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  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>An elevation in packed cell volume (PCV), rather than a raised </li></ul><ul><li>haemoglobin concentration, defines polycythaemia. A raised PCV › 0.52 in M, › 0.48 in F) should be referred to a haematologist for measurement of red cell mass by </li></ul><ul><li>radionuclide labelling of the red cells. </li></ul>
  4. 4. <ul><li>Red cell mass measurements more than 25% above the predicted value constitute true or absolute polycythaemia. When the PCV is raised but the red cell mass is not, the condition is known as apparent or relative polycythaemia and is secondary to a reduction in plasma volume. </li></ul>
  5. 5. Classification of true polycythemia <ul><li>Familial/inherited </li></ul><ul><li>• Mutant erythropoietin receptor </li></ul><ul><li>• High oxygen affinity haemoglobin </li></ul><ul><li>Acquired </li></ul><ul><li>Primary </li></ul><ul><li>• Polycythaemia vera </li></ul><ul><li>Secondary </li></ul><ul><li>• Hypoxia </li></ul><ul><li>cardiac </li></ul><ul><li>pulmonary </li></ul><ul><li>• Ectopic erythropoietin </li></ul><ul><li>renal disease </li></ul><ul><li>neoplasms </li></ul>
  6. 6. 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 yr </li></ul>
  7. 7. 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><ul><ul><li>Gout </li></ul></ul>
  8. 8. Erythromelalgia
  9. 9. 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>
  10. 10. 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 ↑ B12 </li></ul><ul><li> Leukocyte alkaline phosphatase score </li></ul><ul><li>Low Epo levels </li></ul><ul><li>Positive JAK2 </li></ul>
  11. 11. 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>
  12. 12. WHO criteria <ul><li>A criteria </li></ul><ul><li>A1 - Elevated red blood cell mass or Hb >18.5 g/dL in M or >16.5 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>
  13. 13. 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>
  14. 14. 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>
  15. 15. 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>Drawbacks: </li></ul><ul><ul><li>Increased risk of thrombosis </li></ul></ul><ul><ul><li>May be insufficient to control disease </li></ul></ul>
  16. 16. 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>
  17. 17. 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>
  18. 18. Essential Thrombocythemia <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>
  19. 19. 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 & PCV </li></ul>
  20. 20. 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>
  21. 21. 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>
  22. 22. 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>
  23. 23. ET - Abnormal Megakaryocytes Arrows indicate some of the abnormal mega-karyocytes
  24. 24. 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>
  25. 25. ET - therapeutic agents <ul><li>Anagrelide </li></ul><ul><li>Hydroxyurea </li></ul><ul><li>Interferon alpha </li></ul>
  26. 26. 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>
  27. 27. Myelofibrosis <ul><li>The main features are BM fibrosis, extramedullary haemopoiesis (production of blood cells within organs other than the BM), splenomegaly, and leucoerythroblastic blood picture (immature red and white cells in the peripheral blood) </li></ul>
  28. 28. 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>
  29. 29. MF - Physical Findings <ul><li>Massive splenomegaly </li></ul><ul><li>Hepatomegaly </li></ul>
  30. 30. 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>
  31. 31. Leucoerythroblastic blood film in a patient with idiopathic myelofibrosis. Note the nucleated red blood cell and the myelocyte
  32. 32. Causes of leukoerythroblastic blood picture <ul><li>Idiopathic myelofibrosis </li></ul><ul><li>• Bone marrow infiltration </li></ul><ul><li>• Severe sepsis </li></ul><ul><li>• Severe haemolysis </li></ul><ul><li>• Sick neonate </li></ul>
  33. 33. 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>
  34. 34. Chronic myeloid leukemia <ul><li>CML is a clonal malignant myeloproliferative disorder believed to originate in a single abnormal haemopoietic stem cell. The progeny of this abnormal stem cell proliferate over months or years such that, by the time the leukaemia is diagnosed, the BM is grossly hypercellular and the number of leucocytes is greatly increased in the peripheral blood. Normal blood cell </li></ul><ul><li>production is almost completely replaced by leukaemia cells, which, however, still function almost normally. </li></ul>
  35. 35. Incidence <ul><li>Presentation may be at any age, but the peak incidence is at age 50-70 years, with a slight male predominance. This leukaemia is very rare in children. </li></ul>
  36. 36. Presentation <ul><li>Common </li></ul><ul><li>• Fatigue </li></ul><ul><li>• Weight loss </li></ul><ul><li>• Sweating </li></ul><ul><li>• Anaemia </li></ul><ul><li>• Haemorrhage—eg easy bruising, discrete ecchymoses </li></ul><ul><li>• Splenomegaly with or without hepatomegaly </li></ul><ul><li>Rare </li></ul><ul><li>• Splenic infarction </li></ul><ul><li>• Leucostasis </li></ul><ul><li>• Gout </li></ul><ul><li>• Retinal haemorrhages </li></ul><ul><li>• Priapism </li></ul><ul><li>• Fever </li></ul>
