Myeloproliferative Neoplasms

Question 1

What is it?

Answer 1

(Previously myeloproliferative disorders (MPD) interchangeable names)
Bone marrow lineages which proliferate – grow or multiply by rapidly producing new tissue, parts, cells or offspring
Clonal haemopoietic stem cell disorders – increased production of one or more types of haemopoietic cells.
Maturation is relatively preserved in contrast to acute leukaemia

Question 2

what are the subtypes?

Answer 2

BCR-ABL 1 +ve
o Chronic myeloid Leukaemia (over production of granulocytes)

BCR-ABL 1 -ve
o Essential thrombocythaemia (over-production of platelets)
o Primary (myelofibrosis)
o Polycythaemia Vera (over production of red cells)

Question 3

signs to consider MPN

Answer 3

• No reactive explanation and
• High Granulocyte count +/-
• High Red cell count / haemoglobin +/-
• High Platelet count +/-
• Eosinophilia/basophilia
• Splenomegaly
• Thrombosis in an unusual place

Question 4

presentation

Answer 4

asymptomatic
increased cellular turnover (gout, fatigue, weight loss, sweats)
symptoms/signs because of splenomegaly
marrow failure (fibrosis or leukaemic transformation: lower with PRV and ET)
Thrombosis (arterial or venous including TIA, MI, abdominal vessel thrombosis, claudication, erythromegalgia)

Question 5

what is chronic myeloid leukaemia (CML)?

Answer 5

proliferation of myeloid cells - granulocytes and their precursors, other lineages (platelets)
previously, chronic phase with intact maturation 3-5 years, followed by ‘blast crisis’ reminiscent of acute leukaemia with maturation defect
Fatal without stem cell/bone marrow transplantation in the chronic phase

Question 6

progression of chronic myeloid leukaemia (CML)

Answer 6

chronic phase - accelerated phase - blast crisis

Question 7

how does CML present?

Answer 7

•	Asymptomatic 
•	Splenomegaly 
•	Hypermetabolic symptoms 
•	Gout 
•	Misc. problems related to hyperleukocytosis problems. Priapism 
•	Blood count changes: 
- normal/↓Hb
- leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia
- thrombocytosis, 
•	Bone marrow

Question 8

what are the genetics of CML?

Answer 8

• Philadelphia chromosome results in a new (chimaeric) gene: BCR-ABL1
• The gene product is a tyrosine kinase which causes abnormal phosphorylation (signalling) leading to the haematological changes in CML
• Durable disease responses with Tyorsine kinase inhibitors (eg Imatinib)

Question 9

what is polycythaemia vera (PV)?

Answer 9

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

Question 10

what is it important to distinguish polycythaemia vera (PV) from?

Answer 10

o	secondary polycythaemia (chronic hypoxia, smoking, erythropoietin-secreting tumour etc)
o	pseudopolycythaemia (eg dehydration, diuretic therapy, obesity)

Question 11

how does PV present?

Answer 11

• Common MPN features
• Headache
• Fatigue (Remember blood viscosity is raised not plasma viscosity)
• Itch (aquagenic puritis)

Question 12

how is PV investigated?

Answer 12

• History (e.g. history suggestive of a secondary polycythaemia)
• Examination (splenomegaly)
• FBC, film
• JAK2 mutation status (Important)
• Investigation for secondary/pseudo causes (CXR, O2 saturation/arterial blood gases, drug history)
• Infrequent tests: erythropoietin levels, bone marrow biopsy

Question 13

what is JAK2 in relation to PV?

Answer 13

a kinase, mutations in JAK2 present in over 95% of PV patients
Mutation (substitution) results in loss of auto-inhibition
Activation or erythropoiesis in the absence of ligand
Mutational analysis forms part of initial screening and has replaced a number of other tests in routine practice

Question 14

how is PV managed?

Answer 14

venesect to haematocrit <0.45
aspirin
cytotoxic oral chemo (e.g. hydroxycarbamide)

Question 15

what is essential thrombocythaemia (ET)?

Answer 15

• Uncontrolled production of abnormal platelets
• Platelet function abnormal
o thrombosis
o at high levels can also cause bleeding due to acquired von Willebrand disease

Question 16

how does essential thrombocynthemia (ET) present?

Answer 16

• Clinical features common to MPN (particularly vasoocclusive complications)
• Bleeding (unpredictable risk especially at surgery)

Question 17

how is ET diagnosed?

Answer 17

•	Exclude reactive thrombocytosis IMPORTANT!! (Blood loss, inflammation, malignancy, iron deficiency)
exclude CML
characteristic bone marrow appearances 
genetics
o	JAK2 mutations in approx. 50 - 60%
o	CALR (Calreticulin) in approx. 25%
o	MPL mutation in approx. 5%
o	10-20% of patients will be ‘Triple Negative’

Question 18

how is ET managed?

Answer 18

• Anti-platelet agents – Aspirin

* Cytoreductive therapy to control proliferation – hydroxycarbamide, anagrelide, interferon alpha

Question 19

what is myelofibrosis?

Answer 19

Idiopathic
• Marrow failure (variable degrees)
• Bone marrow fibrosis (no alternative cause)
• Extramedullary haemopoiesis (liver and spleen)
• Leucoerythroblastic film appearances (causes are reactive to sepsis, marrow infiltration or myelofibrosis)
• Teardrop shaped RBCs in peripheral blood

Question 20

how does myelofibrosis present?

Answer 20

marrow failure
o	anaemia, bleeding, infection
splenomegaly 
o	LUQ abdominal pain
o	Complications including portal hypertension
Hypercatabolism

Question 21

how is myelofibrosis diagnosed?

Answer 21

• Typical blood film (tear-drop shaped RBC and leucoerythroblastic)
• Dry aspirate
• Fibrosis on trephine biopsy - JAK2, CALR, MPL mutations

Question 22

how is myelofibrosis managed?

Answer 22

• Supportive care (blood transfusion, platelets, antibiotics)
• Allogeneic stem cell transplantation in a select few
• Splenectomy (CONTROVERSIAL)
• JAK2 inhibitors (improve spleen size, constitutional symptoms, ?survival)