mpn
DESCRIPTION
Myeloproliferative neoplasmsTRANSCRIPT
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Myeloproliferative Neoplasms (MPN)
Ahmed Elshebiny, MDAhmed Elshebiny, MDUniversity of MenoufyiaUniversity of Menoufyia
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Case 66 y old woman with mild hypertension Experienced TIA affecting her speech which
resolved completely after 3 hours Smoker Normal liver and kidney functions High hemoglobin =18 gm/dl Decreased Epo level and JAK 2gene mutation
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Case cont. Hb 18 gm/dl Leukocytes 12,500/cu mm Thrombocytes 400,000/cu mm Hct 58% O2 saturation (arterial) 94% Serum erythropoietin Undetectable Erythrocytes and leukocytes were immature in the
peripheral blood smear. Spleen was enlarged.
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Hematological malignancies Hematological malignancies are defined and
distinguished from one another essentially according to 4 parameters:
1. Clinical features
2. microscopic morphology
3. immunophenotype
4. molecular/genetic features.
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Malignant cells Cell adhesion altered – cells able to move
Changes in structure of nucleus
Secretion of enzymes that enable them to invade neighboring tissues
Secretion of substances that inhibit normal cell proliferation
Unlimited number of cell divisions
Growth in the absence of appropriate signals
Avoidance of cell death (apoptosis)
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Hematology lectures
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Myeloproliferative neoplasms (MPN) Chronic clonal hematopoetic stem cell
diseases characterized by overproduction of one or more cell lines
Unlike myelodysplssia, the MPNs are associated with normal cell maturation and effective hematopoiesis
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Epidemiology Most cases encountered in clinical practice
are in patients aged 40-60 years. Myeloproliferative diseases are uncommon in
people younger than 20 years and are rare in childhood.
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Etiology the precise cause of myeloproliferative
disease is unknown. The etiology is complex, incompletely
understood, and likely a multistep process involving more than one gene.
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Genetic abnormalities JAK2 V617F mutation Philadelphia chromosome BCR-ABL others
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Symptoms Non specific of fatigue, wt loss, tennitus,
vertigo Abdominal discomfort and early satiety
secondary to splenomegaly Bleeding Thrombosis Abdominal pain Gout
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CBC, film Bone marrow Cytogenetics Polymerase chain reaction (PCR) or fluorescent in-
situ hybridization (FISH) run on peripheral blood or bone marrow
LAP score Red cell mass Uric acid
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ET
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Myelofibrosis showing Leukoerythroblastic reaction
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CML
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Hyperviscosity syndrome Increased serum viscosity usually results from
increased circulating serum immunoglobulins. It can also result from increased cellular blood
components in hyperproliferative states such as the leukemias, polycythemia, and the myeloproliferative disorders.
Clinically Diagnosis TTT
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Polythycemia Vera
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Polythycemia vera( bone marrow)
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Pathophysiology Normal stem cells are present in the bone
marrow of patients with PV. Also present are abnormal clonal stem cells
that interfere with or suppress normal stem cell growth and maturation.
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Pathophysiology cont. Mutation, or change, in the body's JAK2 gene The JAK2 gene makes an important protein
that helps the body produce blood cells Usually this is not a genetic disease, but in
some families, the gene may be more inclined to mutate
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JAK 2 mutation
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Clinical suspicion Polycythemia vera should be suspected in
patients with elevated hemoglobin or hematocrit levels, splenomegaly, or portal venous thrombosis.
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Manifestations Insidious Tirdeness , verigo, visual disturbances HTN Angina Cl;audications Tendancy to bleeding or thrombosis Itching Peptic ulcer Plethora Conjunctival injection Splenomegaly(70%) Hepatomegaly(50%)
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Course Untreated patients may survive for six to 18
months, whereas adequate treatment may extend life expectancy to more than 10 years.
Fate Myelofibrosis Acute leukemia Complications
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DD Causes of polycythemia Other MPN Causes of
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Acquired Secondary polythycemia Epo-mediated
Hypoxia-driven Central hypoxic process
Chronic lung dz, R to L shunt, high altitude, CO poisoning, hypoventilation Peripheral hypoxic process - renal artery stenosis
Hypoxia-independent (pathologic epo production) Malignant tumors
Hepatoma, renal cell, cerebellar hemangioblastoma, parathyroid carcinoma Non-malignant tumors
Fibroids, renal cysts, pheo, meningioma
Drug Associated - epo, androgens Unknown mechanism - post-renal transplant erythrocytosis
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Essential thrombocythemia (ET)
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Essential Thrombocythemia 50% have JAK2 mutation Incidence is similar to P vera 20% of pts are <40 y.o.
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Diagnosis First, rule out secondary causes of thrombocytosis:
cancer, infection, inflammation, bleeding, iron deficiency
Pts may have splenomegaly Platelet count should be >600 on 2 separate
occasions, at least 1 month apart Exclude CML by absence of Philadelphia
chromosome Exclude P vera by nl hemoglobin without iron
deficiency.
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Reactive thrombocythemia Autoimmune rheumatic disorders Malignancy Splenectomy
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Primary Myelofibrosis
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Myelofibrosis agnogenic myeloid metaplasia with 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.
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Myelofibrosis
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Myelofibrosis Natural History
Median survival is 5 yrs Transforms into AML in 5-20%
Symptoms >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.
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Lab finding in myelofibrosis Early on, pts may have Plts and nl Hgb 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
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Treatment
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TTT of Polycythemia Vera1. Therapeutic phlebotomies alone to maintain
hematocrit level at less than 45%.
2. Myelosupressive therapy(Hydroxyurea)
3. 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.
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Hydroxyurea Antineoplastic agent provides effective
palliative treatment that primarily controls symptoms associated with leukocytosis, thrombocytosis, or hepatosplenomegaly due to MPD.
Inhibitor of deoxynucleotide synthesis Less leukemogenic Uses
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Treatment of ET The aim of treatment is to maintain the
platelet count within the reference range. This usually can be achieved by
hydroxyurea or anagrelide. Interferon -alpha
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Treatment of myelofibrosis No curative treatment is available at the
present time. Conservative, Epo Hydroxyurea Splenic irradiation therapy Splenectomy Allogenic bone marrow transplantation ? Bisphosphonates
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Treatment of CML HSCT Imatinib Dasatinib Interferone Cytosine arabinoside Hydroxyurea When the disease progresses to the blast
phase treat as acute leukemia
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References Bethesda Handbook of Clinical hematology
2010 Hamilton et al : Hematology in Clinical
practice 2005 E-medicine online textbook, Hematology Other web resources
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