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CP reviewer 1 > Chronic Myeloproliferative Disorders and CML > Flashcards

Chronic Myeloproliferative Disorders and CML Flashcards

1
Q

What are chronic myeloproliferative disorders?

A

Malignant clonal stem cell disorders of the bone marrow

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2
Q

What are the 3 types of chronic myeloproliferative disorders?

A

o Polycythaemia Vera (PV)
o Essential thrombocytosis (ET)
o Idiopathic myelofibrosis (IMF)

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3
Q

What is the dangerous disease that 10% of chronic myeloproliferative disorders can transform into?

A

Acute leukaemia

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4
Q

What is polycythaemia vera?

A

A type of blood cancer that causes bone marrow to make too many RBCS. These excess cells causes your blood to thicken, slowing it down.

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5
Q

What are the symptoms of polycythaemia vera?

A

Insidious onset (symptoms are obscure and come on slowly)

o	Itching (aquagenic – hot baths)
o	Plethoric face
o	Headache, muzziness (due to increased viscosity of blood) 
o	General malaise
o	Tinnitus 
o	Peptic ulcer
o	Gout (due to increased RBC turnover) 
o	Gangrene of toes
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6
Q

What is the cause of gangrene in polycythaemia vera?

A

due to increased risk of thrombotic events due to viscosity of blood

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7
Q

What are the 3 main signs of polycythaemia vera?

A

o Plethora (fullness of the face)
o Engorged retinal veins
o Splenomegaly

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8
Q

How is polycythaemia vera diagnosed?

A

Persistent increased Hb/haematocrit >0.5 (on 2 occasions)

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9
Q

What is haematocrit?

A

the ratio of the volume of red blood cells to the total volume of blood.

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10
Q

If a patient does have polycythaemia after a haematocrit test, what are the 2 next questions to find out?

A
  1. Relative or absolute polycythaemia?

2. 1ary or 2ary polycythaemia?

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11
Q

What is extremely important when determining the type of polycythaemia?

A

Detailed history and examination important!

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12
Q

What is relative polycythaemia?

A

loss of plasma volume causing an elevated haematocrit

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13
Q

What is absolute polycythaemia?

A

increase in red cell mass from any cause

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14
Q

What are the causes of relative polycythaemia?

A

Dehydration; often caused by loss of body fluids, such as through burns, dehydration, and stress.

Alcohol excess, unwell, diabetic ketoacidosis

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15
Q

What 4 first line tests are performed when diagnosing the type of polycythaemia?

A
  1. FBC
  2. Ferritin
  3. EPO level
  4. U&Es/LFT
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16
Q

Describe the EPO level in 2ary vs 1ary polycythaemia?

A
  • 2ary polycythaemia driven by hypoxia (kidney makes more EPO so level is increased)
  • 1ary polycythaemia; bone marrow itself is abnormal and makes more RBCs, causing EPO to be suppressed
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17
Q

Why is the EPO suppressed in 1ary polycythaemia?

A

bone marrow itself is abnormal and makes more RBCs, causing EPO to be suppressed

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18
Q

What is the majority of 2ary polycythaemia driven by?

A

Hypoxia

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19
Q

What are the 3 main 2nd line tests done in polycythaemia if the EPO is elevated?

A
  1. CXR
  2. USS abdomen
  3. ABG (arterial blood gas)
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20
Q

If an ABG shows hypoxia when investigating polycythaemia, what does this reveal?

A

2ary polycythaemia

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21
Q

What 2nd line tests are done in polycythaemia if the EPO is normal or low?

A
  1. JAK2 mutation
  2. Bone marrow examination
  3. EXON12 mutation
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22
Q

What is the JAK2 mutation? How can it lead to polycythaemia?

A

o Causes mutation in Janus kinases (JAK2) –> single point mutation
o This causes the receptor for EPO is permanently switched on, causing constant production of RBCs
o The presentation of the JAK2 mutation in peripheral blood DNA is diagnostic of a myeloproliferative disorder

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23
Q

What is the cause of primary polycythaemia?

A

Polycythaemia vera

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24
Q

What are the categories of causes of 2ary polycythaemia?

A 
o Central hypoxic process
o Renal disease 
o EPO producing tumours 
o Drug associated 
o Congenital
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25
Q

What are the causes of hypoxia that can lead to2ary polycythaemia?

A
  • Chronic lung disease
  • Right-to-left shunts heart disease
  • Carbon monoxide poisoning
  • Smoker
  • High altitude
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26
Q

What drugs can lead to 2ary polycythaemia?

A

Treatment with androgen preparations (seen in bodybuilders)

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27
Q

What congenital mutation can lead to polycythaemia?

A

JAK2 mutation (Erythropoietin receptor-mediated)

28
Q

What are the 2 major treatment options for polycythaemia vera?

A
  1. Venesection (drawing blood); quickly reduces the number of RBCs in your blood
  2. Aspirin 75mg daily (reduce risk of thrombosis)
29
Q

What is the prognosis for polycythaemia vera?

A

o Good – 15-year median survival
o Risk developing AML
o Risk developing myelofibrosis

30
Q

What is Primary Essential Thrombocytosis (ET)?

A
  • Bone marrow produces too many platelets

* Can cause abnormal bleeding or clotting (thrombosis risk)

31
Q

What is reactive thrombocytosis?

A

Abnormally high platelet cause in the absence of a chronic myeloproliferative disease, secondary to another disease

32
Q

What are the causes of reactive thrombocytosis?

