Medicine 5th year, 5th lecture/part two (Dr. Abdulla Sharief)

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The lecture has been given on May 12th, 2011 by Dr. Abdulla Sharief.

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Medicine 5th year, 5th lecture/part two (Dr. Abdulla Sharief)

  1. 1. Myelodysplastic syndromes Achievements in understanding and treatment
  2. 2. <ul><li>Clonal hematopoietic stem cell disorder ch a racterized by ineffective hematopoiesis and peripheral cytopenias </li></ul><ul><li>Although a substantial proportion of MDS cases evolve to acute myel o id leukemia (AML), the natural history of these syndromes ranges from more indolent forms of the disease spanning years to those with a rapid evolution to AML </li></ul><ul><li> the leukemic disorder in which neoplastic clone that has been est a blished may or may not fully progress to acute leukemia </li></ul>Myelodysplastic syndromes
  3. 3. <ul><li>Refractory anemia (RA): cytopenia of one PB lineage; normo- or hypercellular marrow with dysplasias; < 1% PB blasts and <5% BM blasts </li></ul><ul><li>Refractory anemia with ringed sideroblasts (RARS): cytopenia, dysplasia and the same % blasts involvement in BM and PB as RA. Ringed sideroblasts account for > 15% of nucleated cells in marrow. </li></ul><ul><li>Refractory anemia with excess of blasts (REAEB): Cytopenia or two or more PB lineages; dysplasia involving all 3 lineages; < 5% PB blasts and 5-20% BM blasts </li></ul><ul><li>Refractory anemia with excess blasts in transformation: (REAEB-t): hematologic features identical to RAEB. >5% blasts in PB or 21-30% blasts in BM, or the presence of Auer rods in the blasts </li></ul><ul><li>Chronic myelomonocytic leukemia (CMML): monocytosis in PB>10 9 /L; < 5% blast in PB and up to 20% BM balsts </li></ul>Myelodysplastic syndromes FAB classification system
  4. 4. <ul><li>Myelodysplastic syndromes : </li></ul><ul><li>Refractory anemia (RA) </li></ul><ul><li>With ringed sideroblasts (RARS) </li></ul><ul><li>Without ringed sideroblasts </li></ul><ul><li>Refractory cytopenia (MDS) with multilineage dysplasia (RCMD) </li></ul><ul><li>Refractory anemia with excess blasts (RAEB) </li></ul><ul><li>5q - syndrome </li></ul><ul><li>Myelodysplastic syndrome, unclassifiable </li></ul><ul><li>Myelodysplastic/Myeloprolipherative diseases </li></ul><ul><li>Chronic myelomonocytic leukemia (CMML) </li></ul><ul><li>Atypic chronic myelogenous leukemia (aCML) </li></ul>Myelodysplastic syndromes WHO classification system
  5. 5. <ul><li>Marrow blast percentage : </li></ul><ul><li>< 5 0 </li></ul><ul><li>5-10 0.5 </li></ul><ul><li>11-20 1.5 </li></ul><ul><li>21-30 2.0 </li></ul><ul><li>Cytogentic fetures </li></ul><ul><li>Good prognosis 0 </li></ul><ul><li>(–Y, 5q - , 20q - ) </li></ul><ul><li>Intermediate prognosis 0.5 </li></ul><ul><li>(+8, miscellaneous singleabnormality, double abnormalities) </li></ul><ul><li>Poor prognosis 1.0 </li></ul><ul><li>(abnor. 7, complex- >3 abnor.) </li></ul><ul><li>Cytopenias </li></ul><ul><li>None or one type 0 </li></ul><ul><li>2 or 3 type 0.5 </li></ul>Myelodysplastic syndromes IPSS risk-based classification system
  6. 6. <ul><li>Overall score : Median survival: </li></ul><ul><li>low </li></ul><ul><li>0 5.7 years </li></ul><ul><li>Intermediate </li></ul><ul><li>1 (0.5 or 1) 3.5 years </li></ul><ul><li>2 (1.5 or 2) 1.2 years </li></ul><ul><li>High </li></ul><ul><li>> 2.5 0.4 years </li></ul>Myelodysplastic syndromes Overall IPSS score and survival
  7. 7. Known molecular abnormalities in MDS 5-10 Point mutation (codon 969 or rarely 301) FMS (encodes M-CSF receptor) 5 Point mutation or deletion of other allele P53 10-30% Point mutation (codon 12, 13 or 61) RAS (N or K) Incidence (%) Type of anomaly Gene
  8. 8. Diagnosis of MDS <ul><li>Aplastic anaemia and some disease accompanied by marrow dysplasia, including wit. B 12 and/or folate deficiency, exposure to haevy metals, recent cytotoxic therapy and ongoing inflamation (including HIV and chronic liver disease/alcohol use) should be ruled out </li></ul>
  9. 9. MDS – clinical findings <ul><li>These are non-specific, and are usually the consequences of cytopenias, including: </li></ul><ul><li>symptoms of anaemia </li></ul><ul><li>infections due to neutropenia, but also to the frequently associated defect in neutrophil function </li></ul><ul><li>bleeding due to thrombocytopenia (may also occur in moderately thrombocytopenic patients or even in patients with normal platelets count, because of thrombocytopathy) </li></ul>
  10. 10. Myelodysplastic features in MDS Bone marrow: multinuclearity, nuclear fragments, megaloblastoid changes, cytoplasmic abnormalities, ringed sideroblasts Peripheral blood: Poikilocytosis, anisocytosis, nucleated red blood cells Dyserythropoiesis Bone marrow and/or peripheral blood findings MDS
  11. 11. Myelodysplastic features in MDS Micromegakariocytes Large mononucle a r forms Multiple small nuclei Dysmegakariopoiesis Nuclear abnormalities including: hypolobulation, ring-shaped nuclei, hypogranulation Dysgranulopoiesis Bone marrow and/or peripheral blood findings MDS
  12. 12. Bone marrow biopsy <ul><li>Blood examination and bone marrow aspirate are sufficient for a diagnosis of MDS </li></ul><ul><li>It is obviously important in cases of difficult diagnosis , and it could brink additional prognostic information in some cases </li></ul><ul><li>normal or increased cellularity is seen in 85-90% od cases </li></ul><ul><li>abnormal localization of immature precusors (ALIP) </li></ul><ul><li>Fibrosis (significant in 15-20% of cases) </li></ul>
  13. 13. Dysplasia, apoptosis and cytokines in MDS <ul><li>Despite increased proliferation of the marrow, there is an increased rate of prgrammed cell death  kinetically the apoptosis prevails over the increased proliferation, causing the peripheral cytopenia </li></ul><ul><li>Cytokines derived from unselected marrow mononuclear cells are belived to be extrinsic factors predisposing to apoptosis (TNF  - inhibit normal and MDS colony growth; INF  , IL1, TGF  - have also be implicated in causing apoptosis) </li></ul>
  14. 14. Evidence for an immune – mediated suppression of the marrow in MDS <ul><li>T cells inhibit MDS CFU-E </li></ul><ul><li>CD8 + cells inhibit CFU-GM </li></ul><ul><li>Immunosuppressive agents improve cytopenia in MDS and eliminate autosuppressive T cells </li></ul><ul><li>T cells are activated in MDS </li></ul><ul><li>T cell are show a skewed T cell receptor V-  repertoire </li></ul><ul><li>HLA-DR 15 over representation in MDS and aplastic anemia </li></ul>

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