Chronic Myeloproliferative Disorders

Question 1

What is meant by myeloproliferative?

Answer 1

The bone marrow makes too many red blood cells, platelets, or certain white blood cells

Question 2

What are CMDs?

Answer 2

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 3

What are the sub types of MPDs?

Answer 3

BCR-ABL1 +ve: CML

BCR-ABL1 -ve: Polycythaemia Rubra Vera, Essential Thrombocytaemia, Idiopathic Myelofibrosis

Question 4

When should a MPD be considered?

Answer 4

High Granulocyte count	
High Red cell count / haemoglobin	
High Platelet count	
Eosinophilia/basophilia
Splenomegaly
Thrombosis in an unusual place
No reactive explanation

Question 5

What occurs in CML?

Answer 5

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

Question 6

What are the clinical features of CML?

Answer 6

Asymptomatic
Splenomegaly
Hypermetabolic symptoms
Gout
Misc:  Problems related to hyperleucocytosis problems, Priapism

Question 7

What are the lab features of CML?

Answer 7

Blood count changes:
normal/↓Hb
leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia
thrombocytosis
Bone marrow- increase in myelocytes and eosinophils

Question 8

What is the hallmark of CML?

Answer 8

Philadelphia chromosome

Question 9

What is the gene product in CML?

Answer 9

Tyrosine kinase which causes abnormal phosphorylation (signalling) leading to the haematological changes in CML

Question 10

What features are common to both BCR-ABL1 + and - MPD?

Answer 10

Asymptomatic
Increased cellular turnover (gout, fatigue, weight loss, sweats)
Symptoms/signs due to splenomegaly
Marrow failure (fibrosis or leukaemic transformation:lower with PRV and ET)
Thrombosis (arterial or venous including TIA, MI, abdominal vessel thrombosis, claudication, erythromelalgia)

Question 11

What occurs in PRV?

Answer 11

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

Question 12

What is it important to distinguish PRV from?

Answer 12

Secondary polycythaemia (chronic hypoxia, 	smoking, erythropoietin-secreting tumour etc)
Pseudopolycythaemia (eg dehydration, 	diuretic therapy, obesity)

Question 13

What are the clinical features of PRV?

Answer 13

Common to MPD
Headache, fatigue (blood viscosity raised not plasma viscosity)
Itch (aquagenic puritis)

Question 14

How is polycythaemia investigated?

Answer 14

History (eg history suggestive of a secondary polycythaemia?)
Examination (eg splenomegaly?)
FBC, film
JAK2 mutation status
Ix for 2’/pseudo causes- CXR, O2 saturation/ABGs, DHx)
Infrequently EPO levels, bone marrow biopsy

Question 15

How many PRV patients have a JAK2 (kinase) mutation?

Answer 15

95%

Question 16

What does the JAK2 mutation?

Answer 16

Mutation (substitution) results in loss of auto-inhibition

Activation of erythropoiesis in absence of ligand

Question 17

How is PRV treated?

Answer 17

Venesect to haematocrit <0.45
Aspirin
Cytotoxic oral chemo (hydroxycarbamide)

Question 18

What is essential thrombocythaemia (ET)?

Answer 18

Uncontrolled production of abnormal platelets

Question 19

What can the abnormal platelet function in ET cause?

Answer 19

Thrombosis

At high levels also bleeding due to acquired vWD

Question 20

What are the clinical features of ET?

Answer 20

Common to MPD (particularly vasoocclusive complications)

Bleeding

Question 21

How is ET diagnosed?

Answer 21

Exclude reactive thrombocytosis
(Blood loss, inflammation, malignancy, iron deficiency)
Exclude CML
Genetics: JAK2 mutations (in 50%), CALR (Calreticulin) in those without mutant JAK2, MPL mutation
Characteristic bone marrow appearances

Question 22

What is the treatment for ET?

Answer 22

Anti-platelet agents- Aspirin

Cytoreductive therapy to control proliferation- hydroxycarbamide, anagrelide, interferon alpha

Question 23

What occurs in idiopathic myelofibrosis?

Answer 23

Marrow failure (variable degrees)
Bone marrow fibrosis (no secondary fibrosis)
Extramedullary hematopoiesis (liver and spleen)
Leukoerythroblastic film appearances
Teardrop-shaped RBCs in peripheral blood

Question 24

What are the clinical features of MF?

Answer 24

Marrow Failure- anaemia, bleeding, infection
Splenomegaly- LUQ abdo pain, complications including portal HT
Hypercatabolism
Common to MPD

Question 25

How is MF diagnosed?

Answer 25

Lab diagnosis
Typical blood film (tear-drop shaped RBC and leucoerythroblastic)
Dry aspirate
Fibrosis on trephine biopsy
JAK2 or CALR mutation in a proportion

Question 26

What are the two types of MF?

Answer 26

Idiopathic(or agnogenic myeloid metaplasia)

Post-polycythaemia or essential thrombocythaemia

Question 27

What are the causes for a leucoerythroblastic film?

Answer 27

Reactive (sepsis)
Marrow infiltration
Myelofibrosis

Question 28

What is the treatment for MF?

Answer 28

Supportive care (blood transfusion, platelets, antibiotics)
Allogeneic stem cell transplantation in a select few
Splenectomy (Controversial)
JAK2 inhibitors e.g. Ruxolitinib (improve spleen size, QoL, ?survival)