Mielodisplasia

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Mielodisplasia

  1. 1. Myelodysplastic Syndromes Terrance Comeau, M.D., F.R.C.P. 3-25-2002
  2. 2. MDS <ul><li>Heterogeneous group of clonal hematopoietic stem cell disorders </li></ul><ul><li>Characterized by: </li></ul><ul><ul><li>ineffective hematopoiesis and </li></ul></ul><ul><ul><li>peripheral cytopenias </li></ul></ul><ul><li>MDS is best considered a preleukemic disorder in which the neoplastic clone that has been established may or may not fully progress to acute leukemia. </li></ul>
  3. 3. <ul><li>Usually affects patients > 65 years of age </li></ul><ul><li>More prominent in men </li></ul>
  4. 5. Pathophysiology <ul><li>Initiating lesion in stem cell: </li></ul><ul><ul><li>Inherited or acquired: </li></ul></ul><ul><ul><ul><li>Somatic DNA damage </li></ul></ul></ul><ul><ul><ul><li>Genomic instability </li></ul></ul></ul><ul><ul><ul><li>Defective DNA repair </li></ul></ul></ul><ul><ul><ul><li>Perturbation in signal transduction pathways </li></ul></ul></ul><ul><li>Gives rise to clones with growth advantage </li></ul><ul><li>Accompanied by mutations in p53, FLT3, RAS </li></ul><ul><li>Promotes acquisition of secondary genetic events (e.g. -5, -7, etc.) </li></ul>
  5. 7. Pathophysiology <ul><li>Transforming event in stem cell </li></ul><ul><li>Results in antigenic changes in stem cell </li></ul><ul><li>Autoimmune response directed at marrow: </li></ul><ul><ul><li>CD8+ CTL: </li></ul></ul><ul><ul><ul><li>Inhibit normal stem cells more than MDS cells </li></ul></ul></ul><ul><ul><li>Increase in TNF-a levels: </li></ul></ul><ul><ul><ul><li>Increased apoptosis </li></ul></ul></ul><ul><li>End result: </li></ul><ul><ul><li>Ineffective hematopoiesis </li></ul></ul>
  6. 8. Pathophysiology <ul><li>Aberrant cytokine production: </li></ul><ul><ul><li>MDS mononuclear cells secrete: </li></ul></ul><ul><ul><ul><li>TNFa: </li></ul></ul></ul><ul><ul><ul><ul><li>Inhibits normal hematopoiesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increases apoptosis </li></ul></ul></ul></ul><ul><ul><ul><li>TGFb: increases apoptosis </li></ul></ul></ul><ul><ul><ul><li>Il-1b: supports clonal expansion of aberrant stem cells </li></ul></ul></ul><ul><li>Altered stem cell adhesion to stroma/endothelium: results in increased apoptosis </li></ul><ul><li>Abnormal marrow microenvironment: </li></ul><ul><ul><li>Mega’s produced increased VEGF which leads to increased marrow vascularity which is associated with leukemic transformation </li></ul></ul>
  7. 9. <ul><li>Early in the disease process: </li></ul><ul><ul><li>Ineffective hematopoiesis and marrow failure </li></ul></ul><ul><li>With progression in acute leukemia: </li></ul><ul><ul><li>Decrease in apoptosis </li></ul></ul>
  8. 11. Clinical Features <ul><li>May be asymptomatic </li></ul><ul><li>Symptoms of anemia </li></ul>
  9. 12. Dyserythropoiesis <ul><li>Peripheral blood: </li></ul><ul><ul><li>Anemia </li></ul></ul><ul><ul><li>Reticulocytopenia </li></ul></ul><ul><ul><li>Anisocytosis </li></ul></ul><ul><ul><li>Poikilocytosis </li></ul></ul><ul><ul><li>Basophilic stippling </li></ul></ul><ul><ul><li>Macrocytosis </li></ul></ul>
  10. 13.                                     
  11. 14. Dyserythropoiesis <ul><li>Bone Marrow: </li></ul><ul><ul><li>Ineffective erythropoiesis </li></ul></ul><ul><ul><li>Erythroid hyperplasia </li></ul></ul><ul><ul><li>Ringed sideroblasts </li></ul></ul><ul><ul><li>Megaloblastoid maturation: </li></ul></ul><ul><ul><ul><li>Multinuclearity </li></ul></ul></ul><ul><ul><ul><li>Nuclear fragments </li></ul></ul></ul><ul><ul><ul><li>Cytoplasmic abnormalities </li></ul></ul></ul>
  12. 15. Bizarre erythroid precursors.                                          
  13. 16. Bizarre erythroid precursors (clover-leaf nuclei).                                     
