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Myeloproliferative neoplasms

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  1. 2. Myeloproliferative Neoplasms (MPN) Ahmed Elshebiny, MD University of Menoufyia
  2. 3. Case <ul><li>66 y old woman with mild hypertension </li></ul><ul><li>Experienced TIA affecting her speech which resolved completely after 3 hours </li></ul><ul><li>Smoker </li></ul><ul><li>Normal liver and kidney functions </li></ul><ul><li>High hemoglobin =18 gm/dl </li></ul><ul><li>Decreased Epo level and JAK 2gene mutation </li></ul>
  3. 4. Case cont. <ul><li>Hb 18 gm/dl </li></ul><ul><li>Leukocytes 12,500/cu mm </li></ul><ul><li>Thrombocytes 400,000/cu mm </li></ul><ul><li>Hct 58% </li></ul><ul><li>O2 saturation (arterial) 94% </li></ul><ul><li>Serum erythropoietin Undetectable </li></ul><ul><li>Erythrocytes and leukocytes were immature in the peripheral blood smear. </li></ul><ul><li>Spleen was enlarged. </li></ul>
  4. 6. Hematological malignancies <ul><li>Hematological malignancies are defined and distinguished from one another essentially according to 4 parameters: </li></ul><ul><li>Clinical features </li></ul><ul><li>microscopic morphology </li></ul><ul><li>immunophenotype </li></ul><ul><li>molecular/genetic features. </li></ul>
  5. 8. Malignant cells <ul><li>Cell adhesion altered – cells able to move </li></ul><ul><li>Changes in structure of nucleus </li></ul><ul><li>Secretion of enzymes that enable them to invade neighboring tissues </li></ul><ul><li>Secretion of substances that inhibit normal cell proliferation </li></ul><ul><li>Unlimited number of cell divisions </li></ul><ul><li>Growth in the absence of appropriate signals </li></ul><ul><li>Avoidance of cell death (apoptosis) </li></ul>
  6. 9. Hematology lectures Myeloproliferative neoplasms
  7. 10. Myeloproliferative neoplasms (MPN) <ul><li>Chronic clonal hematopoetic stem cell diseases characterized by overproduction of one or more cell lines </li></ul><ul><li>Unlike myelodysplssia, the MPNs are associated with normal cell maturation and effective hematopoiesis </li></ul>
  8. 11. Epidemiology <ul><li>Most cases encountered in clinical practice are in patients aged 40-60 years. </li></ul><ul><li>Myeloproliferative diseases are uncommon in people younger than 20 years and are rare in childhood. </li></ul>
  9. 12. Etiology <ul><li>the precise cause of myeloproliferative disease is unknown. </li></ul><ul><li>The etiology is complex, incompletely understood, and likely a multistep process involving more than one gene. </li></ul>
  10. 13. Genetic abnormalities <ul><li>JAK 2 V617F mutation </li></ul><ul><li>Philadelphia chromosome </li></ul><ul><li>BCR-ABL </li></ul><ul><li>others </li></ul>
  11. 15. Symptoms <ul><li>Non specific of fatigue, wt loss, tennitus, vertigo </li></ul><ul><li>Abdominal discomfort and early satiety secondary to  splenomegaly </li></ul><ul><li>Bleeding </li></ul><ul><li>Thrombosis </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Gout </li></ul>
  12. 16. <ul><li>CBC, film </li></ul><ul><li>Bone marrow </li></ul><ul><li>Cytogenetics </li></ul><ul><li>Polymerase chain reaction (PCR) or fluorescent in-situ hybridization (FISH) run on peripheral blood or bone marrow </li></ul><ul><li>LAP score </li></ul><ul><li>Red cell mass </li></ul><ul><li>Uric acid </li></ul>
  13. 17. ET
  14. 18. Myelofibrosis showing Leukoerythroblastic reaction
  15. 19. CML
  16. 20. Hyperviscosity syndrome <ul><li>Increased serum viscosity usually results from increased circulating serum immunoglobulins. </li></ul><ul><li>It can also result from increased cellular blood components in hyperproliferative states such as the leukemias, polycythemia, and the myeloproliferative disorders. </li></ul><ul><li>Clinically </li></ul><ul><li>Diagnosis </li></ul><ul><li>TTT </li></ul>
  17. 21. Polythycemia Vera Myeloproliferative neoplasms
  18. 22. Polythycemia vera( bone marrow)
  19. 23. Pathophysiology <ul><li>Normal stem cells are present in the bone marrow of patients with PV. </li></ul><ul><li>Also present are abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation. </li></ul>
  20. 24. Pathophysiology cont. <ul><li>Mutation, or change, in the body's JAK2 gene </li></ul><ul><li>The JAK2 gene makes an important protein that helps the body produce blood cells </li></ul><ul><li>Usually this is not a genetic disease, but in some families, the gene may be more inclined to mutate </li></ul>
  21. 25. JAK 2 mutation
  22. 26. Clinical suspicion <ul><li>Polycythemia vera should be suspected in patients with elevated hemoglobin or hematocrit levels, splenomegaly, or portal venous thrombosis. </li></ul>
