Myeloproliferative Disorders

Question 1

Which mutations are commonly associated with myeloproliferative disorders?
Why is it important to look genetic mutations for these disorders?

Answer 1

JAK2 = 97% of mutations in polycythemia
CALR
MPL

Can identify and diagnose MPN due to them having a defined genetic abnormality

Question 2

Which cells are in excess in each of these myeloproliferative neoplasms?

CML
PV (polycythaemia Vera)
ET (essential thrombocythaemia)
MF (myelofibrosis)

Answer 2

CML= myeloid cells 
PV= red cells 
ET= platelets 
MF= excessive fibrosis

Question 3

What is the classic presentation + FBC of polycythaemia?

Why are these people at an increased risk of clot formation?

Answer 3

Middle aged man 
DVT in calf 
Pruritus (itchy skin) after hot bath 
Plethoric (red face) 
Palpable spleen (splenomegaly)

FBC:
Hb= 20.4 ie very high
Leads to increased blood viscosity so increased risk of clot formation

Question 4

What are the symptoms of PV and what is the major underlying cause?

What are the signs associated with PV?

Answer 4

Symptoms :
Headache 
Dizziness
Blurred vision 
“Full” feeling head
All due to increase blood viscosity 

Signs:
Plethora
Conjunctival suffusion (reddening of conjunctiva w/o inflammatory cause)
Engorged retinal vessels
Increased thrombosis tendency (DVT, MI, CVA)
Erythromelalgia (burning pain and redness in feet and hands etc)
Increased bleeding tendency
Hypertension
Acquagenic pruritis= itching after contact with water
Splenomegaly

Question 5

What are the causes of PV?

Answer 5

JAK2 mutation= present in 95% of patients

Hypoxia - increasing number of RBC is the normal response to low oxygen environment
I.e. smoking/lung disease/cyanotic heart disease/altitude

Rare tumours

Rare Hb variants

Excess or inappropriate erythropoietin

Question 6

What are the main aims of treatment for PV?

Answer 6

Decrease the risk of thrombosis and haemorrhage

Minimise the risk of transformation to acute leukaemia and myelofibrosis

Question 7

What are the treatment options for PV? Give their role or indications.

Answer 7

Venesection (removing blood)= acts to decrease the haematocrit to below 0.45

Anti-platelets (75mg Asparin)

Hydroxycarbamide (weak chemo) = used when platelet count also raised because removing blood would not lower platelets
I.e. has thrombolysis action to combat thrombocytosis

Question 8

What are the clinical features associated with essential thrombocythaemia? What is the cause of a significant number of these symptoms?

Answer 8

Asymptomatic (applies to most at diagnosis)

Thrombosis

Symptoms caused by microvascular occlusion:
Erythromelalgia
Acroparasthaesia (pins and needles in hands and feet)
Digital ischaemia
TIA
Migraine-like headache
Dizziness
Visual disturbances
Paradoxical bleeding= excess platelets impairs coagulation (platelets >1500)

Question 9

How can essential thrombocythaemia be diagnosed?

Answer 9

Most important= characterising the genetic abnormality i.e. JAK2/MPL/CALR

No other explanation for symptoms i.e. other myeloid malignancy or reactive thrombocytosis

Platelet count sustained above 450 x 10 power 9/L

Question 10

What are differential diagnosis for thrombocytosis seen in ET (i.e. raised platelets) ?

Answer 10

Secondary/reactive 
Cancer 
Iron deficiency 
Acute haemorrhage 
Infections 
Inflammatory state 
Asplenia

Question 11

What is the criteria for a low risk ET patient? How does this correlate to the treatment they receive?

Answer 11

<60 yo 
Platelets <1500
No prior TED or bleeding 
No CVS risk 
No hereditary cytopenia 

TX:
No cytoreductive therapy
Watch and weight (W+W)
Potential for low dose aspirin

Question 12

What is the criteria for a intermediate risk ET patient? How does this correlate to the treatment they receive?

Answer 12

Platelets<1500
Age<60 
No TED (thromboembolic disease) 
CVS risk factors 
Hereditary thrombophilia 

TX:
Decrease CVS risk
ASA (Asparin)
Decrease platelets with cytoreduction

Question 13

What is the criteria for a high risk ET patient? How does this correlate to the treatment they receive?