A

i. Surgery
ii. Infection
iii. Inflammation
iv. Malignancy
v. Iron deficiency
vi. Hyposplenism
vii. Haemolysis
viii. Drug induced (steroids, adrenaline, TPO mimetics)
ix. Rebound post chemo

33
Q

What is important to consider when investigating thrombocytosis?

A

The recent normal platelet count prior to surgery/infection etc

34
Q

What are the 5 main 1st line investigations in thrombocytosis?

A
  1. FBC and film
  2. Ferritin
  3. CRP
  4. CXR
  5. ESR
35
Q

What are the 2 main mutations seen in myeloproliferative disorders?

A
  1. JAK2

2. CARLR

36
Q

How is the CALR mutation different?

A

Acquired after birth (not inherited)

37
Q

How is Primary Essential Thrombocytosis (ET) treated?

A

o Assess thrombotic risk:
o Antiplatelet treatment; aspirin 75mg daily
o Cytoreduction (only if high risk – 1 or more risk factors)

38
Q

What is cytoreduction?

A

impair bone marrows ability to make cells

39
Q

What is the main drug used for cytoreduction?

A

Hydroxycarbamide

40
Q

What is Hydroxycarbamide? Mechanism?

A

o Anti-folate drug

o Inhibits bone marrow’s ability to make platelets

41
Q

Side effects of hydroxycarbamide?

A

o Inhibits bone marrow’s ability to make white and red cells
o Can lead to anaemia or leukopenia

42
Q

Prognosis for ET?

A

o Overall excellent 20-year median survival
o Risk of AML or myelofibrosis
o CALR mutated have lower thrombosis risk

43
Q

Where is red bone marrow located in the body (i.e. marrow that produces red cells)?

A

Proximal part of the long bones, pelvis and sternum

44
Q

What is myelofibrosis?

A

Fibrous tissue within bone marrow leads to low cell counts (pancytopenia); anaemia, thrombocytopenia, leukopenia. Body tries to compensate by making blood cells elsewhere e.g. spleen, other bones

45
Q

When the body tries to compensate by making blood cells elsewhere in myelofibrosis, what can this lead to?

A

o Massive splenomegaly
o Extra-medullary haematopoiesis; occurring outside the medulla of the bone (bone marrow) e.g. spine –> can compress spinal cord

46
Q

3 main presentations of myelofibrosis?

A
  1. Pancytopenia
  2. B symptoms
  3. Massive splenomegaly
47
Q

What are the 3 key B symptoms?

A
  1. Drenching night sweats
  2. Over 10% weight loss over 6 months
  3. Persistent fever
48
Q

Diagnosis tests for myelofibrosis?

A

o Blood film
o Bone marrow results
o JAK2 mutation 50%
o CARLR mutation 30%

49
Q

Treatment for myelofibrosis?

A

o Supportive care (blood transfusions, platelets transfusions)
o JAK2 inhibitor (new treatment); effective at treating splenomegaly and the symptoms
o Bone marrow transplant (if patient is young)

50
Q

Prognosis for myelofibrosis?

A

o Poor

o Median survival 5 years

51
Q

What is the Philadelphia chromosome?

A

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukaemia cancer cells (particularly chronic myeloid leukaemia cells).

52
Q

What is chronic myeloid leukaemia (CML)?

A

Slowly progressing blood and bone marrow disease where bone marrow makes too many white blood cells

53
Q

What is the median age of diagnosis of CML?

A

55-60 years

54
Q

What are the 4 features that CML is characterised by?

A

o Leucocytosis +++
o Leucoerythroblastic blood picture
o Anaemia
o Splenomegaly

55
Q

What is a leucoerythroblastic blood picture?

A

Presence of nucleated erythrocytes (immature) and neutrophilic precursors (immature white cells)

56
Q

What are the symptoms of CML?

A 
o	Abdominal discomfort
o	Abdominal pain: splenic infarction
o	Fatigue: anaemia, catabolic state
o	Venous occlusion: retinal vein, DVT, priapism
o	Gout: hyperuricaemia
57
Q

What is the genetic cause of CML?

A

Translocation between chromosomes 9 and 22 –> ‘Philadelphia chromosome’

58
Q

What is the Philadelphia chromosome?

A

Translocation between chromosomes 9 and 22

This creates an oncogene by this fusion –> creates an active tyrosine kinase which turns the CML process on and causes clone of cells to keep dividing

59
Q

What drug has been the major breakthrough in the treatment of CML?

A

Gleevec (imatinib mesylate)

60
Q

Mechanism of Gleevec (imatinib mesylate)?

A

inhibits the abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML

61
Q

What is a ‘major molecular response’ during treatment of CML?

A

Means that the amount of BCR-ABL gene in your blood is 1/1000th (or less) of what’s expected in someone with untreated CML

62
Q

What is an ‘early molecular response’ during treatment of CML?

A

Means that there is 10% or less BCR-ABL gene in your blood after 3 months and 6 months of treatment.

63
Q

What is Imatinib resistance?

A
  • Activating loop mutations in BCR-ABL confer resistance and loss of disease control
  • New TKI every year to combat this
64
Q

What is the prognosis of CML (in its chronic phase, before acute transformation)?

A

95% long term survival

65
Q

If CML transforms into acute leukaemia, what is the prognosis?

A

Requires intensive chemotherapy, and TKI and bone marrow transplant

Still poor outcome unfortunately

66
Q

What do BCR-ACL mutations confer resistance to?

A

Imatinib

67
Q

What is CML driven by?

A

Driven by the BCR-ACL fusion tyrosine kinase

CP reviewer 1 (59 decks)

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