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Medicine 5th year, 9th lecture/part one (Dr. Sabir)

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The lecture has been given on Apr. 10th, 2011 by Dr. Sabir.

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Medicine 5th year, 9th lecture/part one (Dr. Sabir)

  1. 1. Myeloproliferative Disorders
  2. 2. Overview <ul><li>The Myeloproliferative disorders: </li></ul><ul><ul><li>Polycythemia vera </li></ul></ul><ul><ul><li>Essential Thrombocytosis </li></ul></ul><ul><ul><li>Myelofibrosis </li></ul></ul><ul><ul><li>CML </li></ul></ul>
  3. 3. Polycythemia <ul><li>Erythrocytosis is an increase in the concentration of erythrocytes, whether measured as number of cells, hemoglobin, or packed cell volume (hematocrit) </li></ul>
  4. 4. <ul><li>Erythrocytosis may be the result of </li></ul><ul><li>an increase in the red cell volume or mass (absolute erythrocytosis), or </li></ul><ul><li>may be the result of a reduced plasma volume (called relative or spurious polycythemia or Geisböck's syndrome ) </li></ul><ul><li>Polycythemia accompanies increased total blood volume, whereas relative erythrocytosis does not </li></ul>
  5. 5. <ul><li>Secondary polycythemias are caused by factors extrinsic to red cell precursors </li></ul><ul><li>Physiologically-appropriate (in response to tissue hypoxia ) </li></ul><ul><li>Physiologically-inappropriate </li></ul>
  6. 6. Polycythemia <ul><li>ERYTHROPOETIN (EPO)-mediated : </li></ul><ul><li>Hypoxia driven : </li></ul><ul><li>Central hypoxic process </li></ul><ul><li>Chronic lung disease </li></ul><ul><li>Rt-to-lt cardiopulmonary shunts </li></ul><ul><li>High-altitude habitat </li></ul><ul><li>Carbon monoxide poisoning </li></ul><ul><li>Smoker’s polycythemia (long-term CO exposure) </li></ul><ul><li>Hypoventilation syn including sleep apnea </li></ul><ul><li>Hemoglobinopathy(High–O² affinity variety) </li></ul>
  7. 7. <ul><li>Peripheral hypoxic process : </li></ul><ul><li>Localized: </li></ul><ul><li>Renal artery stenosis </li></ul><ul><li>Diffuse: </li></ul><ul><li>High oxygen-affinity hemoglobinopathy </li></ul>
  8. 8. <ul><li>Hypoxia independent (pathologic EPO production): </li></ul><ul><li>Malignant tumors : </li></ul><ul><li>Hepatocellular carcinoma </li></ul><ul><li>Renal cell cancer </li></ul><ul><li>Cerebellar hemangioblastoma </li></ul><ul><li>Parathyroid carcinoma </li></ul><ul><li>Nonmalignant conditions : </li></ul><ul><li>Uterine leiomyomas </li></ul><ul><li>Renal cysts (polycystic kidney disease) </li></ul><ul><li>hydronephrosis </li></ul><ul><li>Pheochromocytoma </li></ul><ul><li>Meningioma </li></ul>
  9. 9. Polycythemia vera <ul><li>Definition: A neoplastic disorder arising from a pluripotent stem cell, generally characterized by erythrocytosis, with or without thrombocytosis and leukocytosis. </li></ul><ul><li>Incidence 10 new cases per million </li></ul><ul><li>Highest incidence in ages 50-75, but 5% occur in pts < 40 y.o. </li></ul>
  10. 10. P vera - natural history <ul><li>Latent phase - asymptomatic </li></ul><ul><li>Proliferative phase - pts may be hypermetabolic or have sx of hyperviscosity or thrombosis </li></ul><ul><li>Spent phase - anemia, leukopenia, secondary myelofibrosis, increasing liver and spleen size </li></ul><ul><li>Secondary AML </li></ul><ul><ul><li>1-2% of pts treated with phlebotomy alone </li></ul></ul><ul><ul><li>Certain drug therapies increase risk </li></ul></ul>
  11. 11. P vera - symptoms <ul><li>Sx common to all erythrocytosis </li></ul><ul><ul><li>Headache,  mental acuity, weakness </li></ul></ul><ul><li>Sx more specific to P vera: </li></ul><ul><ul><li>Pruritus after bathing </li></ul></ul><ul><ul><li>Erythromelalgia </li></ul></ul><ul><ul><li>Hypermetabolic symptoms </li></ul></ul><ul><ul><li>Thrombosis (arterial or venous) </li></ul></ul><ul><ul><li>Hemorrhage </li></ul></ul>
  12. 12. Erythromelalgia
  13. 13. P vera – signs: <ul><li>Facial plethora </li></ul><ul><li>Splenomegaly (70%) </li></ul><ul><li>Hepatomegaly (40%) </li></ul><ul><li>Distension of retinal veins </li></ul>
