Myeloproliferative Disorders Neoplasms (MPD)

What line does Myeloproliferative line affect?

Myeloid

What do MPDs result in?

Expansion and excessive production and overaccumulation of blood cells

MPDs are characterized by…

Pan-hypercellularity and Trilineage cell involvement

Pan hypercellularity (pan myelosis)

Increase in all blood cells of bone marrow and blood. Results in erythrocytosis, granulocytosis, thrombocytosis in pb

Myeloproliferative disorders include…

• Chronic Myelogenous Leukemia

• Polycythemia Vera

• Essential thrombocythemia

• Myelofibrosis with myeloid metaplasia

What is the predominantly affected cell in Chronic myelogenous leukemia (CML)?

Granulocytes

What is the predominantly affected cell in Polycythemia Vera?

Erythrocytes

What is the predominantly affected cell in Essential thrombocythemia?

Megakaryocytes

What is the predominantly affected cell in Myelofibrosis with myeloid metaplasia?

Megakaryocytes and Fibroblasts

Chronic Myelogenous Leukemia is also known as…

Chronic Myeloid Leukemia and Chronic granulocytic leukemia (CGL)

What has these clinical symptoms?

• Fever and night sweats

• Weight loss

• weakness

• Splenomegaly

• Bruising

• Pallor

CML

What is the problem in CML?

Proliferation of erythroid, myeloid, monocytic, and megakaryocytic cell lines and leads to an excessive increase in mostly mature myeloid cells in pb

Is the leukocyte alkaline phosphatase (LAP) low or high in CML?

low

most patients with CML have the presence of what chromosome mutation?

Philadelphia Chromosome

What is the Ph chromosome mutation?

A reciprocal translocation between chromosome 9 and chromosome 22. 9 will be longer than normal and 22 will be shorter

Translocation of the Ph chromosome mutation occurs in HSC meaning that…

all hematopoietic cells are affected and share the abnormality

the three stages of CML are…

1. Chronic

2. Accelerated

3. Blast crisis

The CBC in the chronic phase of CML has…

Extreme leukocytosis, increase in mature granulocytes, left shift, normocytic, normochromic anemia

The bone marrow in the chronic phase of CML appears…

Hypercellular with granulocytes in all stages of development

What is the M:E ratio of the bone marrow in the chronic phase of CML?

10:1 to 50:1

Only people in what phase of CML respond to chemotherapy treatment?

Chronic phase

These laboratory findings are found in what phase of CML?

• worsening anemia

• development of thrombocytopenia

• basophilia

• increasing number of blasts

Accelerated phase

The third phase and final phase of CML is Blastic crisis. What is it characterized by?

Large number of blasts, thrombocytopenia, and anemia

What is the average span after time lived after entering the blastic crisis phase?

6 months

Treatment of CML includes…

Chemotherapy and bone marrow/stem cell transplant

Two forms of Chemotherapy for CML are Interferon-alpha and Tyrosine Kinase inhibitors. Explain them briefly

Interferon-alpha: myelosuppressive

Tyrosine Kinase inhibitors: will normalize blood cell counts in most patients with CML. Works by blocking the oncogene encoded protein product that instigates the transformation to a leukemic cell

The CML variant, Chronic eosinophilic leukemia is characterized by WBC over … with … eosinophils

30 × 10^9/L ; 30-70%

The rarest variant of CML is Chronic basophilic leukemia with about what percentage of basophils?

40-80%

What is the CML variant, Chronic neutrophilic leukemia?

Leukocytosis without immature myeloid precursors in pb with an increased LAP 

What is Essential Thrombocythemia (ET)?

A neoplastic stem cell disorder causing dysregulated production of large numbers of abnormal platelets. The abnormal platelets aggregate, causing thrombosis, and cause hemmorhages

Thrombosis is another name for…

clot

What is the laboratory finding that is truly indicative of ET?

Increased megakaryopoiesis with thrombocytosis greater than 600 × 10^9/L. Other cells in the blood are normal

What is etiology?

The cause or manner of causation of a disease or condition

What is the etiology of ET?