  23. 27. Manifestations <ul><li>Insidious </li></ul><ul><li>Tirdeness , verigo, visual disturbances </li></ul><ul><li>HTN </li></ul><ul><li>Angina </li></ul><ul><li>Cl;audications </li></ul><ul><li>Tendancy to bleeding or thrombosis </li></ul><ul><li>Itching </li></ul><ul><li>Peptic ulcer </li></ul><ul><li>Plethora </li></ul><ul><li>Conjunctival injection </li></ul><ul><li>Splenomegaly(70%) </li></ul><ul><li>Hepatomegaly(50%) </li></ul>
  24. 28. Course <ul><li>Untreated patients may survive for six to 18 months, whereas adequate treatment may extend life expectancy to more than 10 years. </li></ul><ul><li>Fate </li></ul><ul><ul><li>Myelofibrosis </li></ul></ul><ul><ul><li>Acute leukemia </li></ul></ul><ul><ul><li>Complications </li></ul></ul>
  25. 29. DD <ul><li>Causes of polycythemia </li></ul><ul><li>Other MPN </li></ul><ul><li>Causes of </li></ul>
  26. 30. Acquired Secondary polythycemia <ul><li>Epo-mediated </li></ul><ul><ul><li>Hypoxia-driven </li></ul></ul><ul><ul><ul><li>Central hypoxic process </li></ul></ul></ul><ul><ul><ul><ul><li>Chronic lung dz, R to L shunt, high altitude, CO poisoning, hypoventilation </li></ul></ul></ul></ul><ul><ul><ul><li>Peripheral hypoxic process - renal artery stenosis </li></ul></ul></ul><ul><ul><li>Hypoxia-independent (pathologic epo production) </li></ul></ul><ul><ul><ul><li>Malignant tumors </li></ul></ul></ul><ul><ul><ul><ul><li>Hepatoma, renal cell, cerebellar hemangioblastoma, parathyroid carcinoma </li></ul></ul></ul></ul><ul><ul><ul><li>Non-malignant tumors </li></ul></ul></ul><ul><ul><ul><ul><li>Fibroids, renal cysts, pheo, meningioma </li></ul></ul></ul></ul><ul><li>Drug Associated - epo, androgens </li></ul><ul><li>Unknown mechanism - post-renal transplant erythrocytosis </li></ul>
  27. 31. Essential thrombocythemia (ET) Myeloproliferative neoplasms
  28. 32. Essential Thrombocythemia <ul><li>50% have JAK 2 mutation </li></ul><ul><li>Incidence is similar to P vera </li></ul><ul><li>20% of pts are <40 y.o. </li></ul>
  29. 33. 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>Platelet count should be >600 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 nl hemoglobin without iron deficiency. </li></ul>
  30. 34. Reactive thrombocythemia <ul><li>Autoimmune rheumatic disorders </li></ul><ul><li>Malignancy </li></ul><ul><li>Splenectomy </li></ul>
  31. 35. Primary Myelofibrosis Myeloproliferative neoplasms
  32. 36. Myelofibrosis <ul><li>agnogenic myeloid metaplasia with myelofibrosis </li></ul><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>
  33. 37. Myelofibrosis
  34. 38. Myelofibrosis <ul><li>Natural History </li></ul><ul><ul><li>Median survival is 5 yrs </li></ul></ul><ul><ul><li>Transforms into AML in 5-20% </li></ul></ul><ul><li>Symptoms </li></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>
  35. 39. Lab finding in myelofibrosis <ul><li>Early on, pts may have  Plts and nl Hgb 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>
  36. 40. Treatment Myeloproliferative neoplasms
  37. 41. TTT of Polycythemia Vera <ul><li>Therapeutic phlebotomies alone to maintain hematocrit level at less than 45%. </li></ul><ul><li>Myelosupressive therapy(Hydroxyurea) </li></ul><ul><li>An alternative therapy in older patients is radioactive phosphorous (32P), but this is unsuitable for younger patients because of the potential for causing secondary leukemia. </li></ul>
  38. 42. Hydroxyurea <ul><li>Antineoplastic agent provides effective palliative treatment that primarily controls symptoms associated with leukocytosis, thrombocytosis, or hepatosplenomegaly due to MPD. </li></ul><ul><li>Inhibitor of deoxynucleotide synthesis </li></ul><ul><li>Less leukemogenic </li></ul><ul><li>Uses </li></ul>
  39. 43. Treatment of ET <ul><li>The aim of treatment is to maintain the platelet count within the reference range. </li></ul><ul><li>This usually can be achieved by </li></ul><ul><ul><ul><li>hydroxyurea </li></ul></ul></ul><ul><ul><ul><li>or anagrelide. </li></ul></ul></ul><ul><ul><ul><li>Interferon -alpha </li></ul></ul></ul>
  40. 44. Treatment of myelofibrosis <ul><li>No curative treatment is available at the present time. </li></ul><ul><li>Conservative, Epo </li></ul><ul><li>Hydroxyurea </li></ul><ul><li>Splenic irradiation therapy </li></ul><ul><li>Splenectomy </li></ul><ul><li>Allogenic bone marrow transplantation </li></ul><ul><li>? Bisphosphonates </li></ul>
  41. 45. Treatment of CML <ul><li>HSCT </li></ul><ul><li>Imatinib </li></ul><ul><li>Dasatinib </li></ul><ul><li>Interferone </li></ul><ul><li>Cytosine arabinoside </li></ul><ul><li>Hydroxyurea </li></ul><ul><li>When the disease progresses to the blast phase treat as acute leukemia </li></ul>
  42. 46. References <ul><li>Bethesda Handbook of Clinical hematology 2010 </li></ul><ul><li>Hamilton et al : Hematology in Clinical practice 2005 </li></ul><ul><li>E-medicine online textbook, Hematology </li></ul><ul><li>Other web resources </li></ul>
  43. 47. THANK YOU