  37. 37. Clinical course <ul><li>can be divided into a chronic or “ stable ” phase and an advanced phase, the latter term covering both accelerated and blastic phases. Most patients present with chronic phase disease, which lasts on average 4-5 years. In about two-thirds of patients the chronic phase transforms gradually into an accelerated phase, characterised by a moderate increase in blast cells, increasing anaemia or thrombocytosis. After a variable number of months this accelerated phase progresses to frank acute blastic transformation. The remaining one-third of patients move abruptly from chronic phase to an acute blastic phase (or blastic crisis) without an intervening phase of acceleration </li></ul>
  38. 38. Massive splenomegaly
  39. 39. Pathogenesis <ul><li>All leukaemia cells in patients with CML </li></ul><ul><li>contain a specific cytogenetic marker, the </li></ul><ul><li>Philadelphia or Ph chromosome, which is </li></ul><ul><li>derived from a normal 22 chromosome that has lost part of its long arm as a result of a balanced reciprocal translocation of chromosomal material involving one of the 22 and one of the 9 chromosomes. The translocation is usually referred to as t(9;22) </li></ul>
  40. 40. Lab <ul><li>Usual peripheral blood findings: </li></ul><ul><li>• Raised WBC count (30000-400000). </li></ul><ul><li>Differential shows: </li></ul><ul><li>Granulocytes at all stages of development </li></ul><ul><li>Increased numbers of basophils and eosinophils </li></ul><ul><li>Blast (primitive) cells (maximum 10%)—never present in the blood of normal people </li></ul><ul><li>• Haemoglobin concentration may be reduced; red cell morphology is usually unremarkable; nucleated (immature) red cells may be present </li></ul><ul><li>• Platelet count may be raised (300000-600000) </li></ul>
  41. 41. Investigation <ul><li>to confirm suspected CML </li></ul><ul><li>Routine </li></ul><ul><li>• Full blood count including blood film </li></ul><ul><li>• Neutrophil alkaline phosphatase </li></ul><ul><li>• Urea, electrolytes </li></ul><ul><li>• Serum lactate dehydrogenase </li></ul><ul><li>• BM aspirate (degree of cellularity, chromosome </li></ul><ul><li>analysis) </li></ul><ul><li>Optional </li></ul><ul><li>• BM trephine biopsy (extent of fibrosis) </li></ul><ul><li>• BCR-ABL chimeric gene by fluorescent in situ </li></ul><ul><li>Hybridisation( FISH) or by PCR </li></ul><ul><li>• Vitamin B12 and B12 binding capacity </li></ul><ul><li>• HLA typing for patient and family members </li></ul>
  42. 42. Treatment <ul><li>Imatinib mesylate: </li></ul><ul><li>Induces complete haematological remission in 95% of previously </li></ul><ul><li>untreated patients and at least 50% of these will achieve a complete cytogenetic remission. Toxicity seems to be relatively mild. </li></ul>
  43. 43. Treatment <ul><li>Interferon- а </li></ul><ul><li>restores spleen size and blood counts to normal in 70-80% of </li></ul><ul><li>patients. Some 10-20% of patients achieve a major reduction or </li></ul><ul><li>complete disappearance of cells with the Ph chromosome from their BM </li></ul><ul><li>Currently interferon should be considered for chronic phase patients resistant to imatinib mesylate. </li></ul>
  44. 44. Treatment <ul><li>Allogeneic stem cell transplantation </li></ul><ul><li>Patients under the age of 60 years who have siblings with identical HLA types may be offered treatment by high dose cytoreduction (chemotherapy </li></ul><ul><li>and radiotherapy) followed by transplantation of haemopoietic </li></ul><ul><li>stem cells collected from the donor’s BM or peripheral blood. </li></ul>
  45. 45. Treatment <ul><li>Hydroxyurea </li></ul><ul><li>It is useful for rapid reduction of the leucocyte count in </li></ul><ul><li>newly diagnosed patients </li></ul><ul><li>• start treatment with hydroxyurea then switch to interferon once the patient’s symptoms are relieved and the leucocyte count is restored to normal </li></ul><ul><li>• Hydroxyurea is also valuable for controlling chronic phase </li></ul><ul><li>disease in patients who cannot tolerate interferon </li></ul><ul><li>• started at 2.0 g daily by mouth; maintenance dose is 1.0-1.5 g daily. </li></ul><ul><li>• Treatment with hydroxyurea does not eradicate cells with </li></ul><ul><li>the Ph chromosome </li></ul><ul><li>• Side effects are rare but include rashes, mouth ulceration, </li></ul><ul><li>and gastrointestinal symptoms. </li></ul>
  46. 46. Advanced disease <ul><li>Increasing splenomegaly despite full doses of cytotoxic drugs </li></ul><ul><li>• White blood cell count poorly responsive to full doses of cytotoxic drugs </li></ul><ul><li>• Anaemia or thrombocytopenia unresponsive to cytotoxic drugs </li></ul><ul><li>• Persistent thrombocytosis (1000000) </li></ul><ul><li>• 10% blasts in peripheral blood or marrow </li></ul><ul><li>• 20% blasts plus promyelocytes in blood or marrow </li></ul><ul><li>• Development of myelofibrosis </li></ul>