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Haematology > Introduction to Leukaemias > Flashcards

Introduction to Leukaemias Flashcards

1
Q

Define leukaemia

A

(“leuk” = white, “emia” = blood)

Malignant disorders of haematopoietic stem cells characteristically associated with increased no. of white cells in bone marrow or/and peripheral blood

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2
Q

Give examples of leukocytes

A

Leukocytes consist of many different types of cells including, neutrophils, monocytes, lymphocytes, basophils etc.

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3
Q

What is haematopoiesis?

A

Process of blood cell formation

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4
Q

What are the 3 lineages of blood cells?

A

Blood cells are differentiated into 3 different lineages:

  • Erythrocytes (RBCs)
  • Lymphoid (T/B lymphocytes)
  • Myeloid (innate immune response + blood clotting)
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5
Q

Describe features of haematopoietic stem cells

A

Pluripotent- can give rise to cells of every blood lineage

Self maintaining- a stem cell can divide to produce more stem cells

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6
Q

Describe the development of progenitor cells

A

Can divide to produce many mature cells
But cannot divide indefinitely

Eventually differentiate and mature

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7
Q

What are multipotent progenitors?

A

Undifferentiated (multipotent):

Can’t tell difference between progenitors morphologically as they show no characteristics of mature cells

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8
Q

What are unipotent progenitors?

A

Committed (unipotent):

already committed to what they will become when they generate mature cells

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9
Q

Where does leukaemia stem from?

A

It is a clonal disease- all the malignant cells derive from a single mutant stem cell.

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10
Q

Outline the incidence rates of leukaemias

A

31% childhood cases

38% of leukaemia cancer cases occur among people aged 75+

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11
Q

What are the common symptoms of leukaemia?

A

Varies between types of leukaemia

  • Abnormal bruising-commonest
  • Repeating abnormal infection
  • Sometimes anaemia
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12
Q

What causes the presentation of leukaemia symptoms?

A

Typically first presents with symptoms due to loss of normal blood cell production

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13
Q

What techniques can we use to characterise leukaemia molecularly and pathophysiologically?

A
  • Cytomorphology
  • Immunophenotyping
  • NGS
  • Fluorescence in situ hybridisation (FISH)
  • Flow cytometry
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14
Q

What causes leukaemia?

A

Exact cause is unclear. Combination of predisposing factors:

  • Genetic risk factors
  • Lifestyle related risk factors
  • Uncertain, unproved or controversial factors
  • Environmental factors
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15
Q

What is the genetic risk of inheriting leukaemia?

A

NOT usually hereditary (except for some cases of Chronic Lymphocytic Leukaemia (CLL))

Some rare genetic diseases may predispose to leukaemia, e.g. Fanconi’s anaemia, Down’s syndrome

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16
Q

What are the acquired genetic risk factors of leukaemia?

A
  • Oncogene/TSG mutations
  • Chromosome aberrations
  • Inherited immune problems
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17
Q

What kind of mutations can lead to leukaemia?

A

Gene mutations of oncogenes (activation) or/and tumour suppressors (inactivation)

Can involve genes common to other malignancies (TP53-Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia

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18
Q

Describe the chromosome aberrations causing leukaemia

A
  • Translocations (e.g. BCR-ABL in CML).

- Numerical disorders (e.g. trisomy 21-Down syndrome).

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19
Q

Which inherited immune system disorders predispose to leukaemia?

A

e.g. Ataxia-telangiectasia

and Wiskott-Aldrich syndrome

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20
Q

What are the environmental risk factors of leukaemia?

A
  • Radiation exposure
  • Chemicals and chemotherapy
  • Immune system suppression
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21
Q

How may patients be exposed to radiation?

A
  • acute radiation accidents

- atomic bomb survivors

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22
Q

Describe the chemicals and chemotherapy causing leukaemia?

A
  • Cancer chemotherapy with alkylating agents (e.g. Busulphan)
  • Industrial exposure to benzene
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23
Q

Why may patient immune system be suppressed?

A

e.g. After organ transplant

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24
Q

What are the lifestyle related risk factors for adult cancers?

A

Smoking
Drinking
Excessive exposure to sun
Overweight

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25
Q

What are the controversial risk factors of childhood leukaemia?

A 
Infections early in life
Exposure to electromagnetic fields
Mother’s age when child is born
Parent’s smoking history
Nuclear power stations
Foetal exposure to hormones
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26
Q

How is leukaemia classified?

A

Acute disease
- rapid onset and short but severe course.

Chronic disease
- persisting over a long time.

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27
Q

Describe acute leukaemia

A

Undifferentiated leukaemia

Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)

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28
Q

How is chronic leukaemia characterised?

A

Differentiated leukaemia

Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)

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29
Q

Describe the epidemiology of acute leukaemia

A

Mainly children affected

Sudden onset
Lasts weeks - months

WBC count is variable

30
Q

Outline the chronic leukaemia pidemiology

A

Affects middle aged - elderly

Insidious onset
Lasting years

High WBC count

31
Q

Which cells characterise acute leukaemia?

A

Characterized by large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood

Hard to differ between two cells due to similar morphology

32
Q

Describe normal maturation of blood cells

A

Blood cells undergo differentiation and mature

At some point differentiated cells die via different processes (necrosis / apoptosis)

33
Q

How does maturation differ in acute leukaemia?

