Chronic Myeloproliferative disorders Flashcards
What are chronic myeloproliferative disorders?
Clonal stem cell disorders of the bone marrow
Are chronic myeloproliferative disorders malignant?
Yes, although there is much debate surrounding this
In what percentage of patients do CMDs transform into acute leukaemia?
around 10%
Name 3 CMDs?
1) Polycythaemia vera
2) Essential thrombocytosis
3) Idiopathic myelofibrosis
According to the environment and hormones they are exposed to bone marrow stem cells can differentiate into 1 of what 3 kinds of cells in the bone marrow?
1) Granulocytes
2) Erythrocytes
3) Megakaryocytes
Which organ is involved in removing old red blood cells?
Spleen
What are reticulocytes?
Immature red blood cells
Are reticulocytes normally present in the blood?
No - indicates some pathology
ie. if there is a bleed somewhere the bone marrow expels all the RBCs it has
this includes these immature RBCs
What is polycythaemia vera?
Increased red cells +/- neutrophils, +/- platelets
NB. it should be distinguished from secondary polycythaemia and secondary polycythaemia
What is essential thrombocytopenia?
Body produces too many platelets
NB. it should be distinguished from reactive thrombocytosis
What is myelofibrosis?
Variable cytopenias with a large spleen
Should be distinguished from other causes of splenomegaly
Define cytopenia?
Reduction in the number of blood cells
In what condition will a lay down of fibrosis be seen in the bone marrow?
Myelofibrosis - all 3 conditions are related and can turn into one and other, myelofibrosis is often an end stage where you get a reduction in the number of cells
In what age group does the incidence of polycythaemia vera peak?
50-70
What are the 8 symptoms of polycythaemia vera?
Insidious onset
1) Itching (aquagenic - happens in hot baths)
2) Plethoric face (characterised by an abundance of blood - red)
3) Headache
4) General malaise
5) Tinnitus
6) Peptic ulcer
7) Gout
8) Gangrene
What are the 3 signs of polycythaemia vera?
1) Plethora
2) Engorged retinal veins
3) Splenomegaly
What is haematocrit - what is a normal value for it?
The ratio of the volume of RBCs to the total volume of blood - normally less than 50%
What is the other name for polycythaemia vera?
Primary polycythaemia
What is relative polycythaemia?
Not enough plasma leads to an increase in haematocrit without an actual increase in the volume of RBCs- eg. seen in very dehydrated people
How is a diagnosis of polycythaemia made?
Persistent increased Hb/hct >0.5
Haematocrit over 50%
After a detailed history and examination what are the 4 first line tests in polycythaemia to distinguish primary from secondary?
1) FBC
2) Ferritin
3) Epo level
4) UE/LFT (used to evaluate kidney and liver function)
What is secondary polycythaemia?
Something is causing the polycythaemia rather than a problem in the bone marrow - ie. being at altitude or reduced oxygen level in COPD
Why can renal disease cause secondary polycythaemia?
Kidneys may produce too much Epo
Epo is:
a hormone that your kidney makes to trigger your bone marrow to make red blood cells.
A normal EPO level means that your body can make healthy red blood cells.
What are the 5 possible central hypoxic processes which can lead to secondary polycythaemia?
1) Chronic lung disease
2) Right to left shunts heart disease
3) Carbon monoxide poisoning
4) Smoker
5) Altitude
What are the 6 causes of secondary polycythaemia?
1) Central hypoxic process
2) Renal disease
3) EPO producing tumours
4) Drug associated
5) Congenital
6) Idiopathic eryhtrocytosis
What 2 drug treatments can lead to secondary polycythaemia?
1) Treatment with androgen preparations
2) Postrenal transplant erythrocytosis
What are the 2 congenital causes of secondary polycythaemia?
1) High oxygen-affinity Hb
2) Erythropoeitin receptor-mediated
If the EPO is elevated what are the 3 second line tests in polycythaemia?
1) Chest x ray
2) Arterial blood gas
3) Ultrasound scan the abdomen
If EPO is normal or low what are the 3 second line tests in suspected polycythaemia vera?
Looking for causes of polycythaemia vera, because EPO is low in polycythaemia vera.
THERE IS ALREADY AN EXCESS OF RBCs
It must be tested for…
1) JAK2 mutation
2) Bone marrow examination
3) EXON12 mutation
The presence of what mutation in the peripheral blood DNA is diagnostic of a myeloproliferative disorder?
JAK2 V617F mutation
Is the level of EPO raised in polycythaemia vera?
No - in primary polycythaemia you already have enough RBCs so EPO is normal or low
What is the role of JAK in polycythaemia?
EPO binds to a receptor associated with JAK protein (a tyrosine kinase) which is involved in the signalling pathway
formation of an erythrocyte -
when mutated the JAK constantly signals without the need of EPO binding to the receptor -
get excessive erythrocytosis
Is the JAK2 mutation acquired or inherited?
Aquired
What is the test carried out for JAK2 mutation?
