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PATH FINAL > Haem: CML and myeloproliferative disorders > Flashcards

Haem: CML and myeloproliferative disorders Flashcards

1
Q

What is polycythaemia?

A

A condition characterised by raised Hb concentration and raised haematocrit.

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2
Q

What are the two main types of polycythaemia?

A

Relative - caused by a lack of plasma with normal Hb and HCT (associated with alcoholism, obesity and diuretics)

True - caused by an excess of erythrocytes.

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3
Q

What are the two types of TRUE POLYCYTHAEMIA

A

Primary causes
- noted to have low EPO.
- Myeloproliferative neoplasms (malignant)

Secondary causes
- noted to have raised EPO
- no issue with bone marrow - simply being over-stimulated (which can be appropriate or inappropriate over-stimulation)

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4
Q

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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5
Q

How can primary polycythaemia (or myeloproliferative neoplasms) be broadly categorised?

A
  • Philadelphia positive: CML
  • Philadelphia negative: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis
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6
Q

What is the main clinical worry with polycythaemia - which patients are at increased risk of it

A

Main worry of polycythaemia = vaso-occlusive episode (e.g. stroke)

Pts with primary polycythaemia > secondary polycythaemia

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7
Q

What are the two main processes that cells 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 due acquired mutation.
  • Acute leukaemia: differentiation is abnormal (cells have lost the ability to mature) + proliferation is excessive and abnormal
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8
Q

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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9
Q

Mutations in genes commonly associated with the development of myeloproliferative disorders affect which protein/molecular structure?

A

Tyrosine kinase

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10
Q

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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11
Q

Name three genes that are associated with myeloproliferative disorders.

A
  • JAK2 (V617F)
  • Calreticulin
  • MPL
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12
Q

Outline the mutation seen in Polycythaemia Vera

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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13
Q

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 dimersises, autophosphorylates and phosphorylates JA2 which promotes cell proliferation.
  • Mutated JAK2 is constantly active even in the absence of EPO thereby driving cell replication constantly in the absence of a stimulus.
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14
Q

Outline the typical presentation of polycythaemia vera?

A
  • Often incidental
  • Hyperviscosity: headaches, visual disturbance, stroke, fatigue, dyspnoea, light-headedness
  • Increased histamine release: aquagenic pruritis (itchiness when in warm water and warm environments), peptic ulceration

Note: commonest in men than women, more in elderly

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15
Q

List the investigation findings expected in polycythaemia vera (Hb, HCT, EPO levels, genetic testing)

A

Raised Hb
Raised HCT
Low serum EPO

Mutation Testing - JAK2 (V617F) +ve –> diagnostic in context with above!

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16
Q

Outline the principles of treatment of polycythaemia vera.

A
  1. Venesection (aim to reduce HCT to <45% and plts /< 400x109/L)
  2. Hydroxycarbamide (if venesection not effective to reach aims)

May consider aspirin to control thrombosis risk

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17
Q

What is essential thrombocythaemia?

A

Chronic myeloproliferative disorder mainly involving the megakaryocyte lineage

Characterised by sustained thrombocytosis > 600 x109/L

18
Q

What mutations are seen in essential thrombocythaemia

A

60% = JAK2
30% = Calreticulin (CALR)
5% = MPL

19
Q

Outline the typical presentation of essential thrombocythaemia.

A
  • Incidental finding (50%)
  • Thrombosis (arterial and venous) - CVA, TIA, DVT, PE, gangrene
  • Bleeding (mucous membranes, cutaneous, menorrhagia) - as existing plts are dysfunctional
  • Splenomegaly (modest)
20
Q

List findings you’d expect in Essential Thrombocythaemia (bloods and blood film)

A

Plts >600x10^9

Blood film = large platelets + megakaryocyte fragments

21
Q

Outline the treatment options for essential thrombocythaemia.

A
  • Aspirin
  • Hydroxycarbamide
  • Anagrelide (specifically inhibits platelet function but rarely used because of side-effects (flushing + palpitations)

NOTE: hydroxycarbamide is an antimetabolite that suppresses cell turnover

22
Q

Outline the prognosis for essential thrombocythaemia.

