Myeloproliferative Neoplasms

Question 1

What are myeloproliferative neoplasms?

Answer 1

(previously known as myeloproliferative disorders)

Clonal haemopoietic stem cell disorders with an increased production of one or more types of haemopoietic cells (myeloid lineage)
In contrast to acute leukaemia the maturation is relatively preserved

Question 2

What can all myeloproliferative neoplasms transform into?

Answer 2

acute myeloid leukaemia

Question 3

Two broad categories of MPNs?

Answer 3

BCR-ABL1 negative:

• polycythaemia vera (too many red cells)
• essential thrombocythaemia (too many platelets)
• primary myelofibrosis

BCR-ABL1 positive:
-chronic myeloid leukaemia (too many granulocytes)

can be some overlap between disorders

Question 4

When should you consider a MPN?

Answer 4

high granulocyte count +/- 
high red cell count/ Hb +/- 
high platelet count +/-
eosinophilia/ basophilia +/-
thrombosis in an unusual place 

WITH NO REACTIVE EXPLANATION

Question 5

Explain what chronic myeloid leukaemia is?

Answer 5

proliferation of myeloid cells: granulocytes and their precursors
chronic phase with intact maturation for 3-5 years followed by ‘blast crisis’ reminiscent of acute leukaemia with maturation defect

Question 6

Clinical features of CML?

Answer 6

can be asymptomatic 
splenomegaly
weight loss
sweats
anorexia 
gout 
can get priapism

Question 7

Blood count changes in CML?

Answer 7

normal/ reduced Hb

leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia, thrombocytosis

Question 8

What is the hallmark of CML?

Answer 8

philadelphia chromosome

Question 9

Explain what the philadelphia chromosome is and how it causes disease?

Answer 9

ABL gene (chromosome 9) translocates onto chromosome 22 and fuses with BCR gene 
get shorter chromosome 22- the philadelphia chromosome and a longer chromosome 9 due to reciprocal translocation 
the new BCR-ABL1 gene on the philadelphia chromosome produces a tyrosine kinase which causes abnormal phosphorylation (signalling) leading to the haematological changes seen in CML

Question 10

The BCR-ABL1 negative MPN predominantly affect?

Answer 10

older adults

Question 11

What BCR-ABL1 negative MPN are more prevalent?

Answer 11

ET and PV

Question 12

Common clinical features to all BCR-ABL1 negative MPN?

Answer 12

may be asymptomatic 
due to increased cell turnover: gout, fatigue, weight loss and sweats 
symptoms and signs of splenomegaly 
marrow failure 
increased risk of thrombosis

Question 13

What is polycythaemia vera?

Answer 13

high Hb/ haematocrit accompanied by erythrocytosis (a true increase in red cell mass) but can have excessive production of other lineages

Question 14

What is it important to distinguish polycythaemia vera from?

Answer 14

secondary polycythaemia

pseudopolycythaemia

Question 15

Explain some causes of secondary polycythaemia?

Answer 15

chronic hypoxia from COPD, smoking or sleep apnoea results in increased EPO so more stimulation to increase red cells
or more rarely there is an EPO secreting tumour that results in increased red cells

Question 16

Explain what can cause a pseudopolycythaemia?

Answer 16

dehydration or diuretics

basically there is a normal amount of red cells but a reduced plasma volume so there is a higher proportion of red cells

Question 17

Symptoms of PV?

Answer 17

those of MPNs, fatigue, headache, visual disturbance, aquagenic pruritis (itchy after warm bath or shower), thrombosis

Question 18

Signs of PV?

Answer 18

plethoric (red) and has deep dusky cyanosis, spleen may be enlarged as well as the liver

Question 19

What mutation is often present in the BCR-ABL1 negative MPNs?

Answer 19

JAK2 mutation

Question 20

Investigations for PV?

Answer 20

FBC, blood film, JAK2 mutation is present in > 95% so part of diagnostic criteria now and can be tested for in the blood

Question 21

Management of PV?