A

There is an arrest in blast cell pool

Cells unable to differentiate and mature
⇒ lack of mature cells in blood
⇒ excess blast cells

34
Q

Why do we see high numbers of immature cells in acute leukaemia?

A

Balance between new cells and cell death is broken

High levels of proliferation in blast cells and lack of mature cells ⇒ causes acute leukaemia

35
Q

What causes the acute leukaemia symptoms?

A

Typical symptoms due to bone marrow suppression

36
Q

Outline the acute leukaemia symptoms

A

Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.

Neutropenia: Recurrent infections, fever.

Anaemia: lassitude, weakness, tiredness, shortness of breath.

37
Q

What are the 3 methods of diagnosis of leukaemia?

A
  • Peripheral blood blasts test (PB)
  • Bone marrow test/biopsy (BM)
  • Lumbar puncture
38
Q

How does a peripheral blood blasts test diagnose leukaemia?

A

Checks for the presence of blasts and cytopenia

> 30% blasts are suspected of acute leukaemia

39
Q

When is Lumbar puncture used?

A

To determine if leukemia has spread to CSF

40
Q

How is a bone marrow test carried out?

A

taken from pelvic bone and results compared with PB

41
Q

Describe the prevalence of acute lymphoblastic leukaemia (ALL)

A

Commonest cancer of childhood (overall still not very common)

42
Q

What is the origin of acute lymphoblastic leukaemia (ALL)?

A

Cancer of immature lymphocytes (lymphoblasts or blasts)

43
Q

How is ALL classified?

A

B-cell & T-cell leukaemia

44
Q

How is ALL treated?

A

Chemotherapy. Long term side effects are rare

45
Q

What is the general outcome of ALL treatment?

A

5 year event-free survival (EFS) of 87% in 2010

1 out of 10 ALL patients relapse

Remission in 50% percent of them after second chemotherapy treatment or bone marrow transplant.

46
Q

Why is Adult ALL prognosis poorer than in children?

A

Disease presents different cell of origin and different oncogene mutations

47
Q

Outline the prevalence of acute myeloblastic leukaemia (AML)

A

70 children aged ≤16 y/o diagnosed in the UK every year (very rare)

48
Q

What is the origin of acute myeloblastic leukaemia (AML)?

A

Cancer of immature myeloid white blood cells.

49
Q

What is the treatment available for AML?

A

Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant.

50
Q

Describe the prognosis of AML patients

A

5 year event-free survival (EFS) of 50-60%

51
Q

Describe the prevalence of chronic lymphoblastic leukaemia (CLL)

A

3,800 new cases diagnosed in UK annually (average diagnosis age= 70)

52
Q

What is the origin of chronic lymphoblastic leukaemia?

A

Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood

53
Q

What are the symptoms of CLL?

A
  • Recurrent infections due to neutropenia + lymphocyte function suppression
  • Anaemia
  • Thrombocytopenia
  • Lymph node enlargement
  • Hepatosplenomegaly.
54
Q

What is the available treatment for CLL?

A

Regular chemotherapy to reduce cell numbers

55
Q

What is the prognosis of CLL?

A

5 year event-free survival (EFS) of 83%. Many patients survive >12 years

56
Q

What is the prevalence of chronic myeloid leukaemia (CML)?

A

742 new cases diagnosed in UK every year (peak rate = 85-89y/o)

57
Q

What is the origin of chronic myeloid leukaemia (CML)?

A

Large numbers of mature myeloid white blood cells

58
Q

What are the symptoms of CML?

A

Often asymptomatic and discovered through routine blood tests

59
Q

How is CML diagnosed?

A

Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome

60
Q

What treatments are there for CML?

A

Targeted therapy: Imatinib*

61
Q

Describe the prognosis of CML patients

A

5 year event-free survival (EFS) of 90%

Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant

62
Q

What is the defining chracteristic of CML?

A

95% of cases of CML have a detectable Philadelphia chromosome (Ph’)

63
Q

What causes the presence of the philadelphia chromosome?

A

This is the result of a balanced translocation in t(9;22)(q34;q11)

64
Q

Describe the translocation producing the philadelphia chromosome

A

Translocation brings together 2 small pieces of chromosomes that form a new smaller chromosome BCR-ABL ‘philadelphia’ chromosome

65
Q

Where is the BCR gene normally found?

A

BCR is present in normal Chr.22

66
Q

Where is ABL gene normally located?

A

ABL present in an oncogene on Chr.9

67
Q

What induces the translocation to occur?

A

When the two chromosomes are in close proximity of one another, BCL promoter starts regulating ABL proto-oncogene expression

68
Q

What is the consequence of philadelphia chromosome formation?

A

BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity

69
Q

What is the effect of the BCR-ABL unregulated tyrosine kinase activity?

A
  • Proliferation of progenitor cells in absence of GFs
  • Decreased apoptosis
  • Decreased adhesion to bone marrow stroma
70
Q

What is imatinib?

A

Small molecule inhibitor that targets Abl –CML treatment

71
Q

What is the role of imatinib?

A
  • Inhibits BCR-ABL but not most other tyrosine kinases
  • Causes apoptosis of CML cells
  • Remission induced in more patients, with greater durability and fewer side effects
  • Some patients become drug resistant

Haematology (8 decks)

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