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HaemPath > CML and myeloproliferative disorders > Flashcards

CML and myeloproliferative disorders Flashcards

1
Q
  1. What is polycythaemia?
A

A condition characterised by raised Hb concentration and raised haematocrit

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2
Q
  1. What are the two main types of polycythaemia?
A

Relative – caused by a lack of plasma (associated with alcoholism, obesity and diuretics)
True – caused by an excess of erythrocytes

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3
Q
  1. What is secondary polycythaemia and what can cause it?
A

Polycythaemia that occurs due to excessive stimulation by EPO (there is no problem with the bone marrow itself)
Appropriate causes: high altitude, hypoxic lung disease, cyanotic heart disease, high affinity haemoglobin
Inappropriate causes: renal disease (cysts, tumours), uterine myoma, other tumours

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4
Q
  1. How can myeloproliferative neoplasms be broadly categorised?
A

Philadelphia positive: CML

Philadelphia negative: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis

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5
Q
  1. What are the two processes that cell undergo as they develop and how are these different in acute and chronic leukaemia?
A

Two processes: differentiation + proliferation
Chronic leukaemia: differentiation is intact (produces mature cells) + proliferation is excessive and abnormal
Acute leukaemia: differentiation is abnormal (cells have lost the ability to mature) + proliferation is excessive and abnormal

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6
Q
  1. What are the main types of myeloid malignancy?
A

Acute myeloid leukaemia (blasts > 20%)
Chronic myeloid leukaemia
Myeloproliferative disorders
Myelodysplastic syndromes (blasts 5-19%)

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7
Q
  1. Mutations in which genes are commonly associated with the development of myeloproliferative disorders?
A

Tyrosine kinase

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8
Q
  1. What is the normal physiological role of tyrosine kinase?
A

Transmit cell growth signals from cell surface receptors to the nucleus
They are activated by transferring phosphate groups to itself and downstream proteins
They promote cell growth but they do NOT affect maturation

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9
Q
  1. Name three genes that are associated with myeloproliferative disorders
A

JAK2 (V617F)
Calreticulin
MPL

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10
Q
  1. Which conditions is defined by the presence of one of these mutations?
A

100% of polycythaemia vera has JAK2 V617F mutation

NOTE: it is also found in 60% of primary myelofibrosis and essential thrombocythaemia

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11
Q
  1. What is the normal physiological role of JAK2? How is this different in polycythaemia vera?
A

It is a tyrosine kinase that is normally bound to the inactive EPO receptor
When EPO binds to the receptor, the receptor dimerises, autophosphorylates and phosphorylates JAK2 which promotes cell proliferation
Mutated JAK2 is constitutively active in the absence of EPO thereby driving cell replication in the absence of a stimulus

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12
Q
  1. What is the diagnosis of myeloproliferative disorders based on?
A 
Clinical features (splenomegaly is particularly important)
FBC 
Bone marrow biopsy
EPO level 
Mutation testing
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13
Q
  1. Outline the typical presentation of polycythaemia vera?
A

Often incidental
Hyperviscosity: headaches, visual disturbance, stroke, fatigue, dyspnoea, light-headedness
Increased histamine release: aquagenic pruritus, peptic ulceration

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14
Q
  1. Outline the principles of treatment of polycythaemia vera.
A 
Reduce haematocrit (aim for < 45%) – venesection, cytoreductive therapy (hydroxycarbamide)
Reduce thrombosis risk – control Hct, aspirin, keep platelets < 400 x 109/L
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15
Q
  1. What is essential thrombocythaemia?
A

Chronic myeloproliferative disorder mainly involving the megakaryocyte lineage
Characterised by sustained thrombocytosis > 600 x 109/L

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16
Q
  1. Outline the typical presentation of essential thrombocythaemia.
A

Incidental finding (50%)
Thrombosis (arterial and venous) – CVA, TIA, DVT, PE, gangrene
Bleeding (mucous membrane and cutaneous)
Headaches, dizziness, visual disturbance
Splenomegaly (modest)
NOTE: ET can cause both thrombosis and bleeding depending on the way in which the abnormal platelet function

