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Year 5 - Pathology > HAEM: CML and MPD (polycythaemia) > Flashcards

HAEM: CML and MPD (polycythaemia) Flashcards

1
Q

Define polycythaemia.

A
  • Polycythaemia = raised haemoglobin concentration and raised haematocrit
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2
Q

What is the normal Hb and haematocrit in males and females?

A

Haemoglobin:

M: 130 – 180 g/​L

F: 115 – 165 g/​L

Haematocrit:

M: 0.40 – 0.54 L/​L

F: 0.37 – 0.47 L/​L

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3
Q

What are the 2 types of polycythaemia?

A
  1. Relative (lack of plasma)
  2. True (excess erythrocytes)
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4
Q

What is relative polycythaemia also known as?

A

Pseudopolycythaemia

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5
Q

What test can be used to distinguish relative from true polycythaemia?

A

Dilution studies / Fick’s principle:

  • RBC mass - 51Cr-RBCs
  • Plasma volume - 131I-Albumin
    • Take components out
    • Radiolabel them
    • Reinfuse and measure dilution
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6
Q

Name 3 causes of relative polycythaemia.

A

Usually non-malignant e.g.

  • alcohol
  • obesity
  • diuretics
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7
Q

What are the types of true polycythaemia?

A
  • Primary (myeloproliferative neoplasm) -
  • Secondary (non-malignant)
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8
Q

Summarise the primary polycythaemia causes.

A
  • All myeloproliferative disorders*
    1. Philadelphia chromosome -ve
  • Polycythaemia vera (PV)
  • Essential thrombocythaemia (ET)
  • Myelofibrosis
  1. Philadelphia chromosome +ve
    * Chronic myeloid leukaemia (CML)
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9
Q

Which haematopoietic precursor is targeted to cause polycythaemia vera?

A

BFU-E (=RBC precursor)

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10
Q

What kind of cells are produced in myeloproliferative neoplasms?

A

Abundance of mature cells (compared to acute leukaemia where cells are immature)

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11
Q

Which myeloid neoplasms do NOT cause polycythaemia?

A

AML and myelodysplasia

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12
Q

How are secondary polycythaemias classified?

A
  1. Appropriately raised EPO
  2. Inappropriately raised EPO
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13
Q

What are the causes of appropriately raised EPO causing polycythaemia?

A
  1. Cyanotic heart disease
  2. Hypoxic lung disease (COPD)
  3. High affinity heamoglobin
  4. High altitude
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14
Q

What are the causes of inappropriately raised EPO causing polycythaemia?

A
  1. renal disease
  2. uterine myoma
  3. other tumours (liver, lung)
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15
Q

What are the three types of haematological mutations during proliferation?

A
  1. Type 1 - disrupt cellular proliferation (mature cells)
  2. Type 2 - impair cellular differentiation (blasts)
  3. Anti-apoptosis - prolong cell survival
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16
Q

Name 2 mutation mechanisms in haematological proliferation. How is the Ph translocation BCR ABL1 rearrangement oncogenic?

A
  1. DNA point mutations
  2. Chromosomal translocations –> creation of novel fusion genes OR disruption of proto-oncogenes

BCR ABL1 rearrangement is oncogenic via formation of a novel fusion oncoprotein

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17
Q

What is the normal role of tyrosine kinase?

A
  • Role of Tyrosine Kinases:
    • Transmit cell growth signals from surface receptors to nucleus
    • Activated by transferring phosphate groups
    • Normally held tightly in inactive state
    • Promote cell growth but do NOT block maturation
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18
Q

What happens when tyrosine kinase is mutated?

A

Mutation of TK gene –> expansion of…

  • mature cells of RBCs (polycythaemia),
  • platelets (ET) and
  • granulocytes (CML)
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19
Q

What is the most common JAK mutation?

A

JAK mutations:

  • JAK2 V617F mutation (most common)
  • JAK2 exon 12 mutation
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20
Q

What are the 3 most common MPD associated mutations? Which polycythaemias is each most common in ?

A
  • JAK2
  • Calreticulin
  • MPL
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21
Q

Describe the sequence of activation of JAK2.

A
  1. JAK2 is a TK normally bound to inactive EPO precursor
  2. Normally, when EPO binds to EPO receptor it causes dimerisation of the receptor, autophosphoryation and phosphorylation of JAK2
  3. This activated the JAK2 signalling pathway causing a normal response to EPO
  4. But, in JAK2 mutation this pathway is constitutively active –> EPO response in the absence of EPO
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22
Q

What investigations are done when suspecting a MPD?

A
  1. Clinical examination - symptoms and splenomegaly
  2. FBC +/- BM biopsy
  3. EPO level
  4. Mutation testing (phenotype linked to acquired mutation)
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23
Q

What is the condition defined by isolated expansion of RBC (not plt) with JAK2 V617F mutation absence?