  14. 17. Ringed Sideroblasts                                     
  15. 18. Dysgranulopoiesis <ul><li>Peripheral blood: </li></ul><ul><ul><li>Neutropenia </li></ul></ul><ul><ul><li>Abnormal neutrophil function </li></ul></ul><ul><ul><li>Decreased or abnormal neutrophil granules </li></ul></ul><ul><ul><li>Neutrophil nuclear changes with: </li></ul></ul><ul><ul><ul><li>Hyposegmentation (pseudo-Pelger-Huet anomaly) </li></ul></ul></ul><ul><ul><ul><li>Hypersegmentation </li></ul></ul></ul><ul><ul><ul><li>Bizarre shapes </li></ul></ul></ul>
  16. 19. Hyposegmented/ hypogranular neutrophi                                     
  17. 20. Pelger-Huet hyposegmentation                                     
  18. 21. Abnormal ring nucleus with abnormal granulation pattern.                                  
  19. 22. Dysgranulopoiesis <ul><li>Bone Marrow: </li></ul><ul><ul><li>Granulocytic hyperplasia </li></ul></ul><ul><ul><li>Abnormal or decreased granules in neutrophil precursors </li></ul></ul><ul><ul><li>Increased numbers of blast cells </li></ul></ul>
  20. 23. Dysmegakaryocytopoiesis <ul><li>Peripheral Blood: </li></ul><ul><ul><li>Thrombocytopenia </li></ul></ul><ul><ul><li>Large platelets with abnormal or decreased granularity </li></ul></ul><ul><ul><li>Abnormal platelet function </li></ul></ul>
  21. 24.                                     
  22. 25. Dysmegakaryocytopoiesis <ul><li>Bone Marrow: </li></ul><ul><ul><li>Reduced numbers of megakaryocytes </li></ul></ul><ul><ul><li>Micromegakaryocytes </li></ul></ul><ul><ul><li>Megakaryocytes with large, single nuclei or multiple small nuclei </li></ul></ul>
  23. 26. FAB Classification <ul><li>Refractory Anemia (RA) </li></ul><ul><li>Refractory Anemia with Ringed Sideroblasts (RARS) </li></ul><ul><li>Refractory Anemia with Excess Blasts (RAEB) </li></ul><ul><li>Refractory Anemia with Excess Blasts in Transformation (RAEB-T) </li></ul><ul><li>Chronic Myelomonocytic Leukemia (CMML) </li></ul>
  24. 27. Refractory Anemia (RA) <ul><li>Cytopenia of one peripheral blood lineage </li></ul><ul><li>Normo- or hypercellular marrow with dysplasias </li></ul><ul><li>< 1% blasts in peripheral blood </li></ul><ul><li>< 5% blasts in bone marrow </li></ul>
  25. 28. Refractory Anemia with Ringed Sideroblasts (RARS) <ul><li>Cytopenia of one peripheral blood lineage </li></ul><ul><li>Normo- or hypercellular marrow with dysplasias </li></ul><ul><li>< 1% blasts in peripheral blood </li></ul><ul><li>< 5% blasts in bone marrow </li></ul><ul><li>Ringed sideroblasts account for > 15% of nucleated cells in the marrow </li></ul>
  26. 29. Refractory Anemia with Excess Blasts (RAEB) <ul><li>Cytopenia of two or more peripheral blood lineages </li></ul><ul><li>Dysplasia involving all 3 lineages </li></ul><ul><li>< 5% blasts in peripheral blood </li></ul><ul><li>5%-20% blasts in bone marrow </li></ul>
  27. 30. Refractory Anemia with Excess Blasts in Transformation (RAEB-T) <ul><li>Cytopenia of two or more peripheral blood lineages </li></ul><ul><li>Dysplasia involving all 3 lineages </li></ul><ul><li>> 5% blasts in peripheral blood or </li></ul><ul><li>21%-30% blasts in bone marrow or </li></ul><ul><li>Auer rods in the blasts </li></ul>
  28. 31. Chronic Myelomonocytic Leukemia (CMML) <ul><li>Monocytosis in Peripheral Blood: </li></ul><ul><ul><li>> 1 X 10 9 per liter </li></ul></ul><ul><li>< 5% blasts in peripheral blood </li></ul><ul><li>≤ 20% blasts in bone marrow </li></ul>
  29. 32. FAB Classification > 1 X 10 9 /L ≤ 20% < 5% CMML 21-30% > 5% RAEB-T 5-20% < 5% RAEB < 5% < 1% > 15% RARS < 5% < 1% RA PB Monocytes BM Blasts PB Blasts % Ringed Sideroblasts
