Myeloproliferative Neoplasms

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Myeloproliferative Neoplasms
2011-05-23 12:09:08
Myeloproliferative Neoplasms

Myeloproliferative Neoplasms
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  1. These are clonal proliferations of hematopoietic stem cells or very early precursors. Maturation is maintained. There is an increased number of predominantly mature, normal-appearing cells. And there is a variable predisposition to transform to acute leukemia or myelofibrosis.
    Myeloproliferative Neoplasms (MPNs)
  2. What are the four most common myeloproliferative neoplasms?
    • Chronic Myeloid Leukemia (CML)
    • Polycythemia Vera (P. vera)
    • Essential Thrombocytopenia (ET)
    • Primary Myelofibrosis (PMF)
  3. What are the predominant cells involved in Chronic Myeloid Leukemia (CML)?
  4. What are the predominant cells involved in Polycythemia vera (P. vera)?
  5. What are the predominant cells involved in Essential Thrombocytopenia (ET)?
  6. What are the predominant cells involved in Primary Myelofibrosis (PMF)?
    Fibroblasts (driven by megakaryocytes)
  7. What Myeloproliferative Neoplasm (MPN) has a specific cytogenetic abnormality by routine chromosomal analysis, and what is the abnormality?
    • Chronic Myeloid Leukemia (CML)
    • Philadelphia Chromosome [t(19;22)]
  8. If it looks like a chronic myeloproliferative disorder and it has a Philadelphia chromosome [t(9;22)] or a BCR/ABL rearrangement, then it is _______, even if it looks like one of the other MPNs.
  9. Abnormalities in tyrosine kinases are critical in MPNs. What is the characteristic rearrangement in CML? What is it in the other MPNs?
    • BCR-ABL1
    • JAK2 Mutation
  10. This is the second most common leukemia in the US, following CLL; it is the most common of the chronic myeloproliferative neoplasms.
  11. This myeloproliferative neoplasm has an increasing incidence with age, with the peak age of onset being ~50; however, it can occur in all age groups. It has a higher incidence in males than females. It contains the Philadelphia chromosome [t(9;22)] by standard cytogenetic analysis and the BCR/ABL rearrangement by molecular analysis.
  12. The BCR gene involved in CML has different breakpoints which gives different proteins. What are the two breakpoints, and which is more common with CML?
    • p210: majority of typical CML
    • p190: most Ph-positive ALL; rare CML & AML (more potent than p210)
  13. Before the development of treatment, most cases of CML went through three phases. What were they? In which phase were patients usually diagnosed?
    • Chronic Phase -- most diagnosed
    • Accelerated Phase
    • Blast Crisis -- resembling an acute leukemia
  14. The most common stage at diagnosis for a CML patient was the chronic phase (before the advent of therapy). How long did this phase typically last before transforming into a more aggressive phase? What are the characteristics of this phase?
    • ~3-4 years
    • Marked Granulocytosis; Massive Splenomegaly
    • May have systemic or hypermetabolic symptoms: fever, night sweats, weight loss; hyperuricemia -- gouty arthritis; renal stones
  15. What are the two characteristic features of CML on a blood smear? What are some other characteristics?
    • Complete spectrum of granulocytic maturation present, with a predominance of myelocytes and segmented neutrophils, with rare blasts
    • Basophilia -- always increased in number, though may not be in percent
    • Thrombocytosis common
    • Mild Anemia Common
  16. Identify the MPN from the blood smear shown below:
    CML: can see complete spectrum of granulocyte maturation, from blasts to mature segs; note also presence of several basophils
  17. Identify the MPN from the blood smear below:
    CML: complete spectrum of granulocyte maturation; not also the presence of a basophil
  18. How is CML diagnosed?
    • CBC & Blood Smear
    • Splenomegaly
    • Decreased LAP Score -- leukocyte alkaline phosphatase
    • Increased Serum Vit B12 Level
    • Presence of Ph and/or BCR/ABL rearrangement
  19. How can a BCR/ABL rearrangement in CML be demonstrated?
    • PCR-based test on blood -- usual method
    • FISH
  20. In CML, this is defined as >20% blasts in blood and/or marrow. Most have a myeloid phenotype (resemble AML). ~30% have a lymphoid phenotype (resemble ALL). Survival after onset of this is typically ~3-6 months.
