Myeloproliferative Neoplasms (MPN)

Ahmed Elshebiny, MDAhmed Elshebiny, MDUniversity of MenoufyiaUniversity of Menoufyia

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

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.

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.

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)

Hematology lectures

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

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.

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.

Genetic abnormalities JAK2 V617F mutation Philadelphia chromosome BCR-ABL others

Symptoms Non specific of fatigue, wt loss, tennitus,

vertigo Abdominal discomfort and early satiety

secondary to splenomegaly Bleeding Thrombosis Abdominal pain Gout

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

ET

Myelofibrosis showing Leukoerythroblastic reaction

CML

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

Polythycemia Vera

Polythycemia vera( bone marrow)

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.

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

JAK 2 mutation

Clinical suspicion Polycythemia vera should be suspected in

patients with elevated hemoglobin or hematocrit levels, splenomegaly, or portal venous thrombosis.

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%)

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

DD Causes of polycythemia Other MPN Causes of

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

Essential thrombocythemia (ET)

Essential Thrombocythemia 50% have JAK2 mutation Incidence is similar to P vera 20% of pts are <40 y.o.

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.

Reactive thrombocythemia Autoimmune rheumatic disorders Malignancy Splenectomy

Primary Myelofibrosis

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.

Myelofibrosis

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.

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

Treatment

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.

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

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

Treatment of myelofibrosis No curative treatment is available at the

present time. Conservative, Epo Hydroxyurea Splenic irradiation therapy Splenectomy Allogenic bone marrow transplantation ? Bisphosphonates

Treatment of CML HSCT Imatinib Dasatinib Interferone Cytosine arabinoside Hydroxyurea When the disease progresses to the blast

phase treat as acute leukemia

References Bethesda Handbook of Clinical hematology

2010 Hamilton et al : Hematology in Clinical

practice 2005 E-medicine online textbook, Hematology Other web resources