Allele specific DNA based PCR
Control PCR in the same reaction for normal gene
If mutation is present you will get 2 bands - the mutant and normal
If the mutation is not present you will get the control band only
What is the treatment for polycythaemia vera? 2
1) Venesections (donate a pint of blood for analysis)
2) haematocrit
What is the prognosis for polycythaemia vera - what 2 conditions are you at risk of developing?
Good prognosis - 15 year median survival
1) Risk developing AML (acute myelogenous leukaemia)
2) Risk developing myelofibrosis
What 9 things can cause reactive thrombocytosis?
1) Surgery
2) Infection
3) Inflammation
4) Malignancy
5) Iron deficiency
6) Hyposplenism
7) Haemolysis
8) Drug induced (steroids, adrenaline, TPO mimetics)
9) Rebound post chemo
What is the main risk with primary essential thrombocytosis?
Thrombosis risk
How is a diagnosis of thrombocytosis made?
Persistent platelets >450 x 109/L
What are the 5 first line investigations in thrombocytosis to distinguish primary thrombocytosis from reactive thrombocytosis?
1) FBC and film
2) Ferritin (iron deficiency is an easy cause of reactive to treat)
3) CRP C reactive protein (have they got infection?)
4) CXR - chest x ray(just looking for another cause)
5) Erythrocyte sedimentation rate
What are the 4 second line tests in thrombocytosis to distinguish reactive from primary?
1) JAK2
2) CALR (another mutation)
3) ? Bone marrow biopsy
4) Extensive search for secondary cause
CALR mutation can be present in primary thrombocytosis, what does calreticulin do?
Its a cell signalling protein produced in the ER,
found in myeloid progenitors in essential thrombocytosis (ET)
mechanism unknown at present but mutation may activate cell signalling pathways
What is the treatment for essential thrombocythaemia?
1) Assess thrombotic risk
2) Antiplatelet treatment - aspirin 75mg daily
3) Cytoreduction (treatment to remove the platelets) - if one or more risk factors for thrombosis
What are the 5 main risk factors for thrombosis when assessing thrombotic risk in ET?
1) Age
2) Hypertension
3) Diabetes
4) Platelet count >1500
5) History of thrombosis
What 4 therapies can be used for cytoreduction in ET?
1) Hydroxycarbamide
2) Interferon
3) Anagrelide
4) P32 (radioactive phosphate)
People with what mutation found in ET have a lower thrombosis risk?
CALR mutation
What is the prognosis for ET and what 2 conditions are you at risk of?
Excellent prognosis - 20 yr median survival
Risk of developing
1) AML (acute myelogenous leukaemia)
2) Myelofibrosis
What are the 3 aspects of a presentation of myelofibrosis?
1) Pancytopenia (Deficiency in all blood cells)
2) B symptoms (systemic symptoms of fever, night sweats and weight loss - associated with lymphomas)
3) Massive splenomegaly
What are the 2 investigations carried out in suspected myelofibrosis?
1) FBC and film
2) Haematinics
How is a diagnosis of myelofibrosis made? 4
1) Blood film
2) Bone marrow results
3) JAK2 mutation in 50%
4) CALR mutation in 30%
How should the spleen be measured?
From midclavicular line of costal margin to furthest point spleen reaches - important to do accurately as can be important in measuring progress
What are the 7 causes of splenomegaly? (CHICAGO)
Cancer Haematological - CML, myelofibrosis Infection - Schistosomiasis, malaria Congestion - liver disease/ portal Autoimmune - haemolysis Glycogen store disorders Other - amyloid etc.
What is the treatment for myelofibrosis?
1) Supportive care
2) JAK2 inhibitors
3) Bone marrow transplant
What is the prognosis - median survival - for myelofibrosis?
Poor
Median survival is 5 years
What is the median age of diagnosis of chronic myeloid leukaemia, is it more common in males or females?
More common in females
Median age at diagnosis = 55-60 years
What is chronic myeloid leukaemia?
Increase in production of abnormal WBCs of myeloid line ie. granulocytes
What 4 things in chronic myeloid leukaemia characterised by?
1) Leucocytosis
2) Leucoerythroblastic blood picture
3) Anaemia
4) Splenomegaly
What are the 5 main symptoms of CML and what are the reasons behind each?
1) Abdominal discomfort - splenomegaly
2) Abdominal pain - splenic infarction
3) Fatigue - anaemia, catabolic state
4) Venous occlusion - retinal vein, DVT, priapism (persistent and painful erection of the penis)
5) Gout - hyperuricaemia
Which gene and chromosome has been implicated in CML?
Philadelphia Chromosome - (9;22) translocation
BCR-ABL fusion gene (tyrosine kinase)
What is the treatment for CML?
Imatinib (Gleevec)
How does Imatinib work?
A small molecule specifically designed to block the active sight of the BCR-ABL tyrosine kinase
How does Imatinib resistance occur?
Due to activating loop mutations in BCR-ABL
Which 2 drugs have been helpful in treating Imatinib resistant CML?
New tyrosine kinase inhbitors:
1) Nilotinib
2) Dasatinib
What kind of drug is imatinib?
Tyrosine kinase inhibitor (described as a designer molecular treatment)
What is the course of CML?
Chronic phase followed by acute transformation
