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Clinical Pathology > Chronic myeloproliferative disorders and chronic myeloid leukaemia > Flashcards

Chronic myeloproliferative disorders and chronic myeloid leukaemia Flashcards

1
Q

What are chronic myeloproliferative disorders?

A
  • Malignant clonal stem cell disorders of the bone marrow.
  1. Polycythaemia Vera
  2. Essential thrombocytosis
  3. Idiopathic Myelofibrosis
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2
Q

What percentage of chronic myeloproliferative disorders transform into acute leukaemia?

A

10%

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3
Q

What is polycythaemia vera?

A
  • Increased red cells, +/-neutrophils, +/-platelets

- Distinguish from secondary polycythaemias and relative polycythaemia

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4
Q

What is essential thrombocythaemia?

A
  • Increased platelets

- Distinguish from reactive thrombocytosis

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5
Q

What is myelofibrosis?

A
  • Variable cytopenias with a large spleen

- Distinguish from other causes of splenomegaly

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6
Q

What is the epidemiology of polycythaemia vera?

A

All ages, peak at 50-70 years

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7
Q

What are the signs and symptoms of polycythaemia vera?

A
  • Itching (aquagenic- hot baths)
  • Plethoric face
  • Headache, muzziness,
  • General malaise
  • Tinnitus
  • Peptic ulcer
  • Gout
  • Gangrene of the toes
  • Engorged retinal veins
  • Splenomegaly
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8
Q

How is polycythaemia vera diagnosed?

A
  • Persistent increased Hb/hct >0.5
  • Is it:
    • relative V absolute polycthaemia
    • Primary V Secondary polycythaemia
  • Detailed History and Examination
  • 1st line tests
    • FBC
    • Ferritn
    • Epo level
    • UE/LFT
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9
Q

What is the cause if primary polycythaemia?

A

Polycythaemia vera

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10
Q

What are the causes of secondary polycythaemia?

A

Central hypoxic process

  • Chronic lung disease
  • Right-to-left shunts Heart Disease
  • Carbon monoxide poisoning
  • Smoker
  • High Altitude

Renal disease

EPO production Tumours

Drug associated

  • Treatment with androgen preparations
  • Postrenal transplant erythrocytosis

Congenital

  • High oxygen-affinity haemoglobin
  • Erythropoeitin receptor-mediated

Idiopathic erythrocytosis

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11
Q

What second line tests should be performed in cases of suspected polycythaemia?

A

Epo elevated

  1. CXR
  2. ABG
  3. USS abdomen

Epo normal or low

  1. JAK2 mutation
  2. Bone marrow examination
  3. EXON12 mutation
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12
Q

For which cytokine receptors is JAK the signalling pathway?

A 
GM-CSF
GCSF
EPO
TPO
SCF
interleukins
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13
Q

What are the features of the JAK2 mutation?

A
  • Occurs in the JH2 domain (inactive)
  • G-to-T mutation at nucleotide 1849
  • Phenylalanine for valine at 617 in protein (V617F)
  • Destroys a BsaXI site
  • Patients may be heterozygous or homozygous
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14
Q

The presence of a JAK2 V617F mutation

in peripheral blood DNA is diagnostic of what?

A

A myeloproliferative disorder?

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15
Q

What is the treatment of polycythaemia vera?

A
  • Venesection - aim for a haematocrit of
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16
Q

What is the prognosis for polycythaemia vera?

A
  • Good - 15 year median survival
  • Risk developing AML
  • Risk developing Myelofibrosis
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17
Q

What is primary essential thrombocytosis (ET)?

A

A disease in which abnormal cells in the bone marrow cause an increase in platelets.

18
Q

What is reactive thrombocytosis?

A

An elevated platelet count (> 450,000/μL) that develops secondary to another disorder.

19
Q

What are the causes of reactive thrombocytosis?

A
  • Surgery
  • Infection
  • Inflammation
  • Malignancy
  • Iron deficiency
  • Hyposplenism
  • Haemolysis
  • Drug induced (steroids, adrenaline, TPO mimetics)
  • Rebound post chemo
20
Q

How would you perform a thrombocytosis investigation?

A
  • Good history / examination IMPORTANT (e.g.recent normal count prior to surgery)
  • Persistent Platelets >450 x109/L

1st line investigations

  1. FBC and film
  2. Ferritin
  3. CRP
  4. CXR
  5. ESR
21
Q

What second-line investigations would you perform in suspected thrombocytosis?

