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Clinical Pathology > 19. Intro to Leukaemias > Flashcards

19. Intro to Leukaemias Flashcards

1
Q

What is 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.”
  • Higher number of WBCs
  • There is distorted proliferation and development of leukocytes and their precursors 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

What are 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

What are progenitors cells?

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

There are 2 types:

  • UNDIFFERENTIATED:
  • (multipotent): you cannot tell the difference between them morphologically because they do not show the characteristics of mature cells.
  • DIFFERENTIATED:
  • (unipotent): already committed as to what they will become when they generate mature cells
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4
Q

Leukaemia is a clonal disease. Expand,

A
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5
Q

What is the presentation of leukemia?

A
  • Varies between types of leukaemia
  • 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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6
Q

What is the aetiology of leukaemia?

A
  • Exact cause is unclear. Most cases not associated with any identifiable precipitating cause.
  • Polyetiologic disease: combination of predisposing factors.
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7
Q

What are genetic risk factors of leukaemia?

A

1) 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.

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

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

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8
Q

What are the environmental risk factors associated with leukaemia?

A

1) Radiation exposure
- acute radiation accidents
- atomic bomb survivors

2) Exposure to chemicals and chemotherapy
- Cancer chemotherapy with alkylating agents (e.g. Busulphan)
- e.g. Industrial exposure to benzene

3) Immune system suppression
- e.g. After organ transplant

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9
Q

What are the lifestyle-related risk factors associated with leukaemia?

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

What are the possible link to childhood leukaemia?

A
  • exposures to electromagnetic fields
  • infections early in life
  • mother’s age when child is born
  • nuclear power stations
  • parents smoking history
  • foetal exposure to hormones
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11
Q

Expand on acute disease and acute leukaemia.

A
  • Acute disease: rapid onset and short but severe course.
  • Acute leukaemia:
  • Undifferentiated leukaemia
  • Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)
  • and so can be called:
  • Acute LymphoBLASTIC Leukaemia (ALL)
  • Acute Myeloblastic Leukaemia (AML)
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12
Q

Expand on chronic disease and chronic leukaemia.

A
  • Chronic disease: persisting over a long time.
  • Chronic leukaemia:
  • Differentiated leukaemia
  • Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)

*and so can be called:
- Chronic LymphoCYTIC Leukaemia
(CLL)
- Chronic GRANULOCYTIC Leukaemia
(CML)

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13
Q

What are the main differences between acute and chronic?

A
  • AGE: ~ acute is mainly in children, and chronic in middle age and eldery
  • ONSET ~ acute is sudden, and chronic is insidious
  • DURATION ~ acute is weeks-months, and chronic is years
  • WBC COUNT ~ acute is variable, and chronic is high
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14
Q

What is acute leukaemia characterised by?

A

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

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15
Q

What are the typical symptoms of acute leukaemia?

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.

ALSO:

  • night sweats
  • swelling of lymph nodes
  • spleen enlargement
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16
Q

What is the diagnosis of acute 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).
17
Q

Methods of molecular and pathophysiological characterisation.

A
  1. Cytomorphology ~ Staining and observation of cells microscopically
  2. Immunophenotyping~Use different antibodies that attach to different cell markers
  3. Next Generation Sequencing (NGS)
  4. Fluorescence in situ Hybridation (FISH)
    ~Can establish genetic and genomic profile of the cells
  5. Flow cytometry ~ Find different types of cells in sample
18
Q

Molecular and pathophysiological characterisation of acute leukaemia.

A
  • Many chromosome translocations
    • Involve genes for transcription factors
  • Chromosome abnormalities also help determine prognosis and response to treatment
19
Q

What is the best way to differentiate between ALL and AML?

A
  • As the symptoms are the same ~ best way to differentiate between ALL and AML is by performing all the diagnostic assays (especially bone biopsy)
20
Q

What is chronic leukaemia characterised by?

A

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

21
Q

Summary of CLL

A
  • 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.
22
Q

Summary of CML

A
  • 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: 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.- allogeneic bone marrow transplant.
23
Q

Expand on BCR-ABL oncogene.

A
  • Balanced translocation t(9;22)(q34;q11) ~ between the long arm of chromosome 9 and 22.
  • p210 Bcr-Abl is found in CML
  • p185 Bcr-Abl is found in ALL
24
Q

Function of Bcr and Abl, and then the combined function.

A

NORMALLY:

  • BCR: encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins
  • ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
  • BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity ~ when combined, the ABL bit loses its promoter and the beginning bit where it is regulated. – it will also lose its auto-inhibition and will be controlled by the first part of the BCR gene.
    • upregulated protein kinase activity
25
Q

What does unregulated BCR-ABL tyrosine kinase activity cause?

A
  • Proliferation of progenitor cells in the absence of growth factors
  • Decreased apoptosis
  • Decreased adhesion to bone marrow stroma
26
Q

Application of BCR-ABL oncogene

A
  • 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
27
Q

Therapies

A
  • Chemotherapy
  • Targeted therapy - tyrosine kinase inhibitors (TKIs), immunotherapy-monoclonal antibodies
  • Stem cells and bone marrow transplants (SCBMTs)
28
Q

Difference between targeted therapies and chemotherapy

A
  • Targeted therapies is designed to interact with their targets - but chemotherapy is identified because they kill cells.
  • Targeted therapies act on specific molecular targets associated with cancer - but chemotherapy acts on ALL rapidly dividing cells (cancerous and normal)
  • Targeted therapies are cytostatic - but chemotherapy is cytotoxic
  • Targeted therapies treatment involves many oral agents - but chemotherapy treatment involves mainly intravenous, some oral agents.
29
Q

Expand on chemotherapy.

A

Cytosine arabinoside (ara-C, cytarab) for treatment of AML

  • Cytosine analogue.
  • Interferes with deoxynucleotide synthesis.
  • Prevents successful DNA replication.

Vincristine for treatment of ALL

  • Binds to tubulin dimers.
  • Inhibiting microtubule formation.
  • So blocking the mitotic spindle.
30
Q

Expand on targeted therapy

A

Tyrosine kinase inhibitors (Imatinib (Glivec®, STI571)) for treatment of CML

  • Inhibits BCR-ABL but not most other tyrosine kinases
  • Causes apoptosis of CML cells
  • Entered clinical trials 1999, approved by NICE 2003
  • Remission induced in more patients, with greater durability and fewer side effects
  • Some patients become drug resistant
31
Q

Expand on stem cells andbone marrow transplants (SCBMTs)

A
  • Used mainly for treatment of AML.
  • Haematopoiesis is reconstituted from the quiescent stem cell pool (allogenic and autologous)
  • AML- >80% long term remission in young adults with aggressive treatment.
  • Elderly unable to tolerate aggressive chemotherapy or SCBMT.
32
Q

What is the difference between the allogenic and the autologous stem cell transplant

A
  • In allogeneic, the stem cells are from a donor.

- In autologous, the stem cells are from self.

Clinical Pathology (62 decks)

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