Chronic myeloproliferative disorders

Question 1

what are myeloproliferative disorders?

Answer 1

Clonal proliferation of haemopoeitic stem cells with increased production of one or more types of HSC
In contrast to acute - cell maturation is preserved
= proliferation of granulocytes/RBCs/Platelets

Question 2

How are myeloproliferative disorders classified?

Answer 2

BCR-ABL1 positive - CML

BCR-ABL1 negative:

• polycythaemia rubra vera (RBCs)
• Essential thrombocytosis (platelets)
• idiopathic myelofibrosis

Question 3

When should a MPD be considered?

Answer 3

high granulocyte count
\+/- high RBC count
\+/- high platelet count
\+/- eosinophilia / basophilia
\+ no reactive explanation

Question 4

What features are common to myeloproliferative disorders? 5

Answer 4

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 5

What is polycythaemia rubra vera? what is this important to distinguish from?

Answer 5

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

Important to distinguish from:

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

Question 6

What are the clinical features found in polycythaemia rubra vera?

Answer 6

Clinical features common to MPD

Headache, fatigue (remember blood viscosity raised NOT plasma viscosity)

Itch (aquagenic puritis)

Question 7

What type of mutational analysis is part of the initial screening for polycythaemia rubra vera? what does this mutation cause?

Answer 7

JAK2: a kinase

JAK2 mutations present in over 95% of these patients

Mutation (substitution) results in loss of auto-inhibition

Activation of erythropoiesis in the absence of ligand

Question 8

What is included in the investigation of polycythaemia rubra vera?

Answer 8

Investigation for secondary/pseudo causes (CXR, O2 saturation/arterial blood gases, drug history)

JAK2 analysis

Infrequent tests: erythropoietin levels, bone marrow biopsy

Question 9

What is the treatment of polycythaemia rubra vera?

Answer 9

venesection to HCT<0.45 and aspirin

-if can’t tolerate give cytotoxic oral chemo (hydroxycarbamide but causes megaloblastic anaemia)

Question 10

What is essential thrombocytosis? what is important to exclude?

Answer 10

Uncontrolled production of abnormal platelets

Platelet function abnormal
thrombosis
at high levels can also cause bleeding due to acquired von Willebrand disease

Exclude reactive thrombocytosis:

• blood loss
• inflammation
• malignancy
• iron deficiency
• CML

Question 11

What are the clinical features of essential thrombocytosis?

Answer 11

Clinical features common to MPD (particularly vasoocclusive complications)

Bleeding (unpredictable risk especially at surgery)

Question 12

What genetic mutations are found in essential thrombocytosis?

Answer 12

JAK2 mutations (in 50%)

CALR (Calreticulin) in those without mutant JAK2

MPL mutation

Question 13

what is the treatment for essential thrombocytosis?

Answer 13

Anti-platelet agents
Aspirin

Cytoreductive therapy to control proliferation
hydroxycarbamide, anagrelide, interferon alpha

Question 14

Myelofibrosis:

how can this arise?

Answer 14

Idiopathic(or agnogenic myeloid metaplasia)

Post-polycythaemia or essential thrombocythaemia

Question 15

What happens in myelofibrosis?

Answer 15

abnormal fibrous deposition in the bone marrow = low blood count

Question 16

Idiopathic myelofibrosis:

-what are the features? 6

Answer 16

Marrow failure (variable degrees): anaemia/bleeding/infection

Bone marrow fibrosis (no secondary fibrosis)

Extramedullary hematopoiesis (liver and spleen)

Leukoerythroblastic film appearances IMPORTANT!!

Teardrop-shaped RBCs in peripheral blood

hypercatabolism

Question 17

How is myelofibrosis diagnosed?

Answer 17

typical blood film (tear-drop shaped RBC and leucoerythroblastic)

dry aspirate

fibrosis on trephine biopsy

JAK2 or CALR mutation in a proportion

Question 18

What the 3 causes of a leucoerythroblastic blood film?

Answer 18

Reactive (sepsis)

Marrow infiltration

Myelofibrosis

Question 19

what is the treatment of myelofibrosis?

Answer 19

Supportive care (blood transfusion, platelets, antibiotics)

Allogeneic stem cell transplantation in a select few

Splenectomy (CONTROVERSIAL)

JAK2 inhibitors (improve spleen size, QoL, ?survival)