The document discusses several myeloproliferative disorders including polycythemia vera, essential thrombocytosis, and myelofibrosis. Polycythemia vera is a neoplastic stem cell disorder characterized by erythrocytosis and can lead to symptoms like pruritus, erythromelalgia, and thrombosis. Diagnosis involves meeting criteria such as increased red blood cell mass and the presence of a JAK2 mutation. Treatment options include phlebotomy, hydroxyurea, interferon alpha, and alkylating agents. Essential thrombocytosis is characterized by a platelet count over 600,000 and risks include thrombosis, erythromelalgia and hemorrhage. Myelofibrosis involves

1. Myeloproliferative Disorders

2. Overview The Myeloproliferative disorders: Polycythemia vera Essential Thrombocytosis Myelofibrosis CML

3. Polycythemia Erythrocytosis is an increase in the concentration of erythrocytes, whether measured as number of cells, hemoglobin, or packed cell volume (hematocrit)

4. Erythrocytosis may be the result of an increase in the red cell volume or mass (absolute erythrocytosis), or may be the result of a reduced plasma volume (called relative or spurious polycythemia or Geisböck's syndrome ) Polycythemia accompanies increased total blood volume, whereas relative erythrocytosis does not

5. Secondary polycythemias are caused by factors extrinsic to red cell precursors Physiologically-appropriate (in response to tissue hypoxia ) Physiologically-inappropriate

6. Polycythemia ERYTHROPOETIN (EPO)-mediated : Hypoxia driven : Central hypoxic process Chronic lung disease Rt-to-lt cardiopulmonary shunts High-altitude habitat Carbon monoxide poisoning Smoker’s polycythemia (long-term CO exposure) Hypoventilation syn including sleep apnea Hemoglobinopathy(High–O² affinity variety)

7. Peripheral hypoxic process : Localized: Renal artery stenosis Diffuse: High oxygen-affinity hemoglobinopathy

8. Hypoxia independent (pathologic EPO production): Malignant tumors : Hepatocellular carcinoma Renal cell cancer Cerebellar hemangioblastoma Parathyroid carcinoma Nonmalignant conditions : Uterine leiomyomas Renal cysts (polycystic kidney disease) hydronephrosis Pheochromocytoma Meningioma

9. Polycythemia vera Definition: A neoplastic disorder arising from a pluripotent stem cell, generally characterized by erythrocytosis, with or without thrombocytosis and leukocytosis. Incidence 10 new cases per million Highest incidence in ages 50-75, but 5% occur in pts < 40 y.o.

10. P vera - natural history Latent phase - asymptomatic Proliferative phase - pts may be hypermetabolic or have sx of hyperviscosity or thrombosis Spent phase - anemia, leukopenia, secondary myelofibrosis, increasing liver and spleen size Secondary AML 1-2% of pts treated with phlebotomy alone Certain drug therapies increase risk

11. P vera - symptoms Sx common to all erythrocytosis Headache,  mental acuity, weakness Sx more specific to P vera: Pruritus after bathing Erythromelalgia Hypermetabolic symptoms Thrombosis (arterial or venous) Hemorrhage

12. Erythromelalgia

13. P vera – signs: Facial plethora Splenomegaly (70%) Hepatomegaly (40%) Distension of retinal veins

14. P vera - Lab Findings CBC  Hgb/Hct î red cell mass  WBC in 45%  Plts in 65% Basophilia (seen in all MPDs)  Uric acid (can lead to gout) and îB12  Leukocyte alkaline phosphatase score Low Epo levels Positive JAK2

15. Diagnosis Major Criteria Increased Red Cell Mass (>36ml/kg males, >32 ml/kg females) Arterial oxygen saturation > 92% Splenomegaly Minor Criteria Platelets > 400,000 WBC > 12,000 LAP score > 100 Serum B12 > 900 or serum unbound B12 binding capacity >2200

16. WHO criteria A criteria 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 A2 – No cause of secondary erythrocytosis A3 - Splenomegaly A4 - Clonal genetic abnormality other than Ph-chromosome or BCR/ABL fusion gene in marrow cells

17. WHO criteria B criteria B1 - PLT > 400000 and WBC >12000 B2 - BM biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation B3 - Low serum EPO levels A diagnosis of PV is made when A1 + A2 + any one A A1 + A2 + any two B

