Polycythaemia and Myeloproliferative disorders

Question 1

Define polycythaemia

Answer 1

Raised Hb and Hct

Question 2

What is the difference between true and relative polycythaemia?

Answer 2

• Relative (lack of plasma) - non-malignant
• True (excess erthrocytes)
  
  • Secondary - reactive - elevated EPO (non-malignant)
  • Primary - reduced EPO (myeloproliferative neoplasm)

Question 3

What are the types of myeloproliferative neoplasms (MPDs)?

Answer 3

1. Ph (Philadelphia Chromosome) negative
   
   1. Polycythaemia vera (PV)
   2. Essential Thrombocythaemia (ET)
   3. Primary Myelofibrosis (PMF)
2. Ph positive
   
   1. Chronic myeloid leukaemia (CML)

Question 4

What is the difference between true and relative polycythaemia? How could we tell the difference historically?

Answer 4

True - Red cell mass increases

Relative - Plasma volume decreases

Dilution studies/Fick principle

• Red cell mass: ⁵¹ Cr labelled RBC
• Plasma Vol: ¹³¹ labelled albumin

Question 5

Who gets relative polycythaemia?

Answer 5

• Alcohol
• Obsesity
• Diuretic

Question 6

What are the secondary true polycythaemias due to?

Answer 6

Due to raised EPO

• Appropriate
  
  • High Altitude
  • Hypoxic lung disease
  • Cyanotic heart disease
  • High affinity haemoglobin
• Inappropriate
  
  • Renal disease (cysts, tumours, inflammation)
  • Uterine myoma
  • Other tumours (liver, lung)

Question 7

What is the problem in myeloproliferative neoplasms?

Answer 7

There is excess cells but no problem in functionality (differentiation)

Question 8

What happens when you gain a mutation in an erythrocyte precursor?

Answer 8

Excess red blood cells - Polycythaemia vera

Question 9

What happens when you gain a mutation in the granulocytic series?

Answer 9

You get excess neutrophils - CML

Question 10

What processes are disrupted by these mutation? What types of mutations are these?

Answer 10

Disruption in type 1 processes (cellular proliferation)

Question 11

What are the non-phildaelphia MPD (e.g PV) associated with?

Answer 11

Associated with JAK 2 (Janus kinase 2) mutation

Question 12

What occurs in normal EPO signalling?

Answer 12

1. There are JAK 2 on the EPO receptor (which leads to RBC production)
2. JAK 2 is not usually phosphorylated
3. EPO binds to the receptors and they dimerise causing phosphorylation of JAK 2
4. Downstream signalling

Question 13

What are the consequences of a mutation in the tyrosine kinase?

Answer 13

Question 14

What type of mutation would you see in PV?

Answer 14

JAK2 V617F

Question 15

What type of mutation would you see in ET?

Answer 15

• JAK2 V617F - 60%
• Calreticulin - 30%
• MPL - 5%

Question 16

What type of mutation would you see in PMF?

Answer 16

• JAK2 V617F - 60%
• Calreticulin - 30%

Question 17

How would you diagnose MPD (Ph negative)

Answer 17

Based on combination of:

• Clinical features
  
  • Syptoms
  • Splenomegaly
• FBC +/- Bone marrow biopsy
• EPO level
• Mutation testing

Question 18

Describe the epidemiology of PV

Answer 18

Question 19

How is PV diagnosed?

Answer 19

• Usually incidental diagnosis routine FBC (HB high and Hct high)
• Symptoms of hyperviscosity
  
  • Headaches, light headedness, stroke
  • Visual disturbances
  • Fatigue, dyspnoae
• Increased histamine release
  
  • Aquagenic pruritus
  • Peptic ulceration
• Test for JAK2 V617F mutation

Question 20

How do you treat PV?

Answer 20

• Aim to reduce Hct –> target Hct <45%
  
  • Venesection
  • Cytoreductive therapy hydroxycarbamide
• Aim to reduce risks of thrombosis
  
  • Control Hct
  • Aspirin
  • Keep platelets below 400 x 10⁹/l

Question 21

What defines ET?

Answer 21

Sustained thrombocytosis >600x10⁹/l

Question 22

Describe the epidemiology of ET

Answer 22

Question 23

How does ET present?

Answer 23

• Incidental finding on FBC (50% cases)
• Thrombosis: arterial or venous
  
  • CVA, gangrene, TIA
  • DVT or PE
• Bleeding: mucous membrane and cutaneous
• Headaches, dizziness, visual disturbances
• Splenomegaly (modest)

Question 24

What is the treatment of ET?

