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Fundamentals of P > Introduction to Leukaemias > Flashcards

Introduction to Leukaemias Flashcards

1
Q

Define leukaemia

A

Leukaemia (“leuk” = white, “emia” = blood): “malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood.”

can be classified according to cell linage (lymphoid or myeloid) and degree of terminal differentiation (acute or chronic).

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2
Q

Pluripotent definition

A

Pluripotent- can give rise to cells of every blood lineage

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3
Q

Self maintaining

A

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

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4
Q

Features of progenitor cells

A

Can divide to produce many mature cells
But cannot divide indefinitely
Eventually differentiate and mature

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5
Q

Compare unipotent w/multipotent

A

Progenitor cells- Undifferentiated (multipotent): you cannot tell the difference between them morphologically because they do not show the characteristics of mature cells.

Progenitor cells- Committed (unipotent): already committed as to what they will become when they generate mature cells

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6
Q

Leukaemia derived from

A
  • It is a clonal disease- all the malignant cells derive from a single mutant stem cell.
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7
Q

Describe presentation of leukaemia

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

Abnormal bruising-commonest
Repeating abnormal infection
Sometimes anaemia

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8
Q

Describe diagnosis of leukaemia

A

Molecular and pathophysiological characterisation

Cytomorphology
Immunophenotyping
Next Generation Sequencing (NGS)
Flow cytometry
Fluorescence in situ Hybridation (FISH)
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9
Q

Describe aetiology of leukaemia

A 
Genetic risk factors
Uncertain, unproven or controversial factors
Environmental 
risk factors
Lifestyle-related risk factors
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10
Q

Explain genetic factors of 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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11
Q

Describe the effect of gene mutations on leukaemia

A

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

  • Involving genes common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia.
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12
Q

Describe the effect of chromosome abberations on leukaemia

A

Chromosome aberrations:
Translocations (e.g. BCR-ABL in CML).
Numerical disorders (e.g. trisomy 21-Down syndrome).

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13
Q

Describe the effect of immune system problems on leukaemia

A

Inherited immune system problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).

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14
Q

Describe the environmental risk factors for leukaemia

A

Radiation exposure

  • acute radiation accidents
  • atomic bomb survivors

Exposure to chemicals and chemotherapy

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

Immune system suppression
e.g. After organ transplant

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15
Q

Describe lifestyle-related risk factors for leukaemia

A 
For some adult cancers:
Smoking
Drinking
Excessive exposure to sun
Overweight
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16
Q

Describe the controversial risk factors for leukaemia

A

(Possible link to childhood leukaemia)

Exposure to electromagnetic fields
Infections early in life
Mother’s age when child is born
Nuclear power stations
Parent’s smoking history
Foetal exposure to hormones
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17
Q

Define an acute disease

A

Acute disease: rapid onset and short but severe course

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18
Q

Describe features of

acute leukaemia

A

Undifferentiated leukaemia

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

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19
Q

Define a chronic disease

A

Chronic disease: persisting over a long time

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20
Q

Describe features of

chronic leukaemia

A

Chronic leukaemia:
Differentiated leukaemia
Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)

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21
Q

Describe classification of leukaemia

A

LYMPHOID:
Acute = Acute Lymphoblastic Leukaemia (ALL)
Chronic = Chronic Lymphocytic Leukaemia
(CLL)

MYELOID:
Acute = Acute Myeloblastic Leukaemia (AML)
Chronic = Chronic Granulocytic Leukaemia
(CML)

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22
Q

Compare acute vs chronic leukaemia

A

Acute first then chronic

Age = children vs middle/elderly
Onset = sudden vs insidious
Duration = weeks/months vs years
White Blood Cells (WBC) count = variable vs high

23
Q

Describe how you can characterize acute leukaemia

A

Characterized by a large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- “undifferentiated leukaemia”.

= maturation arrest

24
Q

Acute leukaemia symptoms

A

Typical symptoms due to bone marrow suppression:

Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.
Neutropenia: Recurrent infections, fever.
Anaemia: lassitude, weakness, tiredness, shortness of breath.

25
Q

Acute leukaemia diagnosis

A

Peripheral blood blasts test (PB): to check for presence of blasts and cytopenia. >30% blasts are suspected of acute leukaemia.

