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Pathology by week > W5 - CML & myeloproliferative disorders > Flashcards

W5 - CML & myeloproliferative disorders Flashcards

1
Q

Describe the 2 types of polycythaemia (raised Hb concentration and haematocrit %)

A
  1. Relative => lack of plasma => NON-MALIGNANT
  2. True => excess erythrocytes:
    A) secondary (NON-MALIGNANT)
    B) primary (myeloproliferative NEOPLASM)
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2
Q

Describe the categorisation of primary myeloproliferative neoplasms (MPDs) based on Ph

A

Ph negative:

  • polycythaemia vera (PV)
  • Essential thrombocythaemia (ET)
  • Primary myelofibrosis (PMF)

Ph positive:
- Chronic myeloid leukaemia (CML)

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3
Q

Name 3 risk factors for pseudo (relative) polycythaemia

A
  1. Alcohol
  2. Obesity
  3. Diuretics
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4
Q

What can you check to distinguish primary from secondary true polycythaemia?

A

Erythropoietin (EPO)!

Primary polycythaemia = REDUCED EPO
Secondary polycythaemia = ELEVATED EPO

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5
Q

Categorise the causes of true secondary polycythaemia (non-malignant)

A

Raised EPO:

  1. Appropriate:
    - high altitude
    - cyanotic heart disease
    - high affinity haemoglobin
  2. Inappropriate:
    - renal disease (cysts, tumours, inflammation)
    - uterine myoma
    - other tumours (liver, lung)
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6
Q

Name the 3 groups of myeloid malignancies, starting with the most acute form

A
  1. Acute myeloid leukaemia (>20% blasts)
  2. Myelodysplasia (5-19% blasts)
  3. myeloproliferative disorders (MPD neoplasms):
    - essential thrombocythaemia
    - polycythaemia vera
    - primary myelofibrosis
    - Ph + => Chronic myeloid leukaemia
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7
Q

Name the 2 groups of lymphoid malignancies, starting with the most acute

A
  1. Precursor cell malignancy => Acute lymphoblastic leukaemia (B & T)
  2. Mature cell malignancy:
    - Chronic lymphocytic leukaemia (CLL)
    - Multiple myeloma (MM)
    - Lymphoma (Hodgkin & Non-Hodgkin)
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8
Q

Which MPD neoplasm arises with acquired mutations in the erythroblast precursors?

A

Polycythaemia vera (PV)

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9
Q

Describe the cellular pathophysiology behind polycythaemia, essential thrombocythaemia, chronic myeloid leukaemia (CML)

A

JAK 2 mutations
- JAK2 is involved in tyrosine kinase signalling, which is a signalling cascade for cell growth signals from surface receptor to the nucleus

  • JAK2 (unphosphorylated) is associated with the TK receptor => once phosphorylated, dimerises and transmits downstream signalling

In 3 conditions stated, a JAK2 V617F mutation means that tyrosine kinase is ON => increased cellular proliferation!

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10
Q

In what % of PV, ET, and PMF do you see JAK2 V617F mutations?

A

PV – 100% JAK2 mutations
ET – 60% JAK2 mutations
PMF – 60% JAK2 mutations

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11
Q

What is the mean age at diagnosis for PV?

A

60 years

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12
Q

How is PV usually picked up? What are the FBC ranges?

A

Incidental diagnosis following routine FBC;

median Hb 184 g/L, Hct 0.55

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13
Q

What are the symptoms (6) of PV?

A
  • CNS: Headaches; light-headedness; stroke; visual disturbances**
  • General: fatigue; dyspnoea
  • due to increased histamine release: aquagenic pruritus, peptic ulceration (histamine causes stomach to make more acid)
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14
Q

After routine tests, what test is specific for PV diagnosis?

A

Test for JAK2 V617F mutation

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15
Q

Describe the management of PV

A

Aim 1) reduce Hct => target Hct <45%

  1. Venesection
  2. Cytoreductive therapy using hydroxycarbamide

Aim 2) reduce risk of thrombosis

  1. Control Hct
  2. aspirin
  3. Keep platelets below 400 x 10^9/L => using ET treatments such as anagrelide
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16
Q

Which lineage does ET involve?

A

Mainly the megakaryocyte lineage

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17
Q

What is the age of diagnosis of ET? What is the M:F ratio?

A

Major peak 55 years, minor peak 30 years
F:M equal for 1st peak, F>M for 2nd peak

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18
Q

How is ET usually picked up?

A

Incidental finding on FBC (50%)

19
Q

What are the symptoms/signs of ET?

A
  • asymptomatic (50% of cases)
  • thrombosis: arterial or venous:
    => CVA, gangrene, TIA
    => DVT or PE
  • bleeding: mucous membranes, cutaneous
  • CNS: headaches, dizziness, visual disturbances
  • splenomegaly (modest)
20
Q

Describe the management of ET (& reason for each intervention)

A
  1. Aspirin – prevent thrombosis
  2. Hydroxycarbamide – antimetabolite. S/E: suppression of other cells
  3. anagrelide – specific inhibition of platelet formation. S/E: palpitations, flushing
21
Q

What is the prognosis of patient with ET?

