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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
What are the causes of hypoxia that can lead to2ary polycythaemia?
- Chronic lung disease - Right-to-left shunts heart disease - Carbon monoxide poisoning - Smoker - High altitude
26
What drugs can lead to 2ary polycythaemia?
Treatment with androgen preparations (seen in bodybuilders)
27
What congenital mutation can lead to polycythaemia?
JAK2 mutation (Erythropoietin receptor-mediated)
28
What are the 2 major treatment options for polycythaemia vera?
1. Venesection (drawing blood); quickly reduces the number of RBCs in your blood 2. Aspirin 75mg daily (reduce risk of thrombosis)
29
What is the prognosis for polycythaemia vera?
o Good – 15-year median survival o Risk developing AML o Risk developing myelofibrosis
30
What is Primary Essential Thrombocytosis (ET)?
* Bone marrow produces too many platelets | * Can cause abnormal bleeding or clotting (thrombosis risk)
31
What is reactive thrombocytosis?
Abnormally high platelet cause in the absence of a chronic myeloproliferative disease, secondary to another disease
32
What are the causes of reactive thrombocytosis?
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
What is important to consider when investigating thrombocytosis?
The recent normal platelet count prior to surgery/infection etc
34
What are the 5 main 1st line investigations in thrombocytosis?
1. FBC and film 2. Ferritin 3. CRP 4. CXR 5. ESR
35
What are the 2 main mutations seen in myeloproliferative disorders?
1. JAK2 | 2. CARLR
36
How is the CALR mutation different?
Acquired after birth (not inherited)
37
How is Primary Essential Thrombocytosis (ET) treated?
o Assess thrombotic risk: o Antiplatelet treatment; aspirin 75mg daily o Cytoreduction (only if high risk – 1 or more risk factors)
38
What is cytoreduction?
impair bone marrows ability to make cells
39
What is the main drug used for cytoreduction?
Hydroxycarbamide
40
What is Hydroxycarbamide? Mechanism?
o Anti-folate drug | o Inhibits bone marrow's ability to make platelets
41
Side effects of hydroxycarbamide?
o Inhibits bone marrow's ability to make white and red cells o Can lead to anaemia or leukopenia
42
Prognosis for ET?
o Overall excellent 20-year median survival o Risk of AML or myelofibrosis o CALR mutated have lower thrombosis risk
43
Where is red bone marrow located in the body (i.e. marrow that produces red cells)?
Proximal part of the long bones, pelvis and sternum
44
What is myelofibrosis?
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
When the body tries to compensate by making blood cells elsewhere in myelofibrosis, what can this lead to?
o Massive splenomegaly o Extra-medullary haematopoiesis; occurring outside the medulla of the bone (bone marrow) e.g. spine --> can compress spinal cord
46
3 main presentations of myelofibrosis?
1. Pancytopenia 2. B symptoms 3. Massive splenomegaly
47
What are the 3 key B symptoms?
1. Drenching night sweats 2. Over 10% weight loss over 6 months 3. Persistent fever
48
Diagnosis tests for myelofibrosis?
o Blood film o Bone marrow results o JAK2 mutation 50% o CARLR mutation 30%
49
Treatment for myelofibrosis?
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
Prognosis for myelofibrosis?
o Poor | o Median survival 5 years
51
What is the Philadelphia chromosome?
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
What is chronic myeloid leukaemia (CML)?
Slowly progressing blood and bone marrow disease where bone marrow makes too many white blood cells
53
What is the median age of diagnosis of CML?
55-60 years
54
What are the 4 features that CML is characterised by?
o Leucocytosis +++ o Leucoerythroblastic blood picture o Anaemia o Splenomegaly
55
What is a leucoerythroblastic blood picture?
Presence of nucleated erythrocytes (immature) and neutrophilic precursors (immature white cells)
56
What are the symptoms of CML?
``` o Abdominal discomfort o Abdominal pain: splenic infarction o Fatigue: anaemia, catabolic state o Venous occlusion: retinal vein, DVT, priapism o Gout: hyperuricaemia ```
57
What is the genetic cause of CML?
Translocation between chromosomes 9 and 22 --> ‘Philadelphia chromosome’
58
What is the Philadelphia chromosome?
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
What drug has been the major breakthrough in the treatment of CML?
Gleevec (imatinib mesylate)
60
Mechanism of Gleevec (imatinib mesylate)?
inhibits the abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML
61
What is a 'major molecular response' during treatment of CML?
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
What is an 'early molecular response' during treatment of CML?
Means that there is 10% or less BCR-ABL gene in your blood after 3 months and 6 months of treatment.
63
What is Imatinib resistance?
* Activating loop mutations in BCR-ABL confer resistance and loss of disease control * New TKI every year to combat this
64
What is the prognosis of CML (in its chronic phase, before acute transformation)?
95% long term survival
65
If CML transforms into acute leukaemia, what is the prognosis?
Requires intensive chemotherapy, and TKI and bone marrow transplant Still poor outcome unfortunately
66
What do BCR-ACL mutations confer resistance to?
Imatinib
67
What is CML driven by?
Driven by the BCR-ACL fusion tyrosine kinase

CP reviewer 1 (59 decks)

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