It is an acquired mutation in the JAK2 gene gained function and dramatically increase thrombophilia

ET is a rare disorder but what age group does it normally affect?

Older age group (median age is 65)

These CBC findings are indicative of what?

• thrombocytosis greater than 600 × 10^9/L

• usually anemia

• leukocytosis

• peripheral smear includes megakaryocytes and giant bizarre platelets

Essential Thrombocythemia

How does the bone marrow appear in ET?

Hypercellular with abnormal megakaryocytes (that are larger and clustering)

What are symptoms of ET?

No symptoms, thrombosis, hemorrhage

What are other names Polycythemia Vera?

Polycythemia rubra vera, primary polycythemia

Polycythemia Vera (PV) is what?

A MPD characterized by unregulated proliferation of the erythroid elements in the bm and an increase in the erythrocyte concentration in the pb

What genes are mutated in PV?

JAK2 and TET2

With the gene mutations in PV, is there a loss or gain of function?

Loss of function; myeloid over lymphoid

The etiology of PV is…

an acquired mutation with an unknown cause but it makes stem cells more sensitive to EPO

What are symptoms of PV?

• headache, weakness, fatigue, visual disturbances

• red coloration, especially of the face (Plethora)

• Clots

• Cardiovascular diseases

What are all the symptoms of PV related to?

The sludging of the thickened blood

These CBC findings are for what diagnosis?

• Erythrocytosis (6-10 × 10^12/L)

• Elevated hgb and hct

• RBCs appear crowded even at feathered edge of pb

• mild to moderate leukocytosis

• thrombocytosis

• a general increase in all myeloid cells

Polycythemia vera (PV)

How is the LAP affected in PV?

It is increased

What are the two types of treatment for PV?

1. therapeutic phlebotomy

2. myelosuppressive drugs (chemotherapy)

A purpose of therapeutic phlebotomy is to inhibit RBC production by creating a state of…

iron deficiency 

The major cause of death from a diagnosis of PV is what?

Thrombosis causing strokes or myocardial infarctions

Secondary Polycythemia is a form of PV where…

there is an increase in RBC in response to an underlying condition rather than due to a genetic mutation

What are two causes of secondary polycythemia?

• Tissue hypoxia 

• Renal tumors that secrete so much EPO

Once these underlying problems are fixed, the polycythemia disappears

What is relative polycythemia?

Mild polycythemia due to dehydration resulting in hemoconcentration

What is myelofibrosis?

Scarring of the bone marrow

What is primary myelofibrosis (PMF)?

The unregulated proliferation of hematopoietic cells, extramedullary hematopoiesis and progressive bone marrow fibrosis

Fibroblasts produce what?

Collagen, a normal part of the BM architecture

What happens during PMF?

The fibrotic tissue eventually disrupts the normal architecture of bone marrow and replaces hematopoietic tissue. This causes blood formation to take place in sites other than the marrow

What happens when blood formation takes places in sites other than the bone marrow in PMF?

The liver and spleen become enlarged. RBCs and WBCs do not mature properly, and RBC look like teardrops instead of disc

What are the laboratory findings for PMF?

• anemia

• striking anisocytosis

• poikilocytosis

• polychromasia and NRBCs

• Basophilic stippling

• variable platelet and WBC count

What is the typical poikilocytosis seen in PMF?

Tear drop drops and elliptocytes

Why is a dry tap often encountered in patients with PMF during bone marrow aspiration?

Because extensive bone marrow fibrosis replaces normal hematopoietic tissue making it difficult to aspirate material and often yielding little to no marrow

In PMF, what does the bone marrow aspirate typically tell you?

Nothing, it is a dry tap and therefore nondiagnostic

In PMF, what does the bone marrow core biopsy typically reveal?

A hypercellular marrow with dense collagen fibrosis and atypical megakaryocyte clusters

Why can the marrow biopsy be hypercellular even when the aspirate yields a dry tap?

The marrow is still packed with clonal hematopoietic cells, but they are trapped within the fibrotic stroma, so they cannot be aspirate

What chromosome mutation is not present in PMF?

The Ph chromosome mutation

What is another name for PMF?

Myelofibrosis with myeloid metaplasia (MMM)