A

Idiopathic erythrocytosis

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24
Q

What is the epidemiology of PV?

A
  • M > F
  • Mean age at diagnosis = 60yo (5% <40yo)
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25
Q

What is the clinical presentation of PV?

A

Blood count: high RBC/ Hb/ plts/ WCC

Incidental

  1. Symptoms of hyperviscosity (headaches, light-headedness, stroke can be 1st presentation, visual disturbances, fatigue, dyspnoea)
  2. Symptoms of histamine release (aquagenic pruritus i.e. itching in hot water , peptic ulceration)
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26
Q

What mutation is pesent in PV?

A

Presence of JAK2 V617F mutation

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27
Q

How is PV managed?

A

GOAL = reduce HCT <45% + reduce risk of thrombosis​

  1. Venesection (only suitable in younger/healthy patients)
  2. Hydroxycarbamide (cytoreductive therapy (hydroxycarbamide/hydroxyurea) à less DNA synthesis in RBCs)
    • Keep plts <400 x 109/L
    • Keep Hct <45%
  3. Aspirin
28
Q

What is the blood count in essential thrombocythaemia?

A

High platelets

29
Q

Define ET.

A

Chronic myeloproliferative disorder involving megakaryocytic lineage

Sustained thrombocytosis >600 x 109/L

30
Q

What is the epidemiology of ET?

A
  • Bimodal age distribution –> 30 years (minor peak); 55 years
  • 30yo (M = F); 55 years (F > M)
31
Q

What is a typical clinical presentation of ET? Is Hb elevated?

A

THROMBOSIS or BLEEDING

Incidental (50% of cases)

  1. Symptoms of thrombosis (arterial or venous) – CVA, gangrene TIA, DVT/PE
  2. Symptoms of bleeding (mucous membrane and cutaneous)
  3. Symptoms of hyperviscosity (headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea)
  4. Splenomegaly (modest)

Mutations: JAK2, calreticulin, MPL

32
Q

How is ET differentiated from PV on bloods?

A

In ET the Hb is NOT that elevated (differentiates from PV)

33
Q

What is the management of ET?

A
  • Aspirin (thrombosis prevention)
  • Hydroxycarbamide (antimetabolite that suppresses cell turnover)
  • Anagrelide (inhibits platelet formation but NOT commonly used due to SEs of palpitations and flushing)

N.B. no venesection as it does not reduce platelets AND there is no raised RBC count

34
Q

What is the MOA of anagrelide?

A

Inhibits platelet formation but NOT commonly used due to SEs of palpitations and flushing

35
Q

What is the MOA of hydroxycarbamide?

A

antimetabolite that suppresses cell turnover and reduces DNA synthesis in RBCs AKA cytoreductive therapy (hydroxycarbamide/hydroxyurea)

36
Q

What is the prognosis in ET?

A
  • Normal life span in many patients
  • Leukaemic transformation in about 5% after 10 years
  • Myelofibrosis is also UNCOMMON, unless there is fibrosis at the beginning
37
Q

Define PMF.

A
  • PMF = a clonal myeloproliferative disease associated with reactive bone marrow fibrosis
    • Characterised by extramedullary haematopoiesis (i.e. in liver and spleen)
38
Q

Why can PMF be diagnosed as the other disorders like PV/ET?

A

Other MPD (ET and PV) may transform into PMF

PMF stages progress from pre-fibrotic (can be confused with ET) to fibrotic

39
Q

What age group is most affected by PMF? What is the incidende?

A
  • 60-70yo
  • M=F
  • 0.5-1.5/100,000/year
40
Q

Name 2 causes of massive hepatosplenomegaly.

A

PMF and CML

41
Q

What is the clinical presentation of PMF?

A

Incidental in 30%

Presentations related to:

  • Cytopaenias (anaemia, thrombocytopaenia)
  • Thrombocytosis
  • Splenomegaly (MASSIVE) –> Budd-Chiari syndrome –> Hepatomegaly
  • Hypermetabolic state (WL, fatigue and dyspnoea, night sweats, hyperuricaemia
42
Q

What are the finings on blood film in PMF?

A
  • Leucoerythroblastic picture
  • Tear drop poikilocytosis
  • Giant platelets
  • Circulating megakaryocytes
43
Q

What is found on bone marrow biopsy in PMF?

A

Dry tap

Trephine biopsy:

  • Increased reticulin or collagen fibrosis
  • Increased megakaryocytes with clustering
  • New bone formation
44
Q

What is seen in the liver and spleen in PMF causing massive hepatosplenomegaly?

A

Extramedullary haematopoiesis

45
Q

What DNA mutations are seen in PMF?

A

JAK2 or CALR

46
Q

What are the bad prognostic signs in PMF? Does a high or low score indicate poor prognosis?

