Chronic Myeloproliferative Neoplasms

Question 0

What group of people do chronic myeloproliferative neoplasms predominantly affect?

Answer 0

Adults with a peak incidence in the 5th-7th decade.

Question 1

What is a CMPN?

Answer 1

A group of clonal haematopoitic stem cell disorders characterised by proliferation in the bone marrow of one or more of the myeloid lineages (granulocytes, erythroid, megakaryocytic).

Question 2

Features of a blood test with regards to CMPN.

Answer 2

Increase Hb, WCC, PLT

Question 3

4 classifications of CMPN?

Answer 3

1) chronic myelogenous leukaemia (CML)
2) polycythemia vera (PV)
3) essential thrombocytopenia (ET)
4) primary myelofibrosis (PMF)

Question 4

What do CMPN’s have the potential to progress to?

Answer 4

Myelofibrosis

Acute leukaemia

Question 5

Common clinical features of CMPN’s?

Answer 5

Splenomegaly and hepatomegaly due to sequestration of excess blood cells or extramedullary haematopoiesis.
Thrombosis
Bleeding

Question 6

Pathogenesis of CMPN’s?

Answer 6

Activation of tyrosine kinase signal transduction pathway.

Question 7

What to use in the diagnosis of CMPN’s?

Answer 7

Clinical signs and symptoms.
Laboratory features.
Cytogenetics.
Malcular findings.

Question 8

What causes chronic myeloid leukaemia (CML)?

Answer 8

A mutation in a haematopoietic stem cell.

Translocation: t(9;22)

Question 9

What is chromosome 22 called when there is a translocation with chromosome 9?

Answer 9

Philadelphia chromosome.

Question 10

What does the translocation in CML result in?

Answer 10

The formation of an abnormal fusion protein –> BCR/ABL combination–> enhanced tyrosine kinase activity.

Question 11

What does the abnormal fusion gene, BCR/ABL, lead to?

Answer 11

Increased granulocytic proliferation.
Decreased apoptosis.
Decreased adherence of bone marrow haematopoietic stem cells to stromal cells.

Question 12

What is the gold standard for diagnosing Chronic Myeloid Leukaemia?

Answer 12

Detection of Philadelphia chromosome.

Question 13

Peripheral blood findings in people with chronic myeloid leukaemia?

Answer 13

Increased WCC
Often, basophils and eosinophils increased.
Normochromic, normocytic anaemia

Question 14

Bone marrow findings in CML?

Answer 14

Hypercellular with predominantly granulocyte precursors.

Question 15

What is the normal myeloid:erythroid ratio in bone marrow?

Answer 15

1.5-3.5:1

Question 16

Treatment of chronic myeloid leukaemia?

Answer 16

Tyrosine kinase inhibitors - prolong survival.

Allogeneic bone marrow transplant - curative.

Question 17

Name a tyrosine kinase inhibitor and outline its mechanism of action.

Answer 17

Imatinib.
Acts by occupying the site of the BCR-ABL fusion protein where ATP normally binds. This prevents said fusion protein phosphorylation of its substrate.

Question 18

What are three BCR-ABL negative myeloproliferative neoplasms.

Answer 18

1) essential thrombocythaemia (ET)
2) polycythaemia vera (PV)
3) primary myelofibrosis (PMF)

Question 19

An overview of Ph-ve MPM?

Answer 19

ET, PV and PMF are closely related clonal haemopoietic stem cell disorders.
PV and ET patients have long term survival.
Life expectancy reduced with PMF!

Question 20

What are the main causes of mortality in Ph-ve MPN’s?

Answer 20

Arterial and venous thrombosis are the main causes of mortality and morbidity.

Question 21

Pathogenesis of Ph-ve MPN?

Answer 21

JAK2 mutation underlies the pathogenesis–> proliferation of granulocytes, erythroid series and megakaryocytes.

Question 22

What are the clinical findings in essential thrombocythaemia (ET)?

Answer 22

Hemorrhage due to abnormal platelet function.
Red, warm painful fingers and toes.
Thrombosis.

Question 23

Lab findings in essential thrombocythaemia(ET)?

Answer 23

Increased platelet count (due to increased megakaryocyte proliferation).
Bone marrow shows increased numbers of enlarged mature megakaryocytes.

Question 24

When diagnosing essential thrombocythaemia, what is important to exclude?

Answer 24

NB to exclude reactive causes of thrombocytosis.

Question 25

Name some broad categories of reactive causes of thrombocytosis.

Answer 25

Infection/inflammation.
Chronic haemorrhage.
Iron deficiency.
Post surgery.
Malignancy.

Question 26

Prognosis and treatment of essential thrombocythaemia?

Answer 26

Largely indolent disorder, interrupted by occasional life-threatening thrombo-embolic/haemorrhagic episodes.
Principle treatment is to control platelet count using cytoreductive agents and antiplatelet drugs (eg. Aspirin) .

Question 27

Different causation categories of polycythaemia?

Answer 27

Familial/inherited.
Acquired:
- secondary to tissue hypoxia or ectopic EPO production.
- relative (reduced plasma volume) Eg) diuretic use
- primary acquired = polycythaemia vera

Question 28

The laboratory findings in polycythaemia vera?

Answer 28

Increased Hb and Haematocrit.

Proliferation of granulocytes and megakaryocytes.

Question 29

Risks associated with polycythaemia vera?

Answer 29

Cerebrovascular accident (stroke).
Venous thrombo-embolism.

Question 30

What kind of mutation is found often in polycythaemia vera?

Answer 30

JAK2 mutation in 90-95% of cases.

Question 31

Prognosis and treatment of polycythaemia vera?

Answer 31

Around 10 years.
Most people die due to thrombosis or haemorrhage.
Repeated venesection is only therapy.
Warfarin –> cases of venous thrombosis.

Question 32

What is the predominant feature of primary myelofibrosis?

Answer 32

Progressive generalised fibrosis of the bone marrow in association with development of extramedullary haematopoiesis in the spleen and liver.

Question 33

Clinical picture of primary myelofibrosis?

Answer 33

Anaemia and massive hepatosplenomegaly.

Question 34

What causes primary myelofibrosis?

Answer 34

Caused by cytokine released by abnormal megakaryocyte proliferation.
JAK2 mutation in 50% of cases.

Question 35

The two phases of primary myelofibrosis?

Answer 35

Prefibrotic phase:
- hypercellular marrow with increased neutrophils and markedly abnormal large megakaryocytes and minimal fibrosis.
Fibrotic phase:
- increased reticulin, collagen fibrosis in bone marrow
- bone marrow may be hypercellular/hypocellular

Question 36

What to expect on a peripheral blood slide of someone with primary myelofibrosis?

Answer 36

Leuco-erythroblastosis.

Anisopoikilocytosis.

Question 37

Prognosis of primary myelofibrosis?

Answer 37

Depends on stage of disease. Better prognosis if not yet in stage 2.

Question 38

Treatment of primary myelofibrosis?

Answer 38

Supportive:
- cytoreductive agents Eg) hydroxyurea (reduce spleen size)
- splenectomy/splenic radiation is considered for patients with severe splenomegaly and complications
Cure:
- allogenic bone marrow transplant for young patients