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 and/or peripheral blood.”

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

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2
Q

Describe haematopoietic stem cells (HSCs).

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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3
Q

Describe progenitor cells.

A
  • can divide to produce many mature cells
  • but cannot divide indefinitely
  • eventually differentiate and mature
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4
Q

What is the difference between progenitor cells that are undifferentiated and ones that are committed?

A

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

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

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5
Q

How does leukaemia present?

A

It varies between types of leukaemia.

Typically you first present with symptoms due to loss of normal blood cell production:

  • abnormal bruising (commonest)
  • repeating abnormal infection
  • anaemia (sometimes)
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6
Q

Describe the aetiology of leukaemia.

A

Its exact cause is unclear. Most cases are not associated with any identifiable precipitating cause.

It is a polyetiologic disease, results as a combination of predisposing factors.

Leukaemia is 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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7
Q

List the genetic risk factors of 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
  • Chromosome aberrations:
    translocations (e.g. BCR-ABL in CML and PML-RAR in AML) or numerical disorders (e.g. trisomy 21-Down syndrome).
  • Inherited immune system problems
    (e. g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).
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8
Q

List some environmental risk factors of leukaemia.

A
  • Radiation exposure:
    to acute radiation accidents, atomic bomb survivors, etc.
  • Exposure to chemicals and chemotherapy:
    cancer chemotherapy with alkylating agents (e.g. Busulphan),
    e.g. industrial exposure to benzene, etc.
  • Immune system suppression:
    (e. g. after organ transplant)
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9
Q

List some lifestyle-related risk factors of some adult cancers.

A
  • smoking
  • drinking
  • excessive exposure to sun
  • overweight
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10
Q

What are some controvertial risk factors, with possible links to childhood leukaemia.

A
  • 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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11
Q

What are the 4 classifications of leukaemia?

A
  • Acute Lymphoid Leukaemia (ALL)
  • Acute Myeloid Leukaemia (AML)
  • Chronic Lymphoid Leukaemia (CLL)
  • Chronic Myeloid Leukaemia (CML)
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12
Q

Define acute leukaemia.

A

Acute disease: rapid onset and short but severe course.

  • it’s undifferentiated leukaemia
  • it’s characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)
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13
Q

Define chronic leukaemia.

A

Chronic disease: persisting over a long time.

  • it’s differentiated leukaemia
  • it’s characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
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14
Q

List some differences between acute and chronic leukaemia.

A

ACUTE:

  • age: affects manly children
  • onset: sudden
  • duration: weeks to months
  • WBC count: variable

CHRONIC:

  • age: affects middle age and elderly
  • onset: insidious
  • duration: years
  • WBC count: high
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15
Q

Why is acute leukaemia known as ‘undifferentiated leukaemia’?

A

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

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16
Q

What are some typical symptoms of leukaemia?

A

Typical symptoms occur due to bone marrow suppression:

  • Thrombocytopenia:
    purpura (bruising), epistaxis (nosebleed), bleeding from gums.
  • Neutropenia:
    Recurrent infections, fever.
  • Anaemia:
    lassitude (lack of energy), weakness, tiredness, shortness of breath.
17
Q

What are some different samples that can be taken to diagnose leukaemia?

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).
18
Q

What could we do with the samples after they’ve been obtained?

A

We would get molecular and pathophysiological characterisation.

This can be done by:

  • cytomorphology: staning and observing cells microscopically
  • immunophenotyping: using different antobodies that bind to different cell markers
  • Next Generation Sequencing (NGS): establish genetic and genomic profile of cells
  • flow cytometry: find the different types of cells in sample
  • Fluorescence in situ Hydridation (FISH): establish genetic and genomic profile of cells
19
Q

How does genetic profiling help with the molecular and pathophysiological characterisation of leukaemia?

A

Many chromosome translocations involve genes for transcription factors which control cell differentiation.

Chromosome abnormalities also help determine prognosis and response to treatment.

20
Q

Describe ALL.

A

ALL is acute lymphoblastic leukaemia.

  • it is the commonest cancer of childhood, 420 patients aged ≤24 diagnosed in the UK every year (overall still not very common).
  • it’s a cancer of immature lymphocytes (lymphoblasts or blasts).
  • CLASSIFICATION: it’s B-cell & T-cell leukaemia.
  • TREATMENT: chemotherapy (oral, intravenous, intramuscular, into the CSF (intrathecal chemo)); long term side effects are rare
  • OUTCOME: 5 year event-free survival (EFS) of 35% in 1972, 87% in 2010.
  • 1 out of 10 ALL patients relapse. However, there is remission in 50% percent of them after second chemotherapy treatment or bone marrow transplant.
  • Adult ALL has a poorer prognosis because the disease presents in different cells of origin and different oncogene mutations.
21
Q

Describe AML.

A

AML is acute myeloblastic leukaemia.