    Blast Crisis
  21. What is the main treatment for CML? What are a couple of additional treatment options?
    • Gleevec: tyrosine kinase inhibitor
    • Hydroxyurea -- useful to rapidly lower WBC count
    • Interferon-alpha -- effective at contolling WBC count
    • Bone Marrow (stem cell) Transplant
  22. What drug, used in CML, inhibits BCR/ABL tyrosine kinase? This is taken orally, and is usually well tolerated and has a high hematologic response rate. However, it does not appear to be curative, and resistance can develop.
  23. What is the only proven curative therapy for CML? This was formerly the treatment of choice for young patients, and is best done early in the chronic phase.
    Allogenetic Stem Cell Transplant
  24. In CML, is the accelerated phase or blast crisis treated?
    • Treated as acute leukemia: myeloid blast crisis treated as AML; lymphoid blast crisis treated as ALL
    • Bone marrow transplant may be tried
    • Overall results poor
  25. This is the second most common MPN, after CML. Its main feature is a marked increase in RBC mass. The most common complications and the most common cause of death with this type is thromboembolic events.
    Polycythemia vera
  26. ____________ means a true increase in the RBC mass.
    ____________ means an increase in the measured Hgb. The measured Hgb can go up because of an actual increase in RBC mass or it can go up because of a decrease in plasma volume.
    • Polycythemia
    • Erythrocytosis
  27. In this type, Polycythemia vera is independent of erythropoietin stimulation; the EPO level is typically supressed.

    In this type, polycythemia is EPO driven. This can either be physiologically appropriate (the increase in EPO is due to hypoxemia), or it can be physiologically inappropriate (not due to hypoxemia). Inappropriate EPO production can occur due to renal disease or renal cysts, or a variety of non-hematologic malignancies
    • Primay Polycythemia vera
    • Secondary Polycythemia vera
  28. It is believed that all cases of P. vera are related to a mutation in what gene? Most of them are what variant?
    • JAK2
    • JAK2-V617F
  29. What MPN are the following symptoms associated with?

    Increased Blood Viscosity: headache, dizziness, tinnitus, visual disturbances, dyspnea, weakness
    Splenomegaly: abdominal discomfort or swelling
    Thrombotic Complications
    Bleeding from mucous membranes or into skin (ecchymoses)
    Hyperuricemia: gouty arthritis, kidney stones
    Erythromelalgia: reddening, swelling, and pain in digits
    GI Problems: predisposed to peptic ulcer; GI bleeding; thrombosis of mesenteric vessels; massive hemorrhage from varices in esophagus, stomach, or bowel; may have hepatic vein thrombosis (budd-chiari syndrome)
    CNS: headache; "lassitude"; vertigo; syncopal episodes; numbness or tingling in fingers; visual disturbances; strokes
    P. vera
  30. What is the most serious complication of P. vera? This is an important cause of death.
    CNS Vascular Lesions -- Strokes
  31. What is the typical Hgb level in P. vera? RBC count? Hematocrit? What is the erythrocyte morphology? What other two things are common on a CBC and smear?
    • Hgb: 18-24
    • RBC: 7-10
    • HCT: >60% Men; >55% Women
    • Erythrocyte Morphology: normal (may have mild anisocytosis & microcytosis
    • Leukocytosis & Thrombocytosis
  32. What are the four diagnostic indicators of P. vera?
    • Hgb > 18.5 in men; > 16.5 in women
    • Presence of JAK2 V617F or other
    • Bone Marrow biopsy showing hypercellularity with trilineage growth
    • Serum EPO level below reference range
  33. What is the cornerstone of treatment for P. vera? What are some other treatment options?
    • Phlebotomy -- controls red cell mass by inducing iron deficiency
    • Hydroxyurea
    • Radioactive Phosphorus (32P)
    • Interferon-alpha
  34. Secondary Polycythemia can be due to the following conditions: high altitude; pulmonary disease; cyanotic congenital heart disease; CO poisoning; hypoventilation syndromes; & abnormal Hgb (high O2 affinity). What is the main cause (all of these factors have this as their root)?
    Decreased tissue oxygenation
  35. What is the most common tumors causing aberrant erythropoietin production? Second most common? Third?
    • Renal Cell Carcinomas: kidneys are main site of EPO production
    • Hepatocellular Carcinoma: liver is second site of EPO production
    • Cerebellar Hemangioblastoma: rare tumors, but a high proportion of them are associated with aberrant EPO production
  36. This MPN is characterized by a marked increase in megakaryocytes and platelet mass. This type tends to have the longest survival and lowest rate of acute leukemic transformation of any of the chronic MPNs. The main risk in this is thromboembolic events; hemorrhage is less common. This generally has an indolent course.