Answer 24

• Aspirin: to prevent thrombosis
• Hydroxycarbamide: antimetabolite. Suppression of other cells as well
• Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing

Question 25

What is the prognosis of ET?

Answer 25

* Normal life span may no be changed in many pts * Leukaemic transformation in about 5% after \>10 years * Myelofibrosis also uncommon, unless there is fibrosis at the beginning

Question 26

Define PMF

Answer 26

Primary Myelofibrosis A cloncal myeloproliferative disease associated with reactive bone marrow fibrosis Extramedullary haematopoeieisis

Question 27

Describe the epidemiology of PMF.

Answer 27

Question 28

How does PMF present?

Answer 28

* Incidental in 30% * Presentation related to: * Cytopenias: anaemia or thrombocytopenia * Thrombocytosis * **Splenomgealy: may be massive** * Budd-Chiari syndrome * **Hepatomegaly** * Hypermetabolic state * Weight loss * Fatigue and dyspnoea * Night sweats * Hyperuricaemia ## Footnote *Liver and spleen take up haematopoeieisis*

Question 29

What are the haematological findings in PMF?

Answer 29

* Blood film * Leucoerythroblastic picture * Tear drop poikilocytes * Giant plateletes * Circulating megakaryocytes * Liver and spleen * Extramedullary haematopoeieisis in spleen and liver * Bone marrow * "Dry Tap" * Trephine: * Increased reticulin or collagen fibrosis * Prominent megakaryocyte hyperplasia and clustering with abnormalities * New bone formation * DNA * JAK2 or CALR mutation

Question 30

What is the prognosis of PMF?

Answer 30

* Median 3-5 yrs but very variable * Bad prognostic signs: * Severe anaemia \<100g/L * Thrombocytopenia \<100x10⁹/L * Massive splenomegaly * Prognostic scoring system (DIPPS) * Score 0 - median survival 15 yrs * Score 4-6 - median survival 1.3 yrs

Question 31

What is the treatment of PMF?

Answer 31

* Limited range of options: * Supportive: RBC and plt transfusion often ineffective because of splenomegaly * Cytoreductive therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia) * Ruxolotinib: JAK2 inhibitor (high prognostic score cases) * Allogeneic SCT (potentially curative reserved for high risk eligible cases)

Question 32

Describe the epidemiology of CML.

Answer 32

Question 33

How does CML present?

Answer 33

Question 34

Describe the image.

Answer 34

Question 36

What mutation is present in CML?

Answer 36

The t(9;22) translocation produces the philadelphia chromosome

Question 37

How is the phildelphia chromosome made? How is it transcribed?

Answer 37

* From Ch22 - breakpoint cluster region taken upstream * From Ch9 - ABL gene (Tyrosine kinase) - cell proliferation * RNA transcription will make fusion RNA * 5 prime exons from BCR gene * 3 prime exons from ABL gene * Makes BCR-ABL gene * Has constitutive tyrosine kinase activity

Question 38

How would you look for the philadelphia chromosome?

Answer 38

* Could also do PCR techniques (much more common) * You can use a: * 3' ABL primer * 5' BCR primer * In normal cells - no product amplified * If cells harbours a BCR-ABL fusion protein - primers will amplify this

Question 39

What are the different phases of CML?

Answer 39

Blast crisis- acute leukaemia (differentiation process affected as well)

Question 40

What is imatinib?

Answer 40

Oral Abl Tyrosine kinase inhibitor

Question 41

How can we assess response and monitor therapy with imatinib?

Answer 41

After 10 months - 0% cells Ph posiitve

Question 42

Why do tyrosine kinase inhibitors not work in some patients?

Answer 42

* Failure to respond * Non-compliance * Side effects: Fluid retention, pleural effusions * Loss of MMR * Acquiring abl point mutations leading to resistance * Evolution to blast crisis

Question 43

What should we do if TKI therapy (imatinib) does not work?

Answer 43

Question 44

Answer 44

* JAK 2 Wild type * Raise EPO

Question 45

Name 2 haematological cancers causing massive hepato-splenomegaly with no lymphadenopathy?

Answer 45

1. PMF 2. CML

Question 46

Why do you no get massive hepatosplenomegaly in acute leukaemias?

Answer 46

Patients have sepsis and bleeding before they can build up to massive splenomegaly

Question 47

Answer 47

Chronic phase CML

Question 48

What happened on month 24?

Answer 48

Blast crisis

Question 49

Answer 49

Novel fusion oncoprotein