  • 70 children aged ≤16 y/o diagnosed in the UK every year (very rare).
  • itis a cancer of immature myeloid white blood cells.
  • CLASSIFICATION: based on FAB system (French-American-British): M0-M7.
    Based on stage of differentiation arrest e.g. AML M4 promyelocytic leukaemia
    And predominant cell type e.g. AML M6 erythroleukaemia
  • TREATMENT: chemotherapy (oral, intravenous, into the CSF (intrathecal chemo)) – monoclonal antibody (immunotherapy) +/- allogeneic bone marrow transplant.
  • OUTCOME: 5 year event-free survival (EFS) of 50-60%.
22
Q

Why is chronic leukaemia known as ‘differentiatre leukaemia’?

A

It’s characterised by an increased number of differentiated white blood cells - thus known as “differentiated leukaemia”.

23
Q

Describe CLL.

A

CLL is chronic lymphocytic leukaemia.

  • 3,800 new cases diagnosed in the UK every year (average diagnosis age= 70).
  • characterised by large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood
  • SYMPTOMS: recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly
  • TREATMENT: controlled by regular chemotherapy to reduce cell numbers.
  • OUTCOME: 5 year event-free survival (EFS) of 83%. Many patients survive >12 years.
24
Q

Describe CML.

A

CML is chronic myeloid/granulocytic leukamia.

  • 742 new cases diagnosed in the UK every year (peak rate = 85-89y/o).
  • characterised by large numbers of mature myeloid white blood cells.
  • SYMPTOMS: often asymptomatic and discovered through routine blood tests; anaemia; fatigue; breathlessness; splenomegaly; LU quadrant fullness or pain; weight loss; and other less common.
  • DIAGNOSIS: - Diagnosis: very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome or BCR-ABL gene rearrangements.
  • TREATMENT: controlled (but not cured) with chemotherapy (Imatinib).
  • OUTCOME: 5 year event-free survival (EFS) of 90%. Eventually progresses to accelerated phase and then blast crisis - will need allogeneic bone marrow transplant.
25
Q

How is the BCR-ABL oncogene made?

A

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

It is the balanced translocation between the long arms of chromosomes 9 and 22.

26
Q

Why is the BCR-ABL oncogene so important in leukaemia?

A

Under normal circumstances, BCR encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins, and ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition).

Together, the BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity.

27
Q

What does unregulated BCR-ACL tyrosine kinase activity cause?

A
  • proliferation of progenitor cells in the absence of growth factors
  • decreased apoptosis
  • decreased adhesion to bone marrow stroma
28
Q

What are some applications of the BCR-ABL oncogene?

A
  • DIAGNOSIS: 95% of cases of CML have a detectable Ph’ chromosome (isoform p210). p185/190-ALL.
  • detection of minimal residual disease.
  • THERAPY: drugs that specifically inhibit BCR-ABL. e.g. Imatinib (Glivec®, STI571). Cases negative for BCR-ABL require a different therapy.
29
Q

Generically, what are different types of cancer therapies?

A

1) Chemotherapy

2) Targeted therapy:
- tyrosine kinase inhibitors (TKIs)
- immunotherapy-monoclonal antibodies

3) Stem cells and bone marrow transplants (SCBMTs)

30
Q

Describe chemotherapy examples for AML and ALL.

A

Cytosine arabinoside (ara-C, cytarab) is used for the treatment of AML.

  • it’s a cytosine analogue
  • it interferes with deoxynucleotide synthesis
  • it prevents successful DNA replication

Vincristine is used for the treatment of ALL.

  • it binds to tubulin dimers
  • it acts by inhibiting microtubule formation
  • thus, it blocks the mitotic spindle
31
Q

Describe targeted therapy examples for CML.

A

Tyrosine kinase inhibitors (Imatinib (Glivec®, STI571)) are used for the treatment of CML.

  • they inhibit BCR-ABL, but not most other tyrosine kinases (so it’s quite specific)
  • they cause apoptosis of CML cells
  • they entered clinical trials in 1999, and were approved by NICE in 2003
  • however, remission is induced in more patients, with greater durability and fewer side effects
  • some patients do become drug resistant
32
Q

List some differences betweenchemotherapy and targeted therapy.

A

TARGETED THERAPIES:

  • designed to interact with their targets
  • acts on specific molecular targets associated with cancer
  • cytostatic (medicine that inhibits cell growth)
  • many are oral agents

CHEMOTHERAPY:

  • identified because they kill cells
  • act on all rapidly dividing cells (cancerous and normal)
  • cytotoxic (toxic to living cells)
  • mainly intravenous, some oral agents
33
Q

Describe SCBMTs.

A

SCBMTs are stem cells and bone marrow transplants.

It’s used mainly for treatment of AML.
Haematopoiesis is reconstituted from the quiescent stem cell pool.

There are two types: allogenic and autologous.