Bone marrow test/biopsy (BM): taken from pelvic bone and results compared with PB.

Lumbar puncture: to determine if the leukemia has spread to the cerebral spinal fluid (CSF).

26
Q

Describe prevalence of acute lymphoblastic leukaemia (ALL)

A
  • Prevalence: Commonest cancer of childhood (overall still not very common).
27
Q

Describe origin of acute lymphoblastic leukaemia (ALL)

A
  • Origin: Cancer of immature lymphocytes (lymphoblasts or blasts)
28
Q

Describe classification of ALL

A
  • Classification: B-cell & T-cell leukaemia.
29
Q

Describe treatment of ALL

A
  • Treatment: Chemotherapy. Long term side effects are rare.
30
Q

Describe outcome of ALL

A
  • Outcome: 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.
  • Adult ALL- poorer prognosis because disease presents different cell of origin and different oncogene mutations.
31
Q

Describe prevalence of acute myeloblastic leukaemia (AML)

A
  • Prevalence: 70 children aged ≤16 y/o diagnosed in the UK every year (very rare).
32
Q

Describe origin of AML

A
  • Origin: Cancer of immature myeloid white blood cells.
33
Q

Describe classification of AML

A
  • Classification: based on FAB system (French-American-British): M0-M7.
34
Q

Describe treatment of AML

A
  • Treatment: Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant.
35
Q

Describe outcome of AML

A
  • Outcome: 5 year event-free survival (EFS) of 50-60%.
36
Q

Describe how you can characterise chronic leukaemia

A

Characterised by an increase number of differentiated cells -“differentiated leukaemia”.

37
Q

Describe prevalence of chronic lymphocytic leukaemia (CLL)

A
  • Prevalence: 3,800 new cases diagnosed in the UK every year (average diagnosis age= 70).
38
Q

Describe origin of CLL

A
  • Origin: Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood.
39
Q

Describe symptoms of CLL

A
  • Symptoms: Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly.
40
Q

Describe treatment of CLL

A
  • Treatment: Regular chemotherapy to reduce cell numbers.
41
Q

Describe outcome of CLL

A
  • Outcome: 5 year event-free survival (EFS) of 83%. Many patients survive >12 years.
42
Q

Describe prevalence of chornic myeloid leukaemia

A
  • Prevalence: 742 new cases diagnosed in the UK every year (peak rate = 85-89y/o).
43
Q

Describe origin of CML

A
  • Origin: Large numbers of mature myeloid white blood cells.
44
Q

CML - symptoms

A
  • Symptoms: Often asymptomatic and discovered through routine blood tests.
45
Q

CML - diagnosis

A
  • Diagnosis: Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome.
46
Q

CML - treatment

A
  • Treatment: Targeted therapy: Imatinib.
47
Q

CML - outcome

A
  • Outcome: 5 year event-free survival (EFS) of 90%. Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant.
48
Q

CML - feature of most cases

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

Balanced translocation t(9;22)(q34;q11)

49
Q

BCR-ABL Oncogene structure

A

BCR: encodes a protein that needs to be continuously active

ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)

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

50
Q
  • Unregulated BCR-ABL= tyrosine kinase activity that causes:
A

Proliferation of progenitor cells in the absence of growth factors
Decreased apoptosis
Decreased adhesion to bone marrow stroma

51
Q

BCR-ABL Oncogene - applications

A

Diagnosis: 95% of cases of CML have a detectable Ph’ chromosome.

Detection of minimal residual disease.

Therapy: Drugs that specifically inhibit BCR-ABL. e.g. Imatinib (Glivec®, STI571). Cases negative for BCR-ABL require different therapy

52
Q

BCR-ABL Oncogene - targeted therapy

A

Imatinib (Glivec®, STI571) is a small molecule inhibitor that targets Abl –CML treatment

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

53
Q

Targeted therapy vs chemotherapy

A 
Targeted Therapies:
Design to interact with their targets
Act on specific molecular targets associated with cancer
Cytostatic
Many are oral agents
Chemotherapy:
Identified because they kill cells
Act on all rapidly dividing cells (cancerous and normal)
Cytotoxic
Mainly intravenous, some oral agents

Fundamentals of P (62 decks)

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