Chronic Myeloproliferative Disorders

Question 1

What are the main chronic myeloproliferative disorders?

Answer 1

• Chronic myelogenous leukemia (CML)
• Polycythemia vera
• Primary myelofibrosis
• Essential thrombocytosis (platelets)

Question 2

Certain features are common among the MPDs:

Answer 2

• splenomegaly
• propensity to terminate in a “spent phase” characterized by marrow fibrosis and peripheral blood cytopenias
• ability to progress to acute leukemia

Question 3

How do the myeloproliferative disorders differ from AML?

Answer 3

in MPD, cells can continue to differentiate

Question 4

In general, the target of neoplastic transformation in myeloproliferative disorders is what? What is the exception?

Answer 4

a multipotent progenitor cell; CML is the exception (a pluripotent stem cell giving rise to both lymphoid AND myeloid cells is affected)

Question 5

What is a common pathologic feature in MPDs?

Answer 5

presence of mutated, constitutively activated tyrosine kinases that lead to growth factor independent proliferation

Question 6

What is the gene/mutation implicated in CML?

Answer 6

BCR-ABL fusion gene

Question 7

What is the gene/mutation implicated in polycythemia vera?

Answer 7

JAK2 point mutations

Question 8

What is the gene/mutation implicated in essential thrombocytosis and primary myelofibrosis?

Answer 8

JAK2, CALR, and MPL point mutations

Question 9

Where does the chromosomal transformation occur in CML?

Answer 9

The Ph chromosome can be found in the dividing progeny of the multipotent myeloid stem cells but may occur as early as the pluripotent stem cells.

Question 10

What does the BCR-ABL fusion gene do?

Answer 10

It encodes for the synthesis of a 210 kD fusion protein with tyrosine kinase activity.

Question 11

What is the bone marrow composition of a patient with CML?

Answer 11

It is close to 100% cellular (no adiposity), with maturing granulocytic precursors comprising most of the cellularity.

Question 12

Basophilia on peripheral blood smear is a clue for which disorder?

Answer 12

CML

Question 13

What is the difference b/t CML and leukemoid reaction on peripheral blood smear?

Answer 13

• CML: usually >50,000 WBCs/uL, cells at all stages of maturation, and reduced LAP score, marked splenomegaly, presence of Philadelphia chromosome
• Leukemoid reaction: usually <50,000 WBCs/uL, almost all mature cells, elevated LAP score, variable splenomegaly, no Philadelphia chromosome

Question 14

Describe the clinical course of CML.

Answer 14

• Initial symptoms are non-specific (fatigue, weakness, weight loss, anorexia, abdominal discomfort, splenomegaly)
• Progression is slow, but 50% of patients enter an “accelerated” phase with decreased response to treatment, increasing anemia and thrombocytopenia, and sometimes striking peripheral blood basophilia
• Eventual transformation to “blast” phase/crisis in which clinical picture looks like AML

Question 15

How is CML treated?

Answer 15

• Previously: allogeneic BM transplantation and interferon-α, but these are difficult and not used as much anymore
• Targeted biologic inhibitors of BCR-ABL are superior with dramatically improved outcomes (ex: Imatinib)

Question 16

What is the difference b/t relative and absolute polycythemia vera?

Answer 16

• Relative: caused by decreased plasma volume from dehydration
• Absolute: caused by an increase in total RBC mass

Question 17

How do EPO levels change in polycythemia vera?

Answer 17

EPO levels are low or virtually undetectable, as PV progenitor cells have markedly decreased requirements for EPO

Question 18

What are common complications of polycythemia vera?

Answer 18

Thrombotic episodes leading to MI, stroke, DVT, hemorrhages (minor or life-threatening), and Budd-Chiari syndrome due to elevation in hematocrit, which promotes abnormal blood flow, vascular distension, and stasis.

Question 19

What is the treatment for polycythemia vera?

Answer 19

therapeutic phlebotomies to maintain red cell mass near normal

Question 20

When does polycythemia vera usually appear?

Answer 20

in late middle age (insidious onset)

Question 21

True or false: The majority of polycythemia vera patients are hypertensive.

Answer 21

True! 70% are hypertensive.

Question 22

How does primary myelofibrosis differ from the other CMPDs?

Answer 22

There is early and rapid progression to obliterating marrow fibrosis (morphologically similar to the “spent” phase of other CMPDs).

Question 23

Describe the pathophysiology of primary myelofibrosis.

Answer 23

• Excessive collagen deposition in BM
• Secretion of PDGF and TBF-β by neoplastic megakaryocytes
• Displacement of stem cells/normal marrow elements
• Extramedullary hematopoeisis in spleen, liver, and lymph nodes

Question 24

Describe the clinical course of primary myelofibrosis.

Answer 24

Patients are typically elderly and seek medical attention due to progressive anemia, splenic enlargement, or non-specific symptoms (ex: gout due to high cell turnover). Median survival is 1-5 years with complications such as infections, bleeding, and leukemic transformation in 5-20%.

Question 25

What are the key findings on a peripheral blood smear in primary myelofibrosis?

Answer 25

leukoerythroblastic blood picture with nRBCs, immature RBCs, and tear drop cells. Platelets may be abnormal in size, shape, or function.

Question 26

What are the key findings on a bone marrow biopsy in primary myelofibrosis?

Answer 26

thickened bony trabeculae (sclerosis) with hypercellular marrow

Question 27

What is the stain used to visualize the fibrosis in primary myelofibrosis?

Answer 27

reticulin stain

Question 28

Essential thrombocytosis involves proliferation of which cells?

Answer 28

predominantly megakaryocytic lineage cells (high platelet counts)

Question 29

What does bone marrow show in essential thrombocytosis?

Answer 29

mild to moderate increase in cellularity with increased large abnormal megakaryocytes

Question 30

What is the clinical presentation of essential thrombocytosis?

Answer 30

thrombosis/hemorrhage due to qualitative/quantitative platelet abnormalities

Question 31

Which type of cells primarily compose the BM cellularity in CML?

Answer 31

maturing granulocytic precursors

Question 32

What does peripheral blood show in CML?

Answer 32

marked leukocytosis with left shift to immaturity (basophilia)

Question 33

Polycythemia vera is driven by which mutation?

Answer 33

JAK2

Question 34

What is the typical disease course of essential thrombocytosis?

Answer 34

indolent course with median survival 12-15 yrs