A

normal lifespan in many

  • leukaemia transformation in about 5% after >10 years
  • myelofibrosis uncommon unless fibrosis was present at the beginning
22
Q

What is the age of diagnosis of PMF? What is the M:F ratio?

A

Usually 70s
M=F

23
Q

____ & _____ may transform to PMF

A

ET & PV

24
Q

What are the symptoms/signs of PMF?

A
  • asymptomatic (30%)
  • cytopenias: anaemia or thrombocytopenia
  • thrombocytosis
  • splenomegaly (MASSIVE)
    => Budd-Chiari syndrome:
  • hepatomegaly
  • hypermetabolic status:
    => FLAWS
    => hyperuricaemia
25
Q

Why is there a MASSIVE hepatosplenomegaly in PMF?

A

B/c the BM becomes fibrosed + scarred => haematopoiesis can no longer function => BM cell production moves to LIVER + SPLEEN = extramedullary haemopoiesis

26
Q

Describe blood film findings (4) for PMF

A
  1. Leuco-erythroblastic picture
  2. Tear drop poikilocytes
  3. Giant platelets
  4. Circulating megakaryocytes
27
Q

Describe BM findings (4) for PMF

A
  1. Dry tap
  2. Trephine:
    => increased reticulin or collagen fibrosis
    => prominent megakaryocyte hyperplasia & clustering w/ abnormalities
    => new bone formation
28
Q

What mutation is responsible for PMF?

A

JAK2 or CALR mutation

29
Q

What is the prognosis for PMF? What are 3 signs of poor prognosis?

A

Median 3-5 years but very variable; bad prognostic signs:

  • severe anaemia <100 g/L
  • thrombocytopenia <100x10^9/L
  • massive splenomegaly

Prognostic scoring system is DIPPS

30
Q

Describe the treatment for PMF

A

Treatment is limited.

  1. supportive => RBC and platelet transfusion often ineffective due to splenomegaly
  2. Cytoreductive therapy => hydroxycarbamide (for thrombocytosis)
  3. Ruxolitinib => JAK2 inhibitor (high prognostic score cases)
  4. Allogeneic SCT => potentially curative reserved for high-risk eligible cases)
  5. Splenectomy for symptomatic relief => hazardous and often followed by worsening of condition
31
Q

Ph + MPN is…

A

CML

32
Q

What is the age of diagnosis of CML? What is the M:F ratio?

A

40-60s
M:F 1.4:1

33
Q

What is a RF for CML?

A

Radiation exposure

34
Q

What are the symptoms/signs of CML?

A
  • History => lethargy, hypermetabolism, bruising, bleeding
  • Thrombotic event => monocular blindness, CVA
  • MASSIVE splenomegaly +/- hepatomegaly
35
Q

What is the typical FBC for CML?

A
  • Hb & platelets well preserved or raised
  • MASSIVE leucocytosis 50-500 x 10^9/L
36
Q

What is the typical blood film for CML?

A
  1. high neutrophils
  2. high myelocytes
    *but NONE of 1+ 2 are in blasts if in chronic phase (<5% myeloblasts)
    *bi-phasic peak between neutrophils and myelocytes
  3. basophilia
37
Q

Describe the translocation that produces the Philadelphia chromosome and its MOA

A

t(9;22) translocation producing bcr-abl = fusion oncoprotein with constitutive tyrosine kinase activity, which drives myeloid proliferation

38
Q

What tests can be used to identify the translocation/fusion in CML?

A
  1. conventional karyotyping
  2. FISH metaphase or interphase karyotyping
  3. RT-PCR
39
Q

Describe the course of CML before introducing imatinib

A

Chronic phase (3-4 years) => accelerated phase (10-19% blasts; 6-12 months) => blast crisis (20%; 3–6-month survival)

40
Q

What drug class is imatinib? What’s its ROA?

A

ABL Tyrosine kinase inhibitor
Oral

41
Q

Name 3 responses used for monitoring and assessing response to CML therapy?

A
  1. haematological response
  2. cytogenetic response
  3. molecular response
42
Q

Name how haematological (1), cytogenetic (2), and molecular (3) responses can be used to assess CML therapy?

A
  1. haematological => complete haematological response WBC < 10 x 10^9/L
  2. Cytogenetic (most imp!) => partial = 1-35% Ph positive, complete = 0% Ph positive
  3. Molecular => RQ-PCR of BCR-ABL transcripts => reduction in % BCR-ABL transcripts -> reduce 100% > 10% > 1 % > 0.1%
    Major molecular response (MMR) is <0.1% (3 log reduction)
43
Q

Summarise treatment of CML, and adjunct treatments if presented with TWO failures

A
  1. Chronic phase TKI => imatinib (1st generation), dasatanib nilotonib (2G), bosutinib (3G)
  2. Failure (1) => switch to 2Gen or 3G TKI
    - no complete cytogenetic response at year 1
    - respond but acquire resistance
  3. Failure (2) => consider allogeneic SCT
    - inadequate response or intolerance to 2G TKI
    - Progression to accelerated or blast phase
44
Q

22 yo male – cyanotic congenital heart disease – Hb 210g/L, haematocrit 60%, no splenomegaly. What will the lab result likely show?

A

Increased serum erythropoietin (EPO)

Pathology by week (70 decks)

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