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Y2 Clinical Pathology > Chronic Myeloproliferative Disorders & Chronic Myeloid Leukaemia > Flashcards

Chronic Myeloproliferative Disorders & Chronic Myeloid Leukaemia Flashcards

1
Q

What is meant by chronic myeloproliferative disorders?

A

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

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2
Q

What are the 3 main chronic myeloproliferative disorders?

What % transform into acute leukaemia?

A
  1. polycythaemia vera (PV)
  2. essential thrombocytosis (ET)
  3. idiopathic myelofibrosis (IMF)

transformation into acute leukaemia is approx 10%

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3
Q

What 3 categories of cells are produced by the stem cells in the bone marrow?

A
  • erythrocytes
  • granulocytes - neutrophils, eosinophils, basophils
  • megakaryocytes (platelets)
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4
Q

How are the levels of cells changed in polycythaemia vera?

A

there are increased red cells +/- neutrophils, +/- platelets

need to distinguish from secondary polycythaemias and relative polycythaemia

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5
Q

What is meant by “absolute” polycythaemia?

A

where the body produces too many red blood cells

this is either primary or secondary polycythaemia

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6
Q

What is the difference between primary and secondary polycythaemia?

A

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
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7
Q

What is polycythaemia vera (PV) usually caused by?

What types of cells are elevated in PV and why?

A

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

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8
Q

What is meant by “apparent” or “relative” polycythaemia?

A

red cell count is normal

there is a reduced amount of plasma in the blood, making it thicker

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9
Q

What is essential thrombocythaemia?

A

a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets by megakaryocytes in the bone marrow

it involves increased platelets

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10
Q

What is myelofibrosis?

A

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

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11
Q

What is shown in this image?

A

polycythaemia vera

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12
Q

What is the age distribution like for polycythaemia vera?

A

can affect all ages, but peak is at 50 - 70 years

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13
Q

What are the symptoms of polycythaemia vera?

A
  • aquagenic pruritus
  • plethoric face
  • headache, muzziness
  • general malaise
  • tinnitus
  • peptic ulcer
  • gout
  • gangrene of the toes
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14
Q

What is meant by aquagenic pruritus?

A

a condition in which contact with water of any temperature causes itching without any visible skin changes

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15
Q

What is meant by polycythaemia vera being an insidious disease?

A

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

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16
Q

What are the signs of polycythaemia vera?

A
  • plethora
  • engorged retinal veins
  • splenomegaly
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17
Q

What is meant by “plethora”?

A

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

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18
Q

What questions must be asked on first diagnosis of polycythaemia vera?

A

there must be persistent increased Hb/hct > 0.5

2 questions:

  1. relative vs. absolute polycthaemia
  2. primary vs secondary polycythaemia
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19
Q

What are the first line tests for diagnosis of polycythaemia vera?

A
  1. full blood count
  2. ferritin
  3. Epo level
  4. U&Es / LFTs
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20
Q

What are the different types of primary polycythaemia?

A

polycythaemia vera is the only cause of primary polycythaemia

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21
Q

What are the 6 different categories of secondary polycythaemia?

A
  1. central hypoxic process
  2. renal disease
  3. EPO producing tumours
  4. drug associated
  5. congenital
  6. idiopathic erythrocytosis
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22
Q

What are examples of central hypoxic processes which lead to secondary polycythaemia?

A
  • chronic lung disease
  • right-to-left shunts in heart disease
  • carbon monoxide poisoning
  • smoker
  • high altitude
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23
Q

What are examples of drug-associated and congenital causes of secondary polycythaemia?

A

drug associated:

  • treatment with androgen preparations
  • postrenal transplant erythrocytosis

congenital:

  • high oxygen-affinity haemoglobin
  • erythropoietin receptor-mediated
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24
Q

What are the second line tests performed in polycythaemia vera?

A

Epo elevated:

  • chest X ray
  • arterial blood gas
  • USS of abdomen

Epo normal or low:

  • JAK2 mutation
  • bone marrow examination
  • EXON12 mutation
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25
Q

What are the JAK enzymes?

A

janus kinases

they are a form of tyrosine kinases

JAK is the signalling pathway for cytokine receptors

(GM-CSF, GCSF, EPO, TPO, SCF, interleukins)

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26
Q

What pathway are the janus kinases involved in?

What are the roles of this pathway?

A

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

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27
Q

What is the JAK2 mutation in myeloproliferative disorders?

Where does it occur and what is the result of this?

A

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

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28
Q

What does the presence of a JAK2 V617F mutation in a patient suggest?

A

patients may be heterozygous or homozygous

the presence of a JAK2 V617F mutation in peripheral blood DNA is diagnostic of a myeloproliferative disorder

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29
Q

What is meant by constitutive activation in JAK2 mutations?

A

many G-protein coupled receptors show constitutive activity

this results in the production of a second messenger in the absence of an agonist

30
Q

What is the role of Epo in the JAK-STAT pathway?

A
  1. Epo binds to the Epo receptor, which is composed of 2 identical subunits
  2. 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
  3. phosphorylated tyrosine residues form docking sites for STAT (signal transducer & activator of transcription)
  4. STAT molecules are phosphorylated by JAK kinases
  5. this leads to dimerisation and translocation to the nucleus, where they act as transcription factors
31
Q

What is the test used to look for the JAK2 mutation?