  30. 33. WHO Classification System <ul><li>Myelodysplastic Syndromes: </li></ul><ul><ul><li>Refractory Anemia (RA): </li></ul></ul><ul><ul><ul><li>With ringed sideroblasts (RARS) </li></ul></ul></ul><ul><ul><ul><li>Without ringed siderblasts </li></ul></ul></ul><ul><ul><li>Refractory Cytopenia (MDS) with Multilineage Dysplasia (RCMD) </li></ul></ul><ul><ul><li>Refractory Anemia with Excess Blasts (RAEB) </li></ul></ul><ul><ul><li>5q- syndrome </li></ul></ul><ul><ul><li>Myelodysplastic syndrome, unclassifiable </li></ul></ul>
  31. 34. WHO Classification System <ul><li>Myelodysplastic/Myeloproliferative Diseases: </li></ul><ul><ul><li>Chronic Myelomonocytic Leukemia (CMML) </li></ul></ul><ul><ul><li>Atypical Chronic Myelogenous Leukemia (aCML) </li></ul></ul><ul><ul><li>Leukemia (JMML) </li></ul></ul>
  32. 35. IPSS Risk-Based Classification System <ul><li>Overall IPSS Risk Score is Based on: </li></ul><ul><ul><li>Marrow Blast Percentage </li></ul></ul><ul><ul><li>Cytogenetic Features: </li></ul></ul><ul><ul><ul><li>Good Prognosis </li></ul></ul></ul><ul><ul><ul><ul><li>-Y, 5q-, 20q-, normal </li></ul></ul></ul></ul><ul><ul><ul><li>Intermediate Prognosis </li></ul></ul></ul><ul><ul><ul><ul><li>+8, single misc. abnormality, double abnormalities </li></ul></ul></ul></ul><ul><ul><ul><li>Poor Prognosis </li></ul></ul></ul><ul><ul><ul><ul><li>any chrom. 7 abn, complex (≥3) </li></ul></ul></ul></ul><ul><ul><li>Cytopenias: </li></ul></ul><ul><ul><ul><li>Hgb < 10 g/dl </li></ul></ul></ul><ul><ul><ul><li>ANC < 1500 /mm 3 </li></ul></ul></ul><ul><ul><ul><li>PLT < 100,000 /mm 3 </li></ul></ul></ul>
  33. 36. Marrow Blast % 2 21-30 1.5 11-20 0.5 5-10 0 < 5 IPSS Score Blast %
  34. 37. Cytogenetic Features 1.0 Poor Prognosis 0.5 Intermediate Prognosis 0 Good Prognosis IPSS Score Karyotype
  35. 38. Cytopenias 0.5 2 or 3 Types 0 None or 1 Type IPSS Score Cytopenia
  36. 39. Overall IPSS Score and Survival 0.4 years High (≥ 2.5) 3.5 years 1.2 years Intermediate 1 (0.5 or 1.0) 2 (1.5 or 2.0) 5.7 years Low (0) Median Survival Overall Score
  37. 40. Therapy <ul><li>Supportive care: </li></ul><ul><ul><li>Despite supportive care, 50% of patients die of infection or bleeding even before transformation to acute leukemia </li></ul></ul><ul><li>Only curative therapy: </li></ul><ul><ul><li>Allogeneic Stem Cell Transplant </li></ul></ul><ul><ul><li>Autologous Stem Cell Transplant (if no suitable allogeneic donor) </li></ul></ul>
  38. 43. Therapy <ul><li>Cytokine support: </li></ul><ul><ul><li>G-CSF + Erythropoietin </li></ul></ul><ul><li>Cytokine inhibition: (block TNFa) </li></ul><ul><ul><li>Amifostine </li></ul></ul><ul><ul><li>Pentoxifylline </li></ul></ul><ul><ul><li>Enbrel </li></ul></ul>
  39. 45. Therapy <ul><li>Immunosuppressive therapy: </li></ul><ul><ul><li>Antithymocyte globulin (ATG) </li></ul></ul><ul><ul><li>Cyclosporin </li></ul></ul><ul><ul><li>Thalidomide </li></ul></ul><ul><li>Intensive Chemotherapy: </li></ul><ul><ul><li>High Dose AraC </li></ul></ul><ul><ul><li>Topotecan + AraC </li></ul></ul>
  40. 46. Therapy <ul><li>Low Dose Chemotherapy: </li></ul><ul><ul><li>Low dose AraC </li></ul></ul><ul><ul><li>Melphalan </li></ul></ul><ul><ul><li>5-azacytidine </li></ul></ul><ul><ul><li>5-aza-2’-deoxycytidine </li></ul></ul>
  41. 47. Therapy <ul><li>Supportive Care: </li></ul><ul><ul><li>Transfusion support: </li></ul></ul><ul><ul><ul><li>pRBC’s </li></ul></ul></ul><ul><ul><ul><li>Platelets </li></ul></ul></ul><ul><ul><li>Management of infections </li></ul></ul>
  42. 48. Questions?

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