Myeloproliferative disorders

Question 1

What is the definition of myeloproliferative?

Answer 1

Myelo = bone marrow lineage(s)
(granulocytes, red cells & platelets)

Proliferative = to grow or multiply by rapidly producing new tissue, parts, cells, or offspring

Question 2

Is chronic myeloid leukaemia (CML) BCR-ABL1 positive or negative?

Answer 2

BCR-ABL1 positive

Primary myelofibrosis, polycythaemia vera and essential thrombocythaemia are all BCR-ABL1 negative.

Question 3

What is BCR-ABL1?

Answer 3

An abnormal protein formed by the philadelphia gene.

Question 4

When should a myeloproliferative disorder (MPN) be considered?

Answer 4

High Granulocyte count
+/-
High Red cell count / haemoglobin
+/-
High Platelet count
+/-
Eosinophilia/basophilia

Splenomegaly

Thrombosis in an unusual place

Question 5

What are clonal haemopoietic stem cell disorders and how does this compare to acute leukaemia?

Answer 5

Clonal haemopoietic stem cell disorders with an increased production of one or more types of haemopoietic cells.

In contrast to acute leukaemia, maturation is relatively preserved

Question 6

What is polycythaemia vera?

Answer 6

A clonal haematological malignancy characterised by pronounced symptoms.

An overproduction of RBC’s

Also with increased risk of thrombosis and potential for evolution to myelofibrosis and secondary acute myeloid leukaemia.

Question 7

Aetiology of polycythaemia vera?

Answer 7

Median age of diagnosis is ~65 years old but can affect younger patients.

JAK2 - kinase mutation present in over 95% of PV patients.

Question 8

Pathophysiology of PV?

Answer 8

JAK2 mutation (substitution) results in loss of autoinhibition leading to absence of erythropoiesis in the absence of ligand.

Question 9

How are asymptomatic cases of PV identified?

Answer 9

May be discovered on routine blood count in a person with no related symptoms or there may be non-specific complaints of lethargy and tiredness.

Question 10

Clinical features of PV?

Answer 10

Increased cell turnover - gout, fatigue, weight loss and sweats.

Symptoms/signs due to splenomegaly.

Marrow failure - fibrosis or leukaemic transformation (transformation risk = low)

Thrombosis - arterial or venous including TIA, MI, claudication, abdominal vessel thrombosis.

Headache, fatigue

Itch - aquagenic pruritis

Question 11

What is aquagenic pruritis?

Answer 11

Itching that is worse after a hot shower or bath.

Question 12

Blood test investigations for PV?

Answer 12

FBC, blood film - high haemoglobin/haematocrit accompanied by erythrocytosis (increase in red cell mass) but can also have excessive production of other lineages.

JAK2 mutation status
- If JAK2 negative but high clinical suspicion - erythropoietin levels, bone marrow biopsy.

Question 13

What are some blood test investigations for secondary PV?

Answer 13

Investigations for secondary/pseudocauses - CXR, O2 sats/ABG’s, drug history.

• Secondary polycythaemia - chronic hypoxia, erythropoietin-secreting tumour etc.
• Pseudopolycythaemia e.g. dehydration, diuretic therapy, obesity).

Question 14

Management of PV?

Answer 14

Aspirin

Cytotoxic oral chemotherapy e.g. hydroxycarbamide.

Question 15

What is essential thrombocythaemia?

Answer 15

Uncontrolled production of abnormal platelets

Question 16

Aetiology of essential thrombocythaemia?

Answer 16

Median age of diagnosis is ~65 years old but can affect younger patients.

Question 17

Pathophysiology of essential thrombocythaemia?

Answer 17

Platelet function is abnormal, leading to thrombosis
- At high levels can cause bleeding due to acquired von Willebrand disease.

Question 18

Clinical features of essential thrombocythaemia?

Answer 18

Asymptomatic

Increased cellular turnover - gout, fatigue, weight loss, sweats.

Symptoms/signs due to splenomegaly.

Marrow failure - fibrosis or leukaemic transformation (transformation risk = low)

Thrombosis - arterial or venous including TIA, MI, abdominal vessel thrombosis and claudication.

Bleeding - unpredictable risk

Question 19

Investigations for essential thrombocythaemia?

Answer 19

Exclude reactive thrombocytosis - blood los, inflammation, malignancy, iron deficiency.

Exclude CML (chronic myeloid leukaemia)

Bloods: genetics
* JAK2 mutation in around 50-60%
* CALR mutation in around 25%
* MLP mutation in around 5%
* 10-20% of patients will be “triple negative”.

Bone marrow biopsy

Question 20

Management of essential thrombocythaemia?

Answer 20

Antiplatelet agents - aspirin

Cytoreductive therapy to control proliferation
* Hydroxycarbamide
* Anagrelide
* Interferon alpha

Question 21

What is idiopathic myelofibrosis?

Answer 21

Healthy bone marrow is replaced by fibrosis. Leads to lack of production of normal cells.

Question 22

Aetiology of idiopathic myelofibrosis?

Answer 22

Mean age of diagnosis ~ 65 years old but can affect younger patients.

Unknown underlying cause

There is an association with the mutations JAK2, CALR or MPL gene.

Question 23

Clinical features of idiopathic myelofibrosis?

Answer 23

Asymptomatic

Marrow failure - variable degrees
* Anaemia, bleeding, infection.

Bone marrow fibrosis with no alternative cause.

Extramedullary haematopoiesis (liver and spleen)
- Splenomegaly can cause LUQ abdominal pain, complications include portal hypertension.

Catabolism - night sweats, extreme weight loss.

Question 24

Blood test investigations for idiopathic myelofibrosis?

Answer 24

Leukoerythroblastic film appearances.

Teardrop shaped RBC’s in peripheral blood.

Question 25

Bone marrow investigations for idiopathic myelofibrosis?

Answer 25

Dry aspirate

Fibrosis on trephine biopsy

Question 26

Genetic testing investigations for idiopathic myelofibrosis?

Answer 26

JAK2, CALR, MLP mutations

Approx 10% are “triple negative”

Question 27

Management for idiopathic myelofibrosis?

Answer 27

Supportive - blood transfusion, platelets, antibiotics.

Allogenic stem cell transplantation in few.

Splenectomy (not always recommended)

JAK2 inhibitors e.g. ruxolitinib