A

DIPPS score is used (1-6)

  • BAD prognostic signs:
    • Severe anaemia < 100 g/L
    • Thrombocytopaenia < 100 x 109/L
    • Massive splenomegaly
    • High DIPPS score (score 6 –> 1.3 years)
47
Q

What is the median survival in PMF?

48
Q

What is the treatment for PMF?

A

Very limited

  • Supportive: transfusion of RBC or platelets (often ineffective because splenomegaly à rapid break down RBCs)
  • Cytoreductive Therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
  • Ruxolotinib (JAK2 inhibitor – only used in high prognostic score cases)

Surgical:

  • HSCT: potentially curative (reserved for high risk eligible cases)
  • Splenectomy: symptomatic relief but a dangerous operation- often followed by worsening of condition
49
Q

What is the MOA of Ruxolotinib?

A

JAK2 inhibitor

50
Q

How does CML differ from PMF/PV/ET?

A

It is PhChr +ve

51
Q

What is the mutation causing CML?

A

Chromosomal translocation

BCR-ABL Ph Chr mutation (t (9; 22) –> Ph Chr)

52
Q

What is the cosequence of the chromosomal translocation in CML?

A

Abnormal Ph Chr leads to synthesis of abnormal protein BCR-ABL with TK activity greater than the normal ABL protein. This drives myeloid proliferation.

  • BCR = Breakpoint Cluster Region - Constitutively expressed by itself as a housekeeping gene
  • ABL = Ableson Tyrosine Kinase -A TK that is not constitutively expressed, only in stimulated cells when cells need to proliferate i.e. it is highly suppressed usually
53
Q

What is the typical presentation of CML and what is found on blood count?

A
  • History:
    • Lethargy
    • Hypermetabolism
    • Thrombotic event (mono-ocular blindness, CVA, bruising, bleeding)
  • Massive splenomegaly/hepatomegaly
  • FBC:
    • Hb and platelets are normal or raised
    • MASSIVE leucocytosis (50-500 x 109/L)
54
Q

What is found on blood film in CML?

A
  • Neutrophils
  • Myelocytes (NOT blasts)
  • Basophilia
55
Q

Are blasts seen peripherally in CML?

A

No (i.e. <5% blasts) only myelocytes - all mature myeloid cells

56
Q

What was the clinical course of CML before Imatinib?

A
  1. Chronic phase of making more, but mature cells
  2. Additional mutation that limited the ability to fully differentiate
  3. Blast crisis (where there was accumulation of blasts in the BM)
57
Q

What diagnostic techniques can be used to detect mutations in CML?

A
  • Conventional karyotyping
  • FISH
  • RT-PCR amplification and detection
    • Help determine response to therapy
  • FBC and leucocyte count
58
Q

What is the MOA of imatinib?

A

ABL TK inhibitor

59
Q

What are the most sensitive methods for monitoring the effects of imatinib?

A
  • RQ-PCR monitors molecular response (reduction in % BCR-ABL transcripts) – most sensitive
    • BCR-ABL transcripts reduce 100% > 10% > 1% > 0.1%
    • Major Molecular response (MMR) <0.1% (3 log reduction)
  • Cytogenetics monitors cytogenetic response (on 20 metaphases) – very sensitive
    • Partial 1-35% Philadelphia positive
    • Complete 0% Ph positive
  • FBC monitors haematological response:
    • Complete Haematological Response (WBC<10x109/L)
60
Q

What is classified a major molecular response to imatinib?

A

BCR-ABL transcript 3 log reduction to <0.1%

61
Q

When is response to imatinib assessed?

A

at 18 months

62
Q

What is the prognosis like if there is response to imatinib?

A

Excellent if there is a response to treatment. Average 95% 5 year survival

63
Q

What are the issues with tyrosine kinase inhibitors?

A
  • Failure of treatment(failure to achieve CCyR* by 18 months)
  • Non-compliance and side-effects (fluid retention, pleural effusion)
  • Loss of major molecular response
    • Acquisition of ABL point mutations leads to treatment resistance
    • Evolution of a blast crisis

* complete cytogenetic response

64
Q

What are the treatment options in CML if there is failure with imatinib?

A

1) FAILURE 1

  • Switch to 2nd gen or 3rd gen tyrosine kinase inhibitor
  • Considered a failure if there is NO CCyR at 1 year OR if they respond but acquire resistance

(2) FAILURE 2

  • Consider allogeneic stem cell transplantation
  • Considered a failure if there is an inadequate response to 2nd generation TKIs OR if the disease progresses to accelerated or blast phase
65
Q

What are the 1st/2nd/3rd generation chronic phase tyrosine kinase inhibitors?

A

1st Gen – Imatinib

2nd Gen – Dasatinib, Nilotinib

3rd Gen – Bosutinib

66
Q

What has happened at 24 months?

A

Blast crisis

Year 5 - Pathology (89 decks)

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