Chronic Myeloproliferative Disorders & Chronic Myeloid Leukaemia Flashcards
What is meant by chronic myeloproliferative disorders?
clonal stem cell disorders of the bone marrow
they are malignant
the bone marrow makes too many abnormal red blood cells, white blood cells or platelets, which accumulate in the blood
What are the 3 main chronic myeloproliferative disorders?
What % transform into acute leukaemia?
- polycythaemia vera (PV)
- essential thrombocytosis (ET)
- idiopathic myelofibrosis (IMF)
transformation into acute leukaemia is approx 10%
What 3 categories of cells are produced by the stem cells in the bone marrow?
- erythrocytes
- granulocytes - neutrophils, eosinophils, basophils
- megakaryocytes (platelets)
How are the levels of cells changed in polycythaemia vera?
there are increased red cells +/- neutrophils, +/- platelets
need to distinguish from secondary polycythaemias and relative polycythaemia
What is meant by “absolute” polycythaemia?
where the body produces too many red blood cells
this is either primary or secondary polycythaemia
What is the difference between primary and secondary polycythaemia?
primary polycythaemia:
- there is a problem relating to the cells produced by the bone marrow that become blood cells
secondary polycythaemia:
- too many red blood cells are produced as the result of an underlying condition
What is polycythaemia vera (PV) usually caused by?
What types of cells are elevated in PV and why?
it is usually caused by a change in the JAK2 gene, which causes the bone marrow to produce too many red blood cells
the affected bone marrow cells can also develop into other cells found in the blood
people may also have abnormally high numbers of platelets and red blood cells
What is meant by “apparent” or “relative” polycythaemia?
red cell count is normal
there is a reduced amount of plasma in the blood, making it thicker
What is essential thrombocythaemia?
a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets by megakaryocytes in the bone marrow
it involves increased platelets
What is myelofibrosis?
a type of bone marrow cancer that disrupts the body’s normal production of blood cells
it causes extensive scarring in the bone marrow, leading to severe anaemia, weakness and fatigue
it involves variable cytopenias with a large spleen
What is shown in this image?
polycythaemia vera
What is the age distribution like for polycythaemia vera?
can affect all ages, but peak is at 50 - 70 years
What are the symptoms of polycythaemia vera?
- aquagenic pruritus
- plethoric face
- headache, muzziness
- general malaise
- tinnitus
- peptic ulcer
- gout
- gangrene of the toes
What is meant by aquagenic pruritus?
a condition in which contact with water of any temperature causes itching without any visible skin changes
What is meant by polycythaemia vera being an insidious disease?
an insidious disease is any disease that comes on slowly and does not have any obvious symptoms
the person is not aware of it developing
What are the signs of polycythaemia vera?
- plethora
- engorged retinal veins
- splenomegaly
What is meant by “plethora”?
a bodily condition characterised by an excess of blood
this leads to turgescence and a reddish complexion
plethoric face is a red colouration of the face
What questions must be asked on first diagnosis of polycythaemia vera?
there must be persistent increased Hb/hct > 0.5
2 questions:
- relative vs. absolute polycthaemia
- primary vs secondary polycythaemia
What are the first line tests for diagnosis of polycythaemia vera?
- full blood count
- ferritin
- Epo level
- U&Es / LFTs
What are the different types of primary polycythaemia?
polycythaemia vera is the only cause of primary polycythaemia
What are the 6 different categories of secondary polycythaemia?
- central hypoxic process
- renal disease
- EPO producing tumours
- drug associated
- congenital
- idiopathic erythrocytosis
What are examples of central hypoxic processes which lead to secondary polycythaemia?
- chronic lung disease
- right-to-left shunts in heart disease
- carbon monoxide poisoning
- smoker
- high altitude
What are examples of drug-associated and congenital causes of secondary polycythaemia?
drug associated:
- treatment with androgen preparations
- postrenal transplant erythrocytosis
congenital:
- high oxygen-affinity haemoglobin
- erythropoietin receptor-mediated
What are the second line tests performed in polycythaemia vera?
Epo elevated:
- chest X ray
- arterial blood gas
- USS of abdomen
Epo normal or low:
- JAK2 mutation
- bone marrow examination
- EXON12 mutation
What are the JAK enzymes?
janus kinases
they are a form of tyrosine kinases
JAK is the signalling pathway for cytokine receptors
(GM-CSF, GCSF, EPO, TPO, SCF, interleukins)
What pathway are the janus kinases involved in?
