Haematology - Chronic Myeloproliferative Neoplasms

Question 1

What is the target of imatinib?

Answer 1

BCR-ABL tyrosine kinase seen in CML

BCR gene is normally on chromosome number 22. The ABL gene is normally on chromosome number 9.
aka Philadelphia chromsome

Question 2

What is the normal role of janus kinases?

Answer 2

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

Question 3

How does JAK2 mutation cause uncontrollable replication?

Answer 3

No longer need growth factor to activate

Question 4

Recall 5 symptoms of polycythaemia vera

Answer 4

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

Question 5

Recall 4 clinical findings in polycythaemia vera

Answer 5

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

Question 6

What is the expected level of erythropoietin in polycythaemia vera? why

Answer 6

Low

Independent (not EPO-driven) increased production of RBCs

Question 7

What mutation is present in all patients with polycythaemia vera?

Answer 7

JAK2 V617F mutation (DIAGNOSTIC) - exon 14

Increased red cell production and increased platelets = diagnostic criteria

Question 8

How should pseudopolychthaemia and polycythaemia vera be differentiated?

Answer 8

Isotype dilution method using chromium - measures blood volume

Question 9

Recall 3 causes of increased EPO

Answer 9

Hypoxia
Uterine myoma - fibroids
Renal cancer

Question 10

Recall 3 causes of pseudopolycythaemia

Answer 10

Alcohol
Obesity
Diuretics

Question 11

Recall 3 ways in which polycythaemia vera can be treated

Answer 11

1. Venesection
2. Cytoreductive therapy (hydroxyurea)
3. Aspirin to reduce thrombosis risk

Question 12

What is idiopathic erythrocytosis?

Answer 12

An isolated erythrocytosis with low EPO, where JAK2 V617F mutation is absent (although JAK mutation in exon 12 may be present)

Question 13

How should idiopathic erythrocytosis be treated?

Answer 13

Venesection only

Question 14

How is essential thrombocytothaemia defined?

Answer 14

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

Question 15

Which age group is most at risk of essential thrombocytothaemia?

Answer 15

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

Question 16

What are the 2 most likely presentations for patients with essential thrombocytothaemia?

Answer 16

Thrombosis

or bleeding?? paradoxically

Question 17

Is there a JAK2 mutation in essential thrombocytothaemia?

Answer 17

JAK2 V617F mutation [only present in 50% of ET patients so other criteria needed to diagnose]

Question 18

What is the best treatment for essential thrombocytothaemia?

Answer 18

Hydroxycarbamide (antimetabolite)

Question 19

Which condition is “tear drop poikilocytosis” pathognemonic of?

Answer 19

Myelofibrosis

Question 20

Which cells are hyperproliferating in myelofibrosis?

Answer 20

Mostly megakaryocytes

Question 21

Recall 2 signs of myelofibrosis

Answer 21

Massive spleen

Anaemia

Question 22

What is the best treatment for myelofibrosis?

Answer 22

Ruxolotinib - a JAK2 inhibitor

Question 23

Recall 4 bad prognostic indicators in CLL

Answer 23

LDH raised
CD38+
11q23 deletion
deletion of 17p (TP53)

Question 24

Recall 3 good prognostic indicators in CLL

Answer 24

Hypermutated Ig gene
Low ZAP-70 expression
13q14 deletion

Question 25

What is the 1st line treatment for CLL with a p53 deletion?

Answer 25

Ibrutinib (TKInhibitor)

Question 26

outline the main difference between between myeloproliferation, myelodysplasia and leukaemia

Answer 26

leukaemia = profileration without differentiation 
MPN = proliferation and differentiation 
MDS = ineffective proliferation - hallmark of MDS is dysplasia: the unusual appearance of myeloid precursors in the bone marrow.

Question 27

what 5 blood results are high in polycythaemia?

Answer 27

hb 
haematocrit 
platelets
MCV
plasma volume

(no circulating immature cells(

Question 28

what’s pseudo-polycythaemia

Answer 28

relative increase in RBCs (i.e. plasma volume decrease)

Question 29

give 3 alternative treatment drugs for ET

Answer 29

alpha interferon if under 40
aspirin to prevent thrombosis
o	Anagrelide (specific inhibition of platelet formation;

Question 30

lifespan of someone with ET

Answer 30

normal

Question 31

lifespan of some with with myelofibrosis

Answer 31

o Median 3-5-year survival
o BAD prognostic signs = severe anaemia <10 g/dL, thrombocytopaenia <100 x 109/L, massive splenomegaly

Summary Treatment – note that all MPD diseases can progress to myelofibrosis

Question 32

2 stages of myelofibrosis

Answer 32

o Pre-Fibrotic = Blood changes are mild (may be confused with ET), Hypercellular marrow
o Fibrotic = Splenomegaly, Blood changes, Dry tap, Prominent collagen fibrosis, Later osteosclerosis

Question 33

blood film of myelofibrosis (3)

Answer 33

 Leucoerythroblastic (nucleated RBCs and precursors)
 Tear drop poikilocytosis
 Others: giant platelets, circulating megakaryocytes

Question 34

what’s extrameduallr haemapoesis? in what condition is it seen

Answer 34

myelofibrosis
Extramedullary hematopoiesis (EMH) is the formation and activation of blood cells outside the bone marrow (BM), as a response to hematopoietic stress
in spleen and liver

Question 35

in aiddtion to a dry tap in myelofibroris give 3 BM findings

Answer 35

trephine biopsy
• Increased reticulin or collagen fibrosis
• Prominent megakaryocyte hyperplasia and clustering with abnormalities
• New bone formation

Question 36

what mutations in myelofibrosis?

Answer 36

JAK2 V617F or caclreticulin (CALR) mutation

Question 37

how can you differentiate PV from ET crudely

Answer 37

the Hb is NOT that elevated in ET (differentiates from PV)