  14. 14. P vera - Lab Findings <ul><li>CBC </li></ul><ul><ul><li> Hgb/Hct </li></ul></ul><ul><ul><li>î red cell mass </li></ul></ul><ul><ul><li> WBC in 45% </li></ul></ul><ul><ul><li> Plts in 65% </li></ul></ul><ul><ul><li>Basophilia (seen in all MPDs) </li></ul></ul><ul><li> Uric acid (can lead to gout) and îB12 </li></ul><ul><li> Leukocyte alkaline phosphatase score </li></ul><ul><li>Low Epo levels </li></ul><ul><li>Positive JAK2 </li></ul>
  15. 15. Diagnosis <ul><ul><li>Major Criteria </li></ul></ul><ul><ul><ul><li>Increased Red Cell Mass (>36ml/kg males, >32 ml/kg females) </li></ul></ul></ul><ul><ul><ul><li>Arterial oxygen saturation > 92% </li></ul></ul></ul><ul><ul><ul><li>Splenomegaly </li></ul></ul></ul><ul><ul><li>Minor Criteria </li></ul></ul><ul><ul><ul><li>Platelets > 400,000 </li></ul></ul></ul><ul><ul><ul><li>WBC > 12,000 </li></ul></ul></ul><ul><ul><ul><li>LAP score > 100 </li></ul></ul></ul><ul><ul><ul><li>Serum B12 > 900 or serum unbound B12 binding capacity >2200 </li></ul></ul></ul>
  16. 16. WHO criteria <ul><li>A criteria </li></ul><ul><li>A1 - Elevated red blood cell mass (>25% more than the mean normal predicted value) or Hb >18.5 g/dL in M or >16.5 g/dL in F </li></ul><ul><li>A2 – No cause of secondary erythrocytosis </li></ul><ul><li>A3 - Splenomegaly </li></ul><ul><li>A4 - Clonal genetic abnormality other than Ph-chromosome or BCR/ABL fusion gene in marrow cells </li></ul>
  17. 17. WHO criteria <ul><li>B criteria </li></ul><ul><li>B1 - PLT > 400000 and WBC >12000 </li></ul><ul><li>B2 - BM biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation </li></ul><ul><li>B3 - Low serum EPO levels </li></ul><ul><li>A diagnosis of PV is made when </li></ul><ul><li>A1 + A2 + any one A </li></ul><ul><li>A1 + A2 + any two B </li></ul>
  18. 18. P vera - Treatment <ul><li>Phlebotomy </li></ul><ul><li>Myelosuppressive agents </li></ul><ul><ul><li>Hydroxyurea </li></ul></ul><ul><ul><li>Alkylating agents such as busulfan </li></ul></ul><ul><ul><li>32 P </li></ul></ul><ul><li>Interferon alpha </li></ul>
  19. 19. P vera - phlebotomy <ul><li>Generally, the best initial treatment: </li></ul><ul><ul><li>No increase in progression to AML </li></ul></ul><ul><ul><li>Rapid effect </li></ul></ul><ul><ul><li>No BM suppression </li></ul></ul><ul><li>Remove 500 cc blood 1x/wk to target Hct <45%, then maintain </li></ul><ul><li>Downsides: </li></ul><ul><ul><li>Increased risk of thrombosis </li></ul></ul><ul><ul><li>No effect on progression to spent phase </li></ul></ul><ul><ul><li>May be insufficient to control disease </li></ul></ul>
  20. 20. P vera - Myelosuppression <ul><li>Hydroxyurea </li></ul><ul><ul><li>can be used in conjunction with phlebotomy </li></ul></ul><ul><ul><li>May increase the risk of leukemic transformation from 1-2% to 4-5% </li></ul></ul><ul><li>32 P </li></ul><ul><ul><li>increase the risk of leukemic transformation from 1-2% to 11% </li></ul></ul><ul><ul><li>May be appropriate for pts intolerant of medications or for elderly patients </li></ul></ul><ul><ul><li>Single injection may control hemoglobin and platelet count for a year or more. </li></ul></ul>
  21. 21. P vera - interferon alpha <ul><li>Benefits </li></ul><ul><ul><li>No myelosuppression </li></ul></ul><ul><ul><li>No increase in progression to AML </li></ul></ul><ul><ul><li>No increase in thrombosis risk </li></ul></ul><ul><ul><li>OK in pregnancy </li></ul></ul><ul><li>Drawbacks </li></ul><ul><ul><li>Must be given by injection </li></ul></ul><ul><ul><li>Side effects may be intolerable in many pts, include flu-like symptoms, fatigue, fever, myalgias, malaise </li></ul></ul>
  22. 22. Essential Thrombocythemia <ul><li>Only 50% of these pts have a clonal disorder--the rest have polyclonal increase in megakaryocytes </li></ul><ul><li>Incidence is similar to P vera </li></ul><ul><li>20% of pts are <40 y.o. </li></ul><ul><li>Exact pathophysiology is unclear </li></ul>