A
  • Normal life span in many patients
  • 5% in 10 years risk of leukaemic transformation
  • Myelofibrosis is uncommon
23
Q

What is primary myelofibrosis?

A
  • A clonal myeloproliferative disease associated with reactive bone marrow fibrosis (excessive clone production stimulates reticulin and fibrouse tissue deposits in BM)
  • Characterised by extramedullary haemopoeisis
  • NOTE: other myeloproliferative disorders can transform into myelofibrosis
24
Q

Outline the typical presentation of primary myelofibrosis.

A
  • Cytopaenias (anaemia, thrombocytopaenia)
  • Thrombosis - some pts have a proliferative phase where a cell line number may be increased
  • MASSIVE splenomegaly
  • Hepatomegaly
  • Hypermetabolic state (FLAWS)
25
Q

What might you expect to see in the blood film of a patient with primary myelofibrosis?

A
  • Leucoerythroblastic picture = nucleated erythroblasts and immature leucocytes of neutrophilic myeloid lineage (due to infiltration of BM!)
  • Tear drop poikilocytes
  • Giant platelets
  • Circulating megakaryocytes
26
Q

What is a characteristic feature seen on bone marrow aspirate in primary myelofibrosis?

A

Dry tap

27
Q

Which mutations would you test for in a patient with primary myelofibrosis?

A

JAK2 (60%) and Calreticulin (30%)

NOTE: these are not diagnostic

28
Q

What are some bad prognostic features in primary myelofibrosis?

A
  • Severe anaemia (< 100)
  • Thrombocytopaenia (< 100)
  • Massive splenomegaly at diagnosis

NOTE: median survival is 3-5 years

29
Q

Outline the treatment options for primary myelofibrosis.

A
  • Supportive - RBC and platelet transfusions (usually ineffective becasue of splenomegaly)
  • Hydroxycarbamide (if in proliferative phase but may worsen anaemia)
  • Ruxolitinib - JAK2 inhibitor (for those with worse prognosis)
  • Allogeneic stem cell transplantation (curative but too toxic for esp for elderly pts!)
  • Splenectomy - dangerous operation as is main site of extramedullary haematopoeisis (which pt depends on) but may provide symptomatic relief
30
Q

What might you expect to see in the FBC of a patient with CML?

A
  • Leucocytosis (MASSIVE)
  • Raised neutrophils, basophils!
  • Normal or raised Hb and platelets
31
Q

What would you expect to see in abundance in the blood film of a patient with CML?

A

Biphasic picture! (less mature myelocytes and mature end product cells!)
* Neutrophils
* Basophils
* Myelocytes (NOT blasts)

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

32
Q

Briefly describe the natural history of CML before targeted treatment was available.

A
  • 5-6 years stable phase
  • 6-12 months accelerated phase
  • 3-6 months blasst crisis
33
Q

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

34
Q

What are the two genes that make up the fusion gene in the Philadelphia chromosome?

A

Bcr = breakpoint cluster region

Abl = ableson tyrosine kinase

35
Q

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 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
36
Q

List some diagnostic techniques used to identify the CML 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

37
Q

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)
38
Q

List some examples of Bcr-Abl tyrosine kinase inhibitors.

A
  • 1st generation: imatinib
  • 2nd generation: dasatinib, nilotinib
  • 3rd generation: bosutinib
39
Q

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
40
Q

In haematological cancers what are the 3 types of mutations that can predispose to a haematological malignancy and give an example of each

A

Novel fusion oncoprotein
- translocation causes a novel fusion gene which acts as a oncogene hence a novel oncoprotein.
- seen in philadelphia chromosme with Bcr-ABL

Dysregulated expression of intact proto-oncogene
- mutations or translocations increase expression of existing but usually suppressed proto-oncogenes
- seen in lymphomas (e..g. follicular b cell lymphoma t(14;18) = bcl2)

Activating point mutation of tyrosine kinase
- mutation causes constant activation of a tyrosine kinase
- seen in JAK2 mutation in polycythaemia vera!

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