Answer 21

Venesection to haematocrit < 0.45
Asprin to reduce risk of thrombosis should be given to all patients unless contraindicated
in some patients oral chemo hydroxycarbamide can be helpful

Question 22

What is essential thrombocythaemia?

Answer 22

uncontrolled production of abnormal platelets
platelet function is abnormal so there is risk of thrombosis, at high levels can also cause bleeding due to acquired Von Willebrand disease (because VWF is absorbed onto the surface of abnormal platelets)

Question 23

Clinical features of ET?

Answer 23

those of MPNs, particularly vaso-occlusive symptoms, bleeding, can get erythromelagia which is severe burning pain, erythema and warmth of extremities

Question 24

Investigations of ET?

Answer 24

high platelet count (must exclude a reactive cause), exclude CML, genetics

Question 25

What are reactive causes of high platelets that you must exclude to diagnosis ET?

Answer 25

blood loss
inflammation
malignancy
iron deficiency

Question 26

What are the genetics that can be tested for with ET?

Answer 26

JAK2, CALR, MPL, 10-20% will be triple negative and may be worth doing bone marrow biopsy in these people

Question 27

Management of ET?

Answer 27

anti-platelets: aspirin to reduce thrombosis risk
in patients considered at higher risk of thrombosis cytoreductive therapy to control proliferation e.g. hydroxycarbamide, anagrelide, interferon alpha

Question 28

Explain what myelofibrosis is?

Answer 28

debilitating myeloproliferative neoplasm
there is clonal proliferation of stem cells and abnormal myeloid cells in the bone marrow, liver, spleen and other organs, there is also fibrosis in the bone marrow

Question 29

Clinical features of myelofibrosis?

Answer 29

marrow failure, splenomegaly (LUQ abdo pain, complications including portal hypertensino), massive hypercatabolism with weight loss and night sweats

Question 30

Investigations for myelofibrosis?

Answer 30

• typical blood film appearance > poikilocytes (tear drop shaped red cells) and leucoerythroblastic film (presence of both neutrophil and red cell precursors in the peripheral blood)
• often difficulties in getting bone marrow aspirate due to fibrosis “dry aspirate”
• fibrosis will be seen on trephine biopsy
  (side note: aspirate is when they try to get it with a needle vs trephine where they take out like a proper bit of bone marrow)
• check for JAK2, CALR, MPL mutations, 10% will be triple negative

Question 31

Dry aspirate?

Answer 31

occurs in myelofibrosis because the fibrosis makes it difficult to aspirate

Question 32

What type of biopsy is needed in myelofibrosis?

Answer 32

trephine biopsy

Question 33

What is the typical blood film appearance of myelofibrosis?

Answer 33

poikilocytes (tear drop shaped red cells)
leucoerythroblastic film (presence of both neutrophil and red cell precursors in the peripheral blood)

Question 34

What is the name given to tear dropped shaped red cells? What conditions are they present in?

Answer 34

poikilocytes- myelofibrosis

Question 35

Myelofibrosis may develop as a primary condition or _________

Answer 35

develop late in the course of ET or PV

Question 36

Explain what is meant by leucoerythroblastic film? What conditions is it present in?

Answer 36

presence of both neutrophil and red cell precursors in the peripheral blood

Reactive (sepsis)

Marrow infiltration (e.g. haematological malignancy infiltration or metastatic infiltration)

Myelofibrosis

Question 37

What is the prognosis of myelofibrosis?

Answer 37

MF tends to be much more aggressive than ET and PV and can be a life limiting illness

Question 38

Management of myelofibrosis?

Answer 38

Supportive care: blood transfusions, platelets, antibiotics

allogeneic stem cell transplantation in a select few (only curative treatment but not many are suitable)

splenectomy (not really done now v controversial)

JAK2 inhibitors: no evidence of increased survival but improves quality of life