What are the roles of this pathway?
they are intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway
the JAK-STAT pathway is a chain of interactions between proteins in a cell
it is involved in immunity, cell division, cell death and tumour formation
What is the JAK2 mutation in myeloproliferative disorders?
Where does it occur and what is the result of this?
it occurs in the JH2 domain (inactive)
G - to - T mutation at nucleotide 1849
this results in phenylalanine for valine at 617 in the protein (V617F)
this destroys a BsaXI site
What does the presence of a JAK2 V617F mutation in a patient suggest?
patients may be heterozygous or homozygous
the presence of a JAK2 V617F mutation in peripheral blood DNA is diagnostic of a myeloproliferative disorder
What is meant by constitutive activation in JAK2 mutations?
many G-protein coupled receptors show constitutive activity
this results in the production of a second messenger in the absence of an agonist
What is the role of Epo in the JAK-STAT pathway?
- Epo binds to the Epo receptor, which is composed of 2 identical subunits
- upon ligand binding, the subunits dimerise and janus kinase (JAK2) is recruited to the receptor complex, leading to phosphorylation of several tyrosine residues on the receptor
- phosphorylated tyrosine residues form docking sites for STAT (signal transducer & activator of transcription)
- STAT molecules are phosphorylated by JAK kinases
- this leads to dimerisation and translocation to the nucleus, where they act as transcription factors
What is the test used to look for the JAK2 mutation?
allele specific DNA-based PCR
control PCR in same reaction for normal gene
What are the possible results from the JAK2 mutation test?
- normal control band only
- mutant + control band
- no bands or mutant only = inadequate material
What are the 3 main JAK2 V617F mutations seen in CMPD?
- PRV
- ET
- IMF
What is the treatment for polycythaemia vera?
- venesections aim for HCT < 0.45
- aspirin - 75mg daily
What is meant by “venesections”?
What is the HCT which they aim to lower?
venesection (or plebotomy) is the act of taking blood to reduce red blood cell counts in patients with PV
HCT stands for haematocrit
this is the ratio of red blood cells to the total volume of blood
What is the prognosis of a patient with polycythaemia vera?
good prognosis with 15 year median survival
risk of developing AML and myelofibrosis
What are the 2 different types of thrombocytosis?
primary essential thrombocytosis:
- a chronic myeloproliferative disorder in which sustained megakaryocyte production leads to an increase in the number of circulating platelets
reactive thrombocytosis:
- an elevated platelet count that develops secondary to another disorder
What are causes of reactive thrombocytosis?
- surgery
- infection
- inflammation
- malignancy
- iron deficiency
- hyposplenism
- haemolysis
- drug induced (steroids, adrenaline, TPO mimetics)
- rebound post chemotherapy
Why is a good history and examination important in thrombocytosis investigation?
What is the platelet count?
good history and examination important as patient may have had a normal platelet count prior to surgery
need persistent platelets > 450 x 109 / L
What are the first line investigations for thrombocytosis?
- full blood count and film
- ferritin
- CRP
- chest X ray
- ESR
What are the 2nd line investigations for thrombocytosis?
- JAK2
- CALR
- bone marrow biopsy ?
- extensive search for secondary cause
What is the CALR mutation?
Where is it found?
calreticulin mutation
cell signalling protein produced in the endoplasmic reticulum
mutation is in exon 9 of the gene
it is found in myeloid progenitors in essential thrombocytosis (ET)
What is the mechanism of action of the CALR mutation?
mechanism of action unknown but may activate cell signalling pathways
What mutations are present in the diagnosis of essential thrombocytosis (ET)?
JAK2 mutation in approx 50% of cases
CALR mutation in approx 45% of cases
What must be done before treatment is given for ET?
assess thrombotic risk:
- age
- hypertension
- diabetes
- platelet count > 1500
- history of thrombosis
After assessing thrombotic risk, what is the treatment for ET?
antiplatelet treatment:
- aspirin - 75mg daily
cytoreduction:
- only given to high risk patients with 1 or more risk factors for thrombosis
What drugs are used in cytoreduction?
cytoreductive therapy is used to reduce the risk of haemorrhage in patients with high platelet counts
- hydroxycarbamide
- interferon
- anagrelide
- P32
What is the prognosis like for patients with essential thrombocytosis?
overall excellent 20 year median survival
risk of AML or myelofibrosis
CALR mutations have a lower thrombosis risk
How do patients with myelofibrosis tend to present?