Answer 13

Age>60
Platelets>1500
Prior TED

TX:
ASA
Cytoreduction to decrease platelets

Question 14

What is cytoreductive therapy?

Answer 14

Cytoreductive= used to reduce the risk of haemorrhage in patients with high platelet counts in ET

Question 15

What is the mechanism of hydroxyurea? What are the associated SE?

Answer 15

Ribonucleatide reductase inhibitor = 1st line cytoreductive tx

SE:
BM suppression 
Diarrhoea 
Leukaemogenic 
Skin cancer 
Possible teratogen

Question 16

What is the mechanism of anagrelide? What are the associated SE?

Answer 16

Inhibits megakaryocyte differentiation and platelet aggregation

SE:
Fibrosis 
Haemorrhage on aspirin 
Headaches 
Palpitations 
Arrhythmias
Fluid retention 
HF
Anaemia

Question 17

What is an alternative cytoreductive drug for hydroxyurea? Why is this drug sometimes used instead?

Answer 17

Low dose pegylated IFN alpha 2a

Hydroxyurea is classed as mild chemo which means it carries the associated risk factors and possible carcinogenic effects

Question 18

What is myelofibrosis?

Answer 18

Fibrotic marrow formed due to scarring from MPN i.e. PV or ET

Question 19

How does myelofibrosis present?

Answer 19

Splenomegaly 
Hepatomegaly 
Cytopenia 
Spleen pain 
Fever + sweats 
Back pain 
Infections 
Weight loss = hypermetabolic symptom 
Hyperuricaemia = elevated uric acid levels

Question 20

How can you treat myelofibrosis?

Answer 20

Blood transfusion 
AlloSCT (allogenic stem cell transplant) 
Thalidomide 
Medroxyprogesterone 
Ruxolitinib (JAK inhibitor)

Question 21

What are the benefits of using Ruxolitinib to treat myelofibrosis? What is ruxolitinib withdrawl syndrome?

Answer 21

Decreased constitutional symptoms 
Decreased splenomegaly 
Increased survival benefit 
Improved FBC
Increased QOL
Transfusion independent- benefit if px not suitable for transplant 

Occurs when treatment stopped too abruptly

Question 22

How is myelofibrosis diagnosed?

How would you describe a blood film from MF and what would you expect to see?

Answer 22

Bone marrow aspiration and trephine to identify bone fibrosis

FBC

Molecular test to identify mutations (JAK2/CALR/MPL)

Leucoerythroblastic i.e. in conditions where bone is rapidly/constantly being replaced

Cells:

• nucleated red cell
• myelocyte
• tear drop RBC

Question 23

What is CML and what causes it?

Answer 23

Accumulation of myeloid progenitors due to Philadelphia chromosome i.e. BCR-ABL fusion= increased cell signalling to drive myeloid proliferation

Question 24

How can CML be treated? How do patients respond to the TX?

What are the potential problems with this TX?

Answer 24

Imatinib= inhibits ATP binding to ABL tyrosine kinase to prevent action of BCR-ABL fusion protein

Normal platelet and WC count
Decrease in Philadelphia chromosome number i.e. return to normal cytogenetic
Molecularly normal

Therefore= “cures” patients and leads to progression free survival

Resistance
Alternatives used

Question 25

What is myelodysplasia and what are the causes?

Answer 25

Bone marrow cancer (BM failure) which can be classed as pre-leukaemia (1 step from AML)

Age i.e. disease of the elderly
Secondary to chemo or radiotherapy
Rare inherited BM failure conditions

Question 26

How does MDS present?

Answer 26

Dysmorphic features + abnormal looking cells
Decreased mature RBC/WBC/platelets
Accumulation of primitive myeloid cells due to increase apoptosis rate leading to developing cells being released too early
(Sign of worse prognosis)

Question 27

What are the different treatment options for MDS?

Answer 27

Erythropoietin +/- GCSF (max for 16 weeks)

Azacitidine (hypomethylating agent) i.e. MAIN MDS DRUG
= alters the epigenetics to to increase DNA access

Lenalidomide

ATG (anti-thymocyte globulin)

Transfusion
-can lead to iron overload when done over long time period i.e. need chelating agent