A

allele specific DNA-based PCR

control PCR in same reaction for normal gene

32
Q

What are the possible results from the JAK2 mutation test?

A
  • normal control band only
  • mutant + control band
  • no bands or mutant only = inadequate material
33
Q

What are the 3 main JAK2 V617F mutations seen in CMPD?

A
  • PRV
  • ET
  • IMF
34
Q

What is the treatment for polycythaemia vera?

A
  • venesections aim for HCT < 0.45
  • aspirin - 75mg daily
35
Q

What is meant by “venesections”?

What is the HCT which they aim to lower?

A

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

36
Q

What is the prognosis of a patient with polycythaemia vera?

A

good prognosis with 15 year median survival

risk of developing AML and myelofibrosis

37
Q

What are the 2 different types of thrombocytosis?

A

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
38
Q

What are causes of reactive thrombocytosis?

A
  • surgery
  • infection
  • inflammation
  • malignancy
  • iron deficiency
  • hyposplenism
  • haemolysis
  • drug induced (steroids, adrenaline, TPO mimetics)
  • rebound post chemotherapy
39
Q

Why is a good history and examination important in thrombocytosis investigation?

What is the platelet count?

A

good history and examination important as patient may have had a normal platelet count prior to surgery

need persistent platelets > 450 x 109 / L

40
Q

What are the first line investigations for thrombocytosis?

A
  • full blood count and film
  • ferritin
  • CRP
  • chest X ray
  • ESR
41
Q

What are the 2nd line investigations for thrombocytosis?

A
  • JAK2
  • CALR
  • bone marrow biopsy ?
  • extensive search for secondary cause
42
Q

What is the CALR mutation?

Where is it found?

A

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)

43
Q

What is the mechanism of action of the CALR mutation?

A

mechanism of action unknown but may activate cell signalling pathways

44
Q
A
45
Q

What mutations are present in the diagnosis of essential thrombocytosis (ET)?

A

JAK2 mutation in approx 50% of cases

CALR mutation in approx 45% of cases

46
Q

What must be done before treatment is given for ET?

A

assess thrombotic risk:

  • age
  • hypertension
  • diabetes
  • platelet count > 1500
  • history of thrombosis
47
Q

After assessing thrombotic risk, what is the treatment for ET?

A

antiplatelet treatment:

  • ​aspirin - 75mg daily

cytoreduction:

  • only given to high risk patients with 1 or more risk factors for thrombosis
48
Q

What drugs are used in cytoreduction?

A

cytoreductive therapy is used to reduce the risk of haemorrhage in patients with high platelet counts

  • hydroxycarbamide
  • interferon
  • anagrelide
  • P32
49
Q

What is the prognosis like for patients with essential thrombocytosis?

A

overall excellent 20 year median survival

risk of AML or myelofibrosis

CALR mutations have a lower thrombosis risk

50
Q

How do patients with myelofibrosis tend to present?

A
  • pancytopenia
  • B symptoms
  • massive splenomegaly
51
Q

What is meant by pancytopenia?

A

deficiency of all three cellular components of the blood

(red cells, white cells & platelets)

52
Q

What are the B symptoms associated with myelofibrosis?

A

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
53
Q

What are the investigations performed for myelofibrosis?

A
  • full blood count and film
  • haematinics
54
Q

What is a haematinic?

What is assessed in the haematinic blood test?

A

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
55
Q

How is myelofibrosis diagnosed?

A

through blood film and bone marrow results

JAK2 mutation present in 50% of cases

CALR mutation present in 30% of cases

56
Q

What is the CHICAGO acronym for the causes of splenomegaly?

A

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
57
Q

What are the treatments for myelofibrosis?

A
  • supportive care
  • JAK2 inhibitors
  • bone marrow transplant
58
Q

What is the prognosis like in myelofibrosis?

A

poor prognosis with a median survival of 5 years

59
Q

What is the median age and M:F ratio in chronic myeloid leukaemia?

A

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

60
Q

What is chronic myeloid leukaemia characterised by?

A
  • massively increased leukocytosis
  • leucoerythroblastic blood picture
  • anaemia
  • splenomegaly
61
Q

What is meant by a leucoerythroblastic blood picture?

A

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

62
Q

What are the predictable symptoms of chronic myeloid leukaemia and why do they occur?

A
  • abdominal discomfort - splenomegaly
  • abdominal pain - splenic infarction
  • fatigue - anaemia, catabolic state
  • venous occlusion - retinal vein, DVT, priapism
  • gout - hyperuricaemia
63
Q

What are the 3 stages of CML treatment before 2000?

A

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
64
Q

What is the chromosomal abnormality that is present in chronic myeloid leukaemia (CML)?

A

philadelphia chromosome

this involves an abnormally short chromosome 22

it is involved in a translocation (exchange of material) with chromsome 9

65
Q

What is the result of the philadelphia chromosome translocation in CML?

A

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

66
Q

What is Gleevec?

A

imatinib mesylate

it is a small molecule specifically designed to block the active site in the BCR-ABL tyrosine kinase

67
Q
A
68
Q

Why are new tyrosine kinase inhibitors needed each year to treat CML?

A

due to imatinib resistance

activating loop mutations in BCR-ABL confer resistance and loss of disease control

69
Q

What is involved in CML treatment?

A

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
70
Q
A

Y2 Clinical Pathology (76 decks)

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