17
Q
  1. Outline the treatment options for essential thrombocythaemia.
A

Aspirin
Hydroxycarbamide
Anagrelide (specifically inhibits platelet function but rarely used because of side-effects)
NOTE: hydroxycarbamide is an antimetabolite that suppresses cell turnover)

18
Q
  1. What is primary myelofibrosis?
A

A clonal myeloproliferative disease associated with reactive bone marrow fibrosis
Characterised by extramedullary haemopoiesis
NOTE: other myeloproliferative disorders can transform into myelofibrosis

19
Q
  1. Outline the typical presentation of primary myelofibrosis.
A 
Cytopaenias (anaemia, thrombocytopaenia)
Thrombosis 
MASSIVE splenomegaly 
Hepatomegaly 
Hypermetabolic state (FLAWS)
20
Q
  1. What might you expect to see in the blood film of a patient with primary myelofibrosis?
A

Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes

21
Q
  1. What is a characteristic feature seen on bone marrow aspirate in primary myelofibrosis?
A

Dry tap

22
Q
  1. What might you see on histological analysis of a trephine biopsy in primary myelofibrosis?
A

Increased reticulin and collagen fibrosis
Prominent megakaryocyte hyperplasia and clustering
New bone formation

23
Q
  1. Which mutations would you test for in a patient with primary myelofibrosis?
A

JAK2 and Calreticulin

NOTE: these are not diagnostic

24
Q
  1. What are some bad prognostic features in primary myelofibrosis?
A

Severe anaemia
Thrombocytopaenia
Massive splenomegaly
NOTE: median survival is 3-5 years

25
Q
  1. Outline the treatment options for primary myelofibrosis.
A

Supportive – RBC and platelet transfusions (usually ineffective because of splenomegaly)
Hydroxycarbamide (may worsen anaemia)
Ruxolitinib – JAK2 inhibitor
Allogeneic stem cell transplantation
Splenectomy – dangerous operation but may provide symptomatic relief

26
Q
  1. What might you expect to see in the FBC of a patient with CML?
A

Leucocytosis (MASSIVE)

Normal or raised Hb and platelets

27
Q
  1. What would you expect to see in abundance in the blood film of a patient with CML?
A

Neutrophils
Basophils
Myelocytes (NOT blasts)
NOTE: myelocytes are immature myeloid cells that are NOT blasts (analogous to reticulocytes for red blood cells)

28
Q
  1. Briefly describe the natural history of CML before targeted treatment became available?
A

5-6 years stable phase
6-12 months accelerated phase
3-6 months blast crisis

29
Q
  1. What is the Philadelphia chromosome?
A

CML is caused by a translocation between 9;22 producing a derivative chromosome, 22q, which is called the Philadelphia chromosome

30
Q
  1. Explain how this fusion gene results in excessive proliferation of myeloid cells.
A

Abl is a tyrosine kinase that drives cell proliferation but is rarely expressed unless the cells are receiving a stimulus to proliferation
Bcr, on the other hand, is a housekeeping gene that is constitutively active
The Bcr-Abl fusion gene means that the tyrosine kinase component is constitutively activated thereby driving cell proliferation in the absence of a stimulus

31
Q
  1. List some diagnostic techniques used to identify the disease and monitor response to treatment.
A

FBC and leucocyte count
Cytogenetics and detection of Philadelphia chromosome (FISH)
RT-PCR to detect and quantify the number of copies of Bcr-Abl fusion transcript
NOTE: RT-PCR transcript % is the most sensitive

32
Q
  1. What are some issues associated with 1st generation Bcr-Abl tyrosine kinase inhibitors?
A

Some people fail to achieve a complete cytogenetic response
Non-compliance
Side-effects (fluid retention, pleural effusion)
Loss of major molecular response (due to resistance mutations)

33
Q
  1. List some examples of Bcr-Abl tyrosine kinase inhibitors.
A

1st generation: imatinib
2nd generation: dasatinib, nilotinib
3rd generation: bosutinib

34
Q
  1. What are the next steps in treatment if the first-line fails?
A

1st line fails (no complete cytogenetic response at 1 year or initial response is followed by resistance)  switch to 2nd or 3rd generation
2nd line fails (inadequate response or disease progresses to accelerated or blast phase)  allogeneic stem cell transplantation

HaemPath (8 decks)

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