  23. 23. ET - Diagnosis <ul><li>First, rule out secondary causes of thrombocytosis : cancer, infection, inflammation, bleeding, iron deficiency </li></ul><ul><li>Pts may have splenomegaly </li></ul><ul><li>Plts count should be >600000 on 2 separate occasions, at least 1 month apart </li></ul><ul><li>Exclude CML by absence of Philadelphia chromosome </li></ul><ul><li>Exclude P vera by normal Hb without iron deficiency. </li></ul>
  24. 24. ET - natural history <ul><li>Rarely progresses to AML (<1% of pts) </li></ul><ul><li>May progress to myelofibrosis </li></ul><ul><li>Major complication is thrombosis </li></ul><ul><ul><li>in 20-30% of pts </li></ul></ul><ul><ul><li>- may be arterial or venous </li></ul></ul>
  25. 25. ET - Symptoms <ul><li>Many patients are asymptomatic </li></ul><ul><li>Digital ischemia from microvascular thrombi </li></ul><ul><li>Erythromelalgia </li></ul><ul><li>Pruritus </li></ul><ul><li>Hemorrhage - in 40% of pts </li></ul>
  26. 26. ET - Labs <ul><li>Iron studies should be normal, as should the ESR, which is a measure of inflammation. </li></ul><ul><li>If the plt count is very high, there may be pseudohyperkalemia and pseudohypoglycemia . This goes away if the blood is drawn into a heparinized tube. </li></ul><ul><li>Plts can be very large and bizarrely shaped </li></ul><ul><li>Marrow shows clusters of abnormal megakaryocytes. </li></ul><ul><li>50-75% may have JAK2 mutation </li></ul>
  27. 27. ET - Abnormal Megakaryocytes Arrows indicate some of the abnormal mega-karyocytes
  28. 28. ET - Treatment <ul><li>Treatment targeted at reducing the platelet count. </li></ul><ul><li>Treat those who have had or are at risk for thrombosis , those >65 y.o ., or pts with plts > 1-1.5 million </li></ul><ul><li>Why treat? </li></ul><ul><ul><li>In pts at risk for thrombosis, Rx reduces risk of thrombosis and may reduce 2º myelofibrosis. </li></ul></ul>
  29. 29. ET - therapeutic agents <ul><li>Anagrelide </li></ul><ul><li>Hydroxyurea </li></ul><ul><li>Interferon alpha </li></ul>
  30. 30. ET - anagrelide <ul><li>Interferes with megakaryocyte development without causing depression of other cell lines </li></ul><ul><li>Side effects include: hypotension, severe headache, fluid retention, palpitations/arrhythmias, severe headaches, CHF, bloating/diarrhea (in lactose intolerant patients) </li></ul>
  31. 31. Myelofibrosis <ul><li>Clonal stem cell disorder affecting megakaryocytes predominantly </li></ul><ul><li>All myeloproliferative disorders can result in a spent phase which can be difficult to distinguish from primary MF </li></ul><ul><li>Myeloid metaplasia refers to earlier proliferative phase where extramedullary hematopoiesis predominates. </li></ul>
  32. 32. MF - Natural Hx and Sx <ul><ul><li>Median survival is 5 yrs </li></ul></ul><ul><ul><li>Transforms into AML in 5-20% </li></ul></ul><ul><ul><li>>50% pts present with sx of anemia and thrombocytopenia </li></ul></ul><ul><ul><li>Pts may have fever, sweats, wt loss </li></ul></ul><ul><ul><li>As spleen enlarges (from EMH), pts may have abdominal pain, early satiety. </li></ul></ul>
  33. 33. MF - Physical Findings <ul><li>Massive splenomegaly </li></ul><ul><li>Hepatomegaly </li></ul>
  34. 34. MF - Lab findings <ul><li>Early on, pts may have  Plts and normal Hb and WBC. </li></ul><ul><li>Anemia, and  Plts and  WBC seen as disease progresses </li></ul><ul><li>Peripheral smear shows leukoerythroblastic picture, with teardrops, NRBC and early granulocytes </li></ul><ul><li>“ Dry tap” or inability to aspirate liquid marrow frequently seen </li></ul><ul><li>Increased collagen and reticulin fibrosis on BM biopsy </li></ul><ul><li>40-75% may have JAK2 mutation </li></ul>
  35. 35. Tefferi A. N Engl J Med 2000;342:1255-1265 Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia
  36. 36. MF - Treatment <ul><li>There is no definitive therapy </li></ul><ul><li>If patient is young, BM transplant can be done, but older patients have too high mortality </li></ul><ul><li>Rx is supportive, with transfusions </li></ul><ul><li>Splenectomy can be done for sx of abdominal pain, but frequent complications of thrombosis, hemorrhage, and infection. </li></ul>

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