    Essential Thrombocythemia (ET)
  37. In this type of MPN, the older population is predominantly affected, but there is a frequent occurrence in young women described in some series. The incidence in males and females is about equal. Many patients with this type of MPN are asymptomatic; the major clinical manifestations are usually related to thrombosis. The thrombosis can be in the arterial or venous system, but arterial is more common. Small vessels are affected more often than larger vessels. The neurological and distal extremities are most commonly affected. Neurological manifestations of this include headache, paresthesias, and transient ischemic attacks, which may progress to definitive cerebral infarcts.
    Small vessel involvement include microvascular events involving fingers and toes. Digital pain, increased by warmth, is seen, as well as gangrene in digits. Erythromelalgia -- redness, duskiness, and burning pain in extremities -- is a common symptoms, and can be dramatically relieved with aspirin.
    Essential Thrombocythemia (ET)
  38. In general, the higher the platelet count in Essential Thrombocythemia (ET), the higher the incidence of ____________. What are other risk factors for this?
    • Thromboses
    • Older age (>60); history of previous thrombotic disease; smoking
  39. The hemorrhagic manifestations of ET tend to occur with higher __________ counts. The bleeding is generally mild. What is the most common site of bleeding?
    • Platelet
    • GI Tract
  40. ET is mostly a diagnosis of exclusion. What disease must be excluded?
  41. What is the threshold platelet count for a diagnosis of ET? Leukocytosis is common in ET, but not usually marked. What is the effect on Hgb? What is seen on smear?
    • >450,000
    • Normal
    • Giant & Bizarre Platelets
  42. Identify the MPN based on the smear below:
    Essential Thrombocythemia (ET)
  43. In ET, treatment is generally given to older patients, or patients with a previous thrombotic event. What are the treatment options?
    • Hydroxyurea
    • Aprin
    • Interferon-alpha
    • Anagrelide -- may be less effective than hydroxyurea
    • Plateletpheresis
  44. This drug is one of the treatment options for ET. It works by inhibiting megakaryocyte maturation, which allows it to effectively lower platelet count. Its main side effects are headache, fluid retention, and palpitations -- these are due to vasodilation and inotropic effects. Recent evidence suggests that this may not be as effective as hydroxyurea.
  45. What are the three causes of massive spenomegaly?
    • CML
    • Hairy Cell Leukemia
    • Primary Myelofibrosis (PMF)
  46. This MPN is characterized by fibrosis in the bone marrow. It is a leukoerythroblastic reaction in blood: nucleated RBCs, teardrop RBCs, and immature granulocytes. Splenomegaly is seen, and it is often massive. Extramedullary hematopoiesis is also seen, most commonly in the spleen -- probably accounting for the splenomegaly.
    Pathophysiology includes excessive production of growth factors by neoplastic megakaryocytes and other cells. The growth factors stimulate fibroblast proliferation and production of collagen.
    Primary Myelofibrosis (PMF)
  47. This MPN primarily affects the older population, with an equal incidence in males and females. Possible etiologic factors include ionizing radiation and organic solvents (benzene, toluene).
    Symptoms include fatigue due to anemia; abdominal discomfort, early satiety due to splenomegaly; bleeding: petechiae and purpura to hematemesis from gastroesophageal varices.
    Primary Myelofibrosis (PMF)
  48. Identify the MPN based on the blood smear below:
    Primary Myelofibrosis (PMF): leukoerythroblastic reaction with teardrop RBCs
  49. Identify the MPN based on the blood smear below:
    Primary Myelofibrosis -- nucleated RBC, basophil, giant/bizarre platelet, teardrop RBC
  50. Identify the MPN based on the bone marrow biopsy below:
    Primary Myelofibrosis: the majority of the marrow has been replaced by dense fibrosis. This is a relatively late case of PMF; early stages might have hypercellular marrow, with mild fibrosis which is only apparent on a reticulin stain
  51. Identify the MPN based on the bone marrow biopsy below:
    Primary Myelofibrosis in RETICULIN STAIN. This is an advanced case, with dense, thick fibers replacing most of the hematopoietic cells
  52. Next to CML, what MPN has the highest incidence of acute leukemia transformation?
  53. What is the median survival in PMF? What are the common causes of death?
    • ~5 years
    • Infection, acute leukemic transformation, heart failure, hemorrhage
  54. What are the treatment options for PMF?
    • Treatment is usually palliative.
    • Correct reversible factors: iron, folate deficiencies
    • RBC & Platelet transfusions as needed
    • Splenectomy (?)
    • Interferon-alpha
    • Stem Cell Transplant (experimental)