelet countGiant PlateletDwarf (micro) megakaryocyte
  • MicromegakaryocyteAbnormal platelets
  • Chromosomal abnormalities and MDS Chromosomal abnormalities are present in up to 50%of de novo cases of MDS and in virtually all cases of secondary MDS. The most common are: Abnormality -7 +7 +8 5q- 7q- 11q- 12q- 13q- 20q- inv3 i(17q) t(1;3) t(1;7) t(3;3) Frequency(%) 15 5 19 27 4 7 5 2 5 1 5 1 2 1
  • Deletion of the long arm of chromosome 5 (5q- syndrome )Strongly associated with RA.5q- accounts for up to 70% of cytogenetic abnormalities in this subtype.The q arm of chromosome 5 is particularly rich in genes, which encoded haemopoietic growth factors and their receptors. For example , IL-3 , IL-4 , IL-5 , GM-CSF and the M-CSF receptor are located in this region.The potential for the loss of any or all of these genes contribute to the disruption of ordered haemopoiesis.
  • Monosmy 7 and 7q-Most strongly associated with secondary MDS.Associated with the loss of a major surface glycoprotein (gp 130) in neutrophile and susceptibility to bacterial infection secondary to impaired granulocyte monocyte chemotatic activity.
  • Deletion of the q arm of chromosome 11 (11q-)Account for 20% of the chromosomal abnormalities in RAS.This abnormality is associated with raised iron stores and high ring sidroblast counts. The presence of the gene , which encoded the H- subunit of ferritin at chromosome 11 , may explain this
  • Abnormalities of chromosome 17 (i17q)It involves the loss or disruption of the Р53 tumor suppressor gene are seen in CML in association with transformation to the blastic phase and in up to 5% of cases of primary MDS. This predisposes to certain dysplastic features and neutrophil vaculation.
  • Abnormalities of chromosome 3Dysmegakaryopiesis and thombocytosis appear to be associated with Abnormalities of chromosome 3
  • The importance of indication of chromosomalabnormalities To confirm diagnoses .  To know the stage of disease. To know the direction of progression of disease. Multiple genetic abnormalities indicate late events in MDS.
  • Abnormal localization of immatureprecursors Presence of 3 or more small clusters of myeloblasts and promyelocytes (5 – 8 cells) in marrow trephine biopsy in the central portion of the marrow away from the vascular structure and the endosteal surface of the bone trabeculae
  • Abnormal localization of immatureprecursors
  • Signs and SymptomsExcessive tiredness, shortness of breath, and pale skin can be caused by anemia (shortage of red blood cells).Serious infections with high fevers can be caused by leukopenia (not having enough normal white blood cells) and, in particular, by having neutropenia or granulocytopenia (too few mature granulocytes).Excessive bruising and bleeding, for example, frequent or severe nosebleeds and/or bleeding from the gums, can be due to thrombocytopenia (not having enough of the blood platelets needed for plugging holes in damaged blood vessels).
  • Physical ExamHepatomegaly, splenomegaly, LAD: uncommon Except CMMLCutaneous manifestations: uncommon Sweet’s syndrome( neutrophilic dermatosis): transformation to acute leukemia ( IL-6) Granulocytic sarcoma (chloroma): herald disease transformation into acute leukemia
  • Sweet’s syndrome
  • FAB classification scheme in 1985 for MDS
  • Refractory AnemiaRA Definition:Dyplasia of the erythroid series only.Clinically, anemia is refractory to hematinic therapyMyeloblasts < 1% blood and < 5% marrow<15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of erythroid abnormalities must be excluded. These include: drug/toxin exposure -vitamin deficiency viral infection -congenital disease
  • Refractory AnemiaEpidemiology:5-10% of MDS cases.Older patientsMorphology:Anisopoikilocytosis on peripheral smearsDyserythropoiesis with nuclear abnormalities (megaloblastoid change)< 15% ringed sideroblasts
  • Refractory AnemiaGenetics:25% may have genetic abnormalitiesPrognosis:Median survival is 66 months6% rate of progression to acute leukemia
  • Peripheral Smear - Anisopoikilocytosis
  • Megaloblastoid Change on Bone Marrow Aspirate
  • Refractory Anemia with Ringed SideroblastsRARS definition:Dyplasia of the erythroid series only.Clinically, anemia is refractory to hematinic therapyMyeloblasts < 5% in marrow, absent in blood>15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of ringed sideroblasts must be excluded. These include: Anti- tuberculosis drugs Alcoholism
  • Refractory Anemia with Ringed SideroblastsEpidemiology:10-12% of MDS cases.Older patientsMales > femalesMorphology:Dimorphic pattern on peripheral smears Majority RBC’s normochromic, 2nd population hypochromicDyserythropoiesis with nuclear abnormalities (megaloblastoid change)
  • Refractory Anemia with Ringed SideroblastsGenetics:Clonal chromosomal abnormalities in <10%; in fact, development of such an abnormality should prompt reassessment of diagnosis.Prognosis:Median survival 6 years (72 months)1-2% rate of progression to acute leukemia
  • Dimorphic Red Cell Population
  • Ringed Sideroblasts
  • Ringed Sideroblasts
  • Megaloblastoid Change
  • Refractory Anemia with Excess BlastsRAEB definition:Refractory anemia with 5-19% myeloblasts in the bone marrow. RAEB-1:  5-9% blasts in bone marrow and <5% blasts in blood. RAEB-2:  10-19% blasts in the bone marrow  Auer rods present
  • Refractory Anemia with Excess BlastsEpidemiology: 40% of MDS cases.Older patients (over 50 years) Morphology:Dysplasia of all three cell lines often presentNeutrophil abnormalities may include: Hypogranulation Pseudo-Pelger-huet (hyposegmentation/barbells)Megkaryocyte abnormalities may include Hypolobation -Micromegakaryocytes
  • Refractory Anemia with Excess BlastsMorphology (con’t.)Erythroid precursor abnormalities may include:  Abnormal lobulation -megaloblastoid change  Multinucleation0-19% myeloblasts in the blood5-19% in the marrowBone marrow:  Usually hypercellular (10-15% hypocellular)  Abnormal localization of immature precursors (ALIP) may be presentImmunophenotype:  Blasts express CD 13, CD33 or CD117
  • Refractory Anemia with Excess BlastsGenetics:Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include:  +8 – -5 – del(5q) – -7 – del(7q) – Complex karyotypesPrognosis:Median survival, RAEB-1 = 18 monthsMedian survival, RAEB-2 = 10 monthsRAEB-1 = 25% rate of progression to acute leukemiaRAEB-2 = 33% rate of progression to acute leukemia
  • Hypercellular Bone Marrow
  • Auer Rods
  • Refractory Anemia with Excess Blasts in Transformation (RAEB-t) • 21-30 percent blasts in the marrow; more than 5 percent in the bloodstream • normal or hypercellular (filled with cells) marrow • accounts for about 25 percent of cases
  • Chronic Myelomonocytic Leukemia (CMML) • 5-20 percent blasts in the marrow; less than 5 percent in the bloodstream • cytopenia of at least two cell lines • normal or hypercellular (filled with cells) marrow • accounts for 15 to 20 percent of cases.