18. P vera - Treatment Phlebotomy Myelosuppressive agents Hydroxyurea Alkylating agents such as busulfan 32 P Interferon alpha

19. P vera - phlebotomy Generally, the best initial treatment: No increase in progression to AML Rapid effect No BM suppression Remove 500 cc blood 1x/wk to target Hct <45%, then maintain Downsides: Increased risk of thrombosis No effect on progression to spent phase May be insufficient to control disease

20. P vera - Myelosuppression Hydroxyurea can be used in conjunction with phlebotomy May increase the risk of leukemic transformation from 1-2% to 4-5% 32 P increase the risk of leukemic transformation from 1-2% to 11% May be appropriate for pts intolerant of medications or for elderly patients Single injection may control hemoglobin and platelet count for a year or more.

21. P vera - interferon alpha Benefits No myelosuppression No increase in progression to AML No increase in thrombosis risk OK in pregnancy Drawbacks Must be given by injection Side effects may be intolerable in many pts, include flu-like symptoms, fatigue, fever, myalgias, malaise

22. Essential Thrombocythemia Only 50% of these pts have a clonal disorder--the rest have polyclonal increase in megakaryocytes Incidence is similar to P vera 20% of pts are <40 y.o. Exact pathophysiology is unclear

23. ET - Diagnosis First, rule out secondary causes of thrombocytosis : cancer, infection, inflammation, bleeding, iron deficiency Pts may have splenomegaly Plts count should be >600000 on 2 separate occasions, at least 1 month apart Exclude CML by absence of Philadelphia chromosome Exclude P vera by normal Hb without iron deficiency.

24. ET - natural history Rarely progresses to AML (<1% of pts) May progress to myelofibrosis Major complication is thrombosis in 20-30% of pts - may be arterial or venous

25. ET - Symptoms Many patients are asymptomatic Digital ischemia from microvascular thrombi Erythromelalgia Pruritus Hemorrhage - in 40% of pts

26. ET - Labs Iron studies should be normal, as should the ESR, which is a measure of inflammation. 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. Plts can be very large and bizarrely shaped Marrow shows clusters of abnormal megakaryocytes. 50-75% may have JAK2 mutation

27. ET - Abnormal Megakaryocytes Arrows indicate some of the abnormal mega-karyocytes

28. ET - Treatment Treatment targeted at reducing the platelet count. Treat those who have had or are at risk for thrombosis , those >65 y.o ., or pts with plts > 1-1.5 million Why treat? In pts at risk for thrombosis, Rx reduces risk of thrombosis and may reduce 2º myelofibrosis.

29. ET - therapeutic agents Anagrelide Hydroxyurea Interferon alpha

30. ET - anagrelide Interferes with megakaryocyte development without causing depression of other cell lines Side effects include: hypotension, severe headache, fluid retention, palpitations/arrhythmias, severe headaches, CHF, bloating/diarrhea (in lactose intolerant patients)

31. Myelofibrosis Clonal stem cell disorder affecting megakaryocytes predominantly All myeloproliferative disorders can result in a spent phase which can be difficult to distinguish from primary MF Myeloid metaplasia refers to earlier proliferative phase where extramedullary hematopoiesis predominates.

32. MF - Natural Hx and Sx Median survival is 5 yrs Transforms into AML in 5-20% >50% pts present with sx of anemia and thrombocytopenia Pts may have fever, sweats, wt loss As spleen enlarges (from EMH), pts may have abdominal pain, early satiety.

33. MF - Physical Findings Massive splenomegaly Hepatomegaly

34. MF - Lab findings Early on, pts may have  Plts and normal Hb and WBC. Anemia, and  Plts and  WBC seen as disease progresses Peripheral smear shows leukoerythroblastic picture, with teardrops, NRBC and early granulocytes “ Dry tap” or inability to aspirate liquid marrow frequently seen Increased collagen and reticulin fibrosis on BM biopsy 40-75% may have JAK2 mutation

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. MF - Treatment There is no definitive therapy If patient is young, BM transplant can be done, but older patients have too high mortality Rx is supportive, with transfusions Splenectomy can be done for sx of abdominal pain, but frequent complications of thrombosis, hemorrhage, and infection.