A
  • JAK2
  • CALR
  • ? Bone marrow biopsy
  • Extensive search for secondary cause
22
Q

What is the CALR mutation?

A
  • Calreticulin mutation
  • cell signalling protein produced in ER (endoplasmic Reticulin)
  • Mutation in EXON 9 of gene
  • Found in Myeloid progenitors in ET
  • Mechanism of action unknown at present but may activate cell signal pathways
  • found in upto 90% of JAK2 negative ET
23
Q

What percentage of ET patients have a JAK2 mutation?

A

50%

24
Q

What percentage of ET patients have a CALR mutation?

A

45%

25
Q

What is the treatment of ET?

A
  • Assess thrombotic risk
    • Age
    • Hypertension
    • Diabetes
    • Platelet count >1500
    • History of thrombosis
  • Antiplatelet treatment
    • Aspirin 75mg daily
  • Cytoreduction (only if High risk)
    • 1 or more risk factors
26
Q

What drugs are used for cytoreduction?

A
  • Hydroxycarbamide
  • Interferon
  • Anagrelide
  • P32
27
Q

What is the prognosis for ET?

A
  • Overall excellent 20 year median survival
  • Risk of AML or Myelofibrosis
  • CALR mutated have lower thrombosis risk
28
Q

What is myelofibrosis?

A

The proliferation of an abnormal clone of haematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.

29
Q

What is the presentation of myelofibrosis?

A
  • Pancytopenia
  • B symptoms
  • Massive splenomegaly
30
Q

What investigations should you perform if you suspect myelofibrosis?

A
  • FBC and film

- Haematinics

31
Q

How is the diagnosis of myelofibrosis reached?

A
  • Blood film
  • Bone marrow results
  • JAK2 mutation 50%
  • CALR mutation 30%
32
Q

What are the possible causes of splenomegaly?

A
  • C Cancer
  • H Haematological - Myelofibrosis, CML
  • I Infection - Schistosomiasis,malaria
  • C Congestion - Liver disease / portal
  • A Autoimmune- haemolysis
  • G Glycogen storage disorders
  • O Other - Amyloid, etc
33
Q

What is the treatment for myelofibrosis?

A
  • Supportive care
  • JAK2 Inhibitors
  • Bone marrow Transplant
34
Q

What is the prognosis for myelofibrosis?

A
  • Poor

- Median survival 5 years

35
Q

What is the epidemiology of chronic myeloid leukaemia?

A
  • Rare: Aproximately 1 per 100,000 per year

-

36
Q

What are the characteristics of chronic myeloid leukaemia?

A
  • Leucocytosis+++
  • Leucoerythroblastic blood picture
  • Anaemia
  • Splenomegaly
37
Q

What are the symptoms of CML and their causes?

A
  • Abdominal discomfort: Splenomegaly
  • Abdominal pain: Splenic infarction
  • Fatigue: Anaemia, catabolic state
  • Venous occlusion: Retinal vein, DVT, priapism
  • Gout: Hyperuricaemia
38
Q

What is the treatment for CML?

A
  1. Chronic phase:
    - Low dose oral cytotoxic drugs (busulphan, hydroxycarbamide)
    - Interferon
  2. Acute leukaemic transformation/blast crisis
    - Myeloid and Lymphoid types
    - Intensive chemotherapy, poor outcome
  3. Allogeneic bone marrow transplantation
    - Curative in ~ 50% of patients
39
Q

What is Gleevec (imatinib)?

A

A small molecule specifically designed to block the active site in the bcr-abl tyrosine kinase.

40
Q

What is the cause of imatinib resistance?

A

Activating loop mutations in BCR-ABL confer resistance and loss of disease control.

41
Q

What new tyrosine kinase inhibitors are available?

A

Nilotinib and Dasatinib

42
Q

What are the main features of CML (ie a summary of key points)?

A
  • Pluripotent stem cell disorder
  • Defined by the t(9;22) translocation
  • Driven by BCR-ABL fusion tyrosine kinase
  • Chronic phase followed by acute transformation
  • Designer molecule treatment (imatinib) has proved highly successful
  • BCR-ABL mutations confer resistance to imatinib.

Clinical Pathology (65 decks)

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