- pancytopenia
- B symptoms
- massive splenomegaly
What is meant by pancytopenia?
deficiency of all three cellular components of the blood
(red cells, white cells & platelets)
What are the B symptoms associated with myelofibrosis?
B symptoms refers to systemic symptoms including:
- tiredness / weakness / shortness of breath due to anaemia
- easy bruising & bleeding
- night sweats
- fever
- weight loss
- bone pain
- pain or fullness below the ribs on the left side due to enlarged spleen
What are the investigations performed for myelofibrosis?
- full blood count and film
- haematinics
What is a haematinic?
What is assessed in the haematinic blood test?
a nutrient required for the formation of blood cells in the process of haematopoiesis / increases the haemoglobin in the blood
the main hematinics are iron, folate and B12
the test looks for:
- level of haemoglobin in the blood
- whether RBCs are larger than normal
- level of vitamin B12 and folate in the blood
How is myelofibrosis diagnosed?
through blood film and bone marrow results
JAK2 mutation present in 50% of cases
CALR mutation present in 30% of cases
What is the CHICAGO acronym for the causes of splenomegaly?
C - cancer:
H - haematological:
- myelofibrosis, CML, CLL, hairy cell leukaemia
I - infection:
- schistosomiasis, malaria, leishmaniasis, EBV
C - congestion:
- liver disease / portal
A - autoimmune:
- haemolysis, SLE
G - glycogen storage disorders
O - other:
- amyloid, sarcoid
What are the treatments for myelofibrosis?
- supportive care
- JAK2 inhibitors
- bone marrow transplant
What is the prognosis like in myelofibrosis?
poor prognosis with a median survival of 5 years
What is the median age and M:F ratio in chronic myeloid leukaemia?
it is very rare with around 1 per 100,000 per year
<10% aged < 20 years
median age at diagnosis 55-60 years
M:F ratio is around 1.5 : 1
What is chronic myeloid leukaemia characterised by?
- massively increased leukocytosis
- leucoerythroblastic blood picture
- anaemia
- splenomegaly
What is meant by a leucoerythroblastic blood picture?
a leucoerythroblastic reaction is characterised by the presence of immature erythrocytes and neutrophilic precursors in the peripheral blood
the presence of immature cells usually suggests evidence of a neoplastic / structural problem of the bone marrow
What are the predictable symptoms of chronic myeloid leukaemia and why do they occur?
- abdominal discomfort - splenomegaly
- abdominal pain - splenic infarction
- fatigue - anaemia, catabolic state
- venous occlusion - retinal vein, DVT, priapism
- gout - hyperuricaemia
What are the 3 stages of CML treatment before 2000?
1 - chronic phase (>90% patients presenting):
- low dose oral cytotoxic drugs (bulsulphan, hydroxycarbamide)
- alpha - interferon
2 - acute leukaemic transformation / blast crisis:
- myeloid and lymphoid types
- intesive chemotherapy but very poor outcomes
3 - allogenic bone marrow transplantation:
- curative in 50% of patients
What is the chromosomal abnormality that is present in chronic myeloid leukaemia (CML)?
philadelphia chromosome
this involves an abnormally short chromosome 22
it is involved in a translocation (exchange of material) with chromsome 9
What is the result of the philadelphia chromosome translocation in CML?
It produces the BCR-ABL fusion gene
this codes for an active tyrosine kinase
BCR gene is normally on chromsome 22 and ABL gene is usually on chromosome 9
What is Gleevec?
imatinib mesylate
it is a small molecule specifically designed to block the active site in the BCR-ABL tyrosine kinase
Why are new tyrosine kinase inhibitors needed each year to treat CML?
due to imatinib resistance
activating loop mutations in BCR-ABL confer resistance and loss of disease control
What is involved in CML treatment?
chronic phase:
- tyrosine kinase inhibitors
- > 95% long term survival
acute leukaemic transformation / blast crisis:
- intesive chemotherapy and TKI and bone marrow transplant
- still poor outcome