  • CMML Splenomegaly (10%) Maculopapular skin infiltration Monocytic pleural or pericardial effusion JMML (MPD/MDS)1. Pallor, bleeding, hepatosplenomegaly, skin involvement
  • WHORefractory anemiaRefractory anemia e ringed siderblastRefractory cytopenia e multilineage dysplasiaRefractory cytopenia e multilineage dysplasia & ringed sideroblastsRefractory anemia e excess blast-1Refractory anemia e excess blast-2Myelodysplastic syndrome unclassifiedMDS associated e isolated del (5q)
  • WHOSubtype Blood Bone MarrowRA Anemia Erythroid dysplasia onlyRARS Anemia Erythroid dys >15% ringedRCMD Bi- pancytopenia >10%Dysp in 2 or more cell lineageRCMD-RS Bi-pancytopenia >10%Dys 2 or more cell lineage >15% ringed
  • WHOsubtype Blood Bone MarrowRAEB-1 Cytopenia Uni-multilineage <5% blast dys, 5-9%blastRAEB-2 Cytopenia, Uni-multi dys 5-19%blast or Auer 10-19%blast rods Or Auer rodsMDS-U cytopenia Myeloid or megakaryocte dysMDS with 5q Anemia,nor or Mega e hypolobated increased PLT nuclei, <5%blast
  • Prognostic GroupsTwo groups based on survival and evolution to acute leukemia1.) “Good” group  Refractory anemia (RA)  Refractory anemia with ringed sideroblasts (RARS)  5q - syndrome2.) “Bad” group  Refractory anemia with excess blasts (RAEB)  Refractory anemia with excess blasts in transformation (RAEB-t)  CMMLMDS unclassified can be either
  • International Prognostic Scoring System (IPSS) Factors(1) the percentage of blasts in the bone marrow.(2)whether chromosome abnormalities are present and, if so, which ones.(3)how low the patients blood counts are. These are given a score; the lowest scores have the best outlook for survival.
  • Prognostic ScoringThe International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables: 0 0.5 1.0 1.5 2.0% Blasts <5 5-10 -- 11-20 20-30Karyotyp Normal, -Y, Single ≥3 abnormalities,e del(5q), karyotypic chr 7 del(20q) anomaly, abnormalities Double Chr 3 abn. abnormaliyCytopenia 0-1 2-3
  • Median Survival in MDS
  • MDS: Differential DiagnosisB12/folate deficiencyHeavy metals (Arsenic)Congenital dyserythropoietic anemiaParvovirus B19GCSF therapy (increased blasts)
  • Treatment o Chemotherapy. o Supportive therapy, such as WBCs, RBCs, Platelets transfusions.o B.M transplantation in young patients.
  • SPEAKER- DR. Narmada Prasad Tiwari THANK YOU
  • Prevention & Treatmentof InfectionsPrevention Prophylactic antibiotics  no role Patient education  know your nadir report a fever recognize signs of infection avoid illness, crowds update vaccinationsTreatment  Febrile neutropenia guidelines www.nccn.org/MDS v1..2008
  • Iron Chelation OptionsDeferoxamine (Desferal®) Route: SQ t ½: 0.5 hours Dosing: Infused over 8-12 hrs 5-7 nights/weekDeferasirox (Exjade®) Route: PO t ½: 12-16 hours Dosing: Dissolved in solution, taken daily
  • Pharmacotherapy In MDSAzacitidineDecitabineLenalidomideAnti-thymocyte Globulin (ATG)
  • IPSS
  • Median Survival in MDS
  • Large pronormoblast in pervovirus .infection
  • Differential Diagnosis Non-neoplastic simulators Other myelodysplastic disorderseoplastic disorders may simulate myelodysplasia Vitamin/micronutrient deficiencies B12/folate Copper Ring sideroblasts present Cytoplasmic vacuoles May be due to Zinc excess Gastrectomy Total parenteral nutrition Infections HIV Parvovirus HHV-6 in children Toxins Ethanol Heavy metals Growth factors -macrophage colony-stimulating factor (GMCSF Erythropoietin )Drugs (numerous