Polycythaemia and Myeloproliferative disorders Flashcards
Define polycythaemia
Raised Hb and Hct
What is the difference between true and relative polycythaemia?
- Relative (lack of plasma) - non-malignant
- True (excess erthrocytes)
- Secondary - reactive - elevated EPO (non-malignant)
- Primary - reduced EPO (myeloproliferative neoplasm)
What are the types of myeloproliferative neoplasms (MPDs)?
- Ph (Philadelphia Chromosome) negative
- Polycythaemia vera (PV)
- Essential Thrombocythaemia (ET)
- Primary Myelofibrosis (PMF)
- Ph positive
- Chronic myeloid leukaemia (CML)
What is the difference between true and relative polycythaemia? How could we tell the difference historically?
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
Who gets relative polycythaemia?
- Alcohol
- Obsesity
- Diuretic
What are the secondary true polycythaemias due to?
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)
What is the problem in myeloproliferative neoplasms?
There is excess cells but no problem in functionality (differentiation)
What happens when you gain a mutation in an erythrocyte precursor?
Excess red blood cells - Polycythaemia vera
What happens when you gain a mutation in the granulocytic series?
You get excess neutrophils - CML
What processes are disrupted by these mutation? What types of mutations are these?
Disruption in type 1 processes (cellular proliferation)
What are the non-phildaelphia MPD (e.g PV) associated with?
Associated with JAK 2 (Janus kinase 2) mutation
What occurs in normal EPO signalling?
- There are JAK 2 on the EPO receptor (which leads to RBC production)
- JAK 2 is not usually phosphorylated
- EPO binds to the receptors and they dimerise causing phosphorylation of JAK 2
- Downstream signalling
What are the consequences of a mutation in the tyrosine kinase?
What type of mutation would you see in PV?
JAK2 V617F
What type of mutation would you see in ET?
- JAK2 V617F - 60%
- Calreticulin - 30%
- MPL - 5%
What type of mutation would you see in PMF?
- JAK2 V617F - 60%
- Calreticulin - 30%
How would you diagnose MPD (Ph negative)
Based on combination of:
- Clinical features
- Syptoms
- Splenomegaly
- FBC +/- Bone marrow biopsy
- EPO level
- Mutation testing
Describe the epidemiology of PV
How is PV diagnosed?
- 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
How do you treat PV?
- 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
What defines ET?
Sustained thrombocytosis >600x109/l
Describe the epidemiology of ET
How does ET present?
- 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)
What is the treatment of ET?
- Aspirin: to prevent thrombosis
- Hydroxycarbamide: antimetabolite. Suppression of other cells as well
- Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing
What is the prognosis of ET?
- 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
Define PMF
Primary Myelofibrosis
A cloncal myeloproliferative disease associated with reactive bone marrow fibrosis
Extramedullary haematopoeieisis
Describe the epidemiology of PMF.
How does PMF present?
- 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
Liver and spleen take up haematopoeieisis
What are the haematological findings in PMF?
- 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
What is the prognosis of PMF?
- 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
What is the treatment of PMF?
- 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)
Describe the epidemiology of CML.
How does CML present?
Describe the image.
What mutation is present in CML?
The t(9;22) translocation produces the philadelphia chromosome
How is the phildelphia chromosome made? How is it transcribed?
- 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
How would you look for the philadelphia chromosome?
- 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
- You can use a:
What are the different phases of CML?
Blast crisis- acute leukaemia (differentiation process affected as well)
What is imatinib?
Oral Abl Tyrosine kinase inhibitor
How can we assess response and monitor therapy with imatinib?
After 10 months - 0% cells Ph posiitve
Why do tyrosine kinase inhibitors not work in some patients?
- 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
What should we do if TKI therapy (imatinib) does not work?
- JAK 2 Wild type
- Raise EPO
Name 2 haematological cancers causing massive hepato-splenomegaly with no lymphadenopathy?
- PMF
- CML
Why do you no get massive hepatosplenomegaly in acute leukaemias?
Patients have sepsis and bleeding before they can build up to massive splenomegaly
Chronic phase CML
What happened on month 24?
Blast crisis
Novel fusion oncoprotein
