Haematology 4 - Chronic myeloproliferative neoplasms

Question 1

How should pseudopolychthaemia and polycythaemia vera be differentiated?

Answer 1

Isotype dilution method

Question 2

Recall 3 causes of pseudopolycythaemia

Answer 2

Alcohol
Obesity
Diuretics

Question 3

Causes of secondary polycythaemia

Answer 3

(non-malignant)

Question 4

Classification of myeloproliferative disorders

Answer 4

a) philadelphia negative
- essential thrombocythaemia
- polycythaemia vera
- primary myelofibrosis
b) philadelhpia positive
- CML

**proliferation increased, differentiation normal

Question 5

What is the most common gene that is mutated in philadelphia negative MPDs?

Answer 5

JAK2- this is a tyrosine kinase

(other genes: calreticulin, MPL)

Question 6

What is the normal role of janus kinases?

Answer 6

They activate the STAT pathway, which promotes cell growth and replication

Question 7

How does JAK2 mutation cause uncontrollable replication?

Answer 7

No longer need growth factor to activate

Question 8

In polycythaemia vera, what else will be abnormal on the FBC other than red cell count?

Answer 8

Pronounced thrombophilia and slight increase in granulocyte count

Question 9

Recall some symptoms of polycythaemia vera

Answer 9

Due to hyperviscosity:
- Headaches
- visual disturbances
- dyspnoea
Due to increased histamine release:
- peptic ulcer
- aquagenic pruritis

Question 10

Recall four clinical findings in polycythaemia vera

Answer 10

Plethora
Erythromelalgia (red, painful extremities)
Gout
Retinal vein engorgement

Question 11

What is the expected level of erythropoietin in polycythaemia vera?

Answer 11

Low

Question 12

What mutation is present in all patients with polycythaemia vera?

Answer 12

JAK2

Question 13

Recall 3 ways in which polycythaemia vera can be treated

Answer 13

1. Venesection
2. Cytoreductive therapy eg hydroxycarbamide
3. Aspirin to reduce thrombosis risk

Question 14

What is idiopathic erythrocytosis?

Answer 14

An isolated erythrocytosis with low EPO, where JAK2 V617 mutation is absent (although JAK mutation in exon 12 may be present)

Question 15

How should idiopathic erythrocytosis be treated?

Answer 15

Venesection only

Question 16

How is essential thrombocytothaemia defined?

Answer 16

Chronic myeloproliferative neoplasm with a sustained thrombocytosis > 600 x 10^9/L

Question 17

Which age group is most at risk of essential thrombocytothaemia?

Answer 17

Bimodal:
Small peak at 30y (M=F)
Larger peak at 55y (F>M)

Question 18

How does ET present?

Answer 18

• most likely an incidental finding
• or can present with clinical features
  a) thrombosis- venous or arterial
  b) bleeding - mucous membrane and cutaneous **bc of abormal quality of platelets

Headaches, dizziness, visual disturbance

Modest splenomegaly

investigations

• raised platelet count
• blood film: large platelets and megakaryocyte fragments
• increased BM megakaryocytes (not reactive)

Question 19

Is there a JAK2 mutation in essential thrombocytothaemia?

Answer 19

Yes in 50%

Question 20

What is the best treatment for essential thrombocytothaemia?

Answer 20

Hydroxycarbamide to reduce platelet count

Aspirin to reduce risk of thrombosis

and anagrelide- reduce formation of platelets form megakaryocytes

Question 21

Blood film and trephine biopsy in primary myelofibrosis

Answer 21

Also blood counts:

• high platelet count (you get increased production of abnormal platelets–>pushing out other cells)
• high LDH and high uric acid - reflecting increased RBC turnover

Question 22

Which condition is “tear drop poikilocytosis” pathognemonic of?

Answer 22

Myelofibrosis

Question 23

Recall 2 signs of myelofibrosis

Answer 23

1. Massive spleen - (and maybe hepatomegaly)

As bone marrow is fibrosed you get extramedullary haematopoiesis

2. Anaemia (leukoerythroblastic anaemia)

**can also present with budd chiari syndrome (occlusion of the hepatic vein)

Question 24

Prognosis of primary myelofibrosis

and treatment options?

Answer 24

BAD. worse than other philadelhpia negative MPDs

Tx: mainly supportive.

Question 25

What is the best treatment for myelofibrosis?

Answer 25

Ruxolotinib - a JAK2 inhibitor

Question 26

Even though chronic MPDs are “less deadly”, what is a major risk?

Answer 26

They can tranform into acute leukaemias

Question 27

How does CML present?

Answer 27

**raised cell counts

**even though you have thrombocytosis, you can present with bleeding or clotting as the platelets are dysfunctional

Question 28

FBC and blood film features of CML

Answer 28

• leucocytosis (predominantly due to granulocytes)
• biphasic peak: neutrophilia and myelocytes
• basophils raised as well
• <5% myeloblasts (unelss in blast crisis)
• raised (or upper normal) platelet count- contrast with acute leukaemia

Triad: leukocytosis, basophilia, neutrophilia - think CML!!

(you also see a thrombocytosis

Question 29

Genetics of philadelphia positvie MPD

Answer 29

BCR-ABL1 fusion gene positive

Translocation of chromosome 9 and 22

Question 30

How do you diagnose and monitor CML?

Answer 30

RT-PCR is most accurate

Question 31

Clinical phases of CML

Answer 31

Accelerated phase: 10-19% blasts

Blast crisis: >20% blasts

Question 32

What is the target of imatinib?

Why is imatinib not 100% successful?

Answer 32

Mutated tyrosine kinase (by BCR-ABL gene)

Not 100% successful because you can get resistance to treatment or disease may progress to blast crisis which evades treatment

Question 33

Which 2 haematological cancers cause massive hepatosplenomegaly with no lymphadenopathy?

Answer 33

1. CML
2. myelofibrosis

*both examples of MPDs!!

(because of extramedullary haematopoiesis)

(if you have lymphadenopathy, it’s a lymphoid problem)

Question 34

What does low leukocyte alkaline phosphatase suggest?

Answer 34

CML

Question 35

How to classify myeloproliferative disorders?

Answer 35

Question 36

what two conditions can MPNs transform into?

Answer 36

myelofibrosis or acute luekaemia

Question 38

What causes myelofibrosis?

Answer 38

can be idiopathic or can progress from other MPNs