Dysplastic Syndromes

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    Myelodysplastic Syndrome

    • Stem cell clonal disorders characterized by ineffective hematopoiesis and various peripheral cytopenias.
    • "Sick Marrow Syndrome"
    • Risk of transformation to AML
    • Pathophysiology:
      • Reduced mature cells in periphery due to:
        • 1. Disordered maturation - ineffective hematopoesis despite adequte numbers of progenitors in BM. (but usually hypercellular).
        • 2. Apoptosis in BM
      • 30-40% develop AML
    • Risk Factors:
      • Post-chemo (esp. topoisomerase inhibitors and alkylating agents, mycophenolate - DNA damage)
      • Radiation exposure
      • Elderly
      • DNA Repair Defects (Down's Syndrome, Fanconi Anemia)
      • Incidence: 60/100,000 in >60yrs old.
    • Clinical Features:
      • Insidious onset - usually see pancytopenia.
      • Any aplastic anemia symptoms (anemia, thrombocytopenia, neutropenia)
      • Classically: Megaloblastic anemia (can be normocytic)
      • Infections and bleeding not consistent with peripheral blood counts?
      • On Exam:
        • NO Lymphadenopathy
        • NO splenomegaly
    • Classification: (WHO classification)
      • Many categories
        • Variable survival.
        • Many sideroblasts (long survival 69mo)
        • 5q deletion (median survival 160mo - longest)
      • Refractory Anemia With Multilineage Dysplasia (survival down to 33mo)
      • Blast Numbers:
        • 5-9% Blasts: "Refractory Anemia With Excess Blasts 1" (median survival 18mo)
        • 10-19% Blasts: "Refractory Anemia With Excess Blasts 2" (median survival 10mo)
        • 20% Blasts: AML  (in past is "Refractory Anemia with Transformation")
      • MDS Unclassified (survival unknown)
    • Investigations:
      • Exclude B12, Folate, Medication effects (i.e. mycophenolate), HIV
      • CBC ( Anemia ± thrombocytopenia ± neutropenia. )
        • Peripheral Blood film: Shows Dysplastic Features!
          • RBC - macrotycic nucleated with oval shaped RBC (macro-ovalocytes).
          • "Pelger Huetoid Cells" - dumb-bell shaped neutrophils or "glasses" look.
            • "Prince Nez Glasses" Cells - type of eye glasses.
            • Aka hypolobulated neutrophils
              • pelgerhuet.JPG
          • Dysplasia in any cell line.
      • Bone Marrow:
        • Dysplastic, bone marrow can be normo/hypercellular. (depends on cytogenetics).
        • Cytogenetics (REQUIRED FOR DX)
          • Many chromosomal abnormalities:
          • i.e. partial or total loss of chromosomes 5,7,Y, or  trisomy 8.
          • MDS.jpg
    • Prognosis:
      • MDS International Prognostic Scoring System (IPSS), uses 4 factors.
           1. % of bone marrow blasts.
           2. Karyotype (good, intermediate, poor)
           3. Number of cytopenias
           4. Age  (<60 or >60)
      • Predicts outcome
      • Calculate IPSS score:
        • 1 - "low" (mean survival 5.7yrs)
        • 2 - "interm. 1" - 1.2 yrs.
        • 3 - "interm. 2" - 3.5 yrs.
        • 4 - "high" - 0.4yrs.
    • Treatment:
      • Based on risk of transformation to AML
      • LOW RISK
        • Supportive (RBC/platelet transfusions)
        • EPO SC weekly
      • HIGH RISK
        • Supportive (as above)
        • Stem cell transplant if <65yrs.
        • Epigenetic therapy (DNA methyltransferase inhibitors and histone deacetylase inhibitors).
      • NOTES:
        • Transfusions
          • Be careful, at risk of iron overload.
          • Iron chelators (only benefit in primary hemochromatosis), unclear in MDS.  
          • Consider if ferritin > 1000 if expected to have long survival.
        • Erythropoesis Stimulating Agents (ESA)
          • May be beneficial in pts with symptomatic anemia.
          • Useful if EPO count not high.
          • GCSF: may increase erythroid response (in addition to WBC)
          • DO NOT increase risk of progression to AML
        • Drugs:
          • Azacitidine & another. - Pyrimidine analogue when compared to standard of care:
            • Better response rate
            • Decrease risk of transformation to AML
            • Improves median overall survival in high risk MDS.
            • Hypomethylating agents (when demethylate, improve differention to myeloid cells).
          • Lenolidomide
            • Effective in making transfusion (70% of pts) independence in 5q- deletion pts. 

    Sideroblastic Anemia

    • Type of MDS
    • Stain marrow with iron and counterstain with sapharin.
      • See iron in siderosomes (don't get into nucleus)
      • Called "sideroblasts"
      • sideroblastic-anemia-disease.jpg
    • Causes:
      • Can be associated with MDS
      • Congenital
      • Drugs: Chloramphenicol, Isoniazid, Alcoholism
      • Metabolic: Copper Deficiency, Zinc Excess
        • (Both characterized by iron deficiency)

     

    Chronic Myelomonocytic Leukemia

    • Features of myelodysplastic and myeloproliferative disorder.
      • (CML is a myeloproliferative disorder)
    • Symptoms
      • Constitutional (Wt loss, nt sweats)
      • Hepatosplenomegaly
    • Dx:
      • Peripheral Smear (mature monocytes, leukocytosis is common)
      • Monocytes > 1000 (normal 850)
    • Treatment:
      • Supportive.
      • If WBC too high > 100,000 --> Hydroxyurea, helps constitutional sx and HSM.
      • Hypomethylating agents azacitidine,  (limited experience).
      • Young patients (like almost all myelodysplastic syndromes)  --> consider for allogeneic stem cell transplant.
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