Introduction to Leukaemia

Question 1

What is leukaemia

Answer 1

Malignant disorders of haematopoietic stem cells characteristically associated with an increased number of white cells in bone marrow or/and peripheral blood

Question 2

What are haematopoetic stem cells

Answer 2

Multipotent- can give rise to cells of every blood lineage

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

Question 3

What are progenitor cells

Answer 3

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

Question 4

What is the difference between undifferentiated and committed progenitor cells

Answer 4

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

Question 5

How does leukaemia arise

Answer 5

It is a clonal disease- all the malignant cells derive from a single mutant stem cell
It form sit sown progenitor cells

Question 6

What is the incidence of leukaemia

Answer 6

The higher incidence rate in the elderly, increases with ageing

Childhood cases are rising now at 31%

Question 7

what are the initial symptoms of leukaemia

Answer 7

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

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

Question 8

How can we clinically diagnose leukaemia and what does each test show

Answer 8

• 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).

Question 9

How can we diagnose leukaemia pathologically

Answer 9

• Cytomorphology
• Immunophenotyping
• Next-generation sequencing
• Flow cytometry
• Fluorescence in situ hybridation (FISH)

Question 10

What are the predisposing factors for leukaemia

Answer 10

• Genetic risk factors
• Lifestyle-related
• Uncertain, unproven or controversial factors
• Environmental risk factors

Question 11

How can genetic risk factors cause disease

Answer 11

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

Question 12

what genetic risk factors that cause leukaemia

Answer 12

• Gene mutations involving oncogenes (activation) or/and tumour suppressors (inactivation).
• Chromosome aberrations:
  Translocations (e.g. BCR-ABL in CML).
  Numerical disorders (e.g. trisomy 21-Down syndrome).
• Inherited immune system problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).

Question 13

what environmental risk factors that cause leukaemia

Answer 13

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

Question 14

what lifestyle-related risk factors that cause leukaemia

Answer 14

• Smoking
• Drinking
• Excessive exposure to sun
• Overweight

Question 15

what controversial risk factors that cause leukaemia

Answer 15

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

Question 16

What are the 4 types in leukaemia classifaction

Answer 16

• Acute lymphoid leukaemia
• Chronic lymphoid leukaemia
• Acute myeloid leukaemia
• Chronic myeloid leukaemia

Question 17

Describe acute leukaemia

Answer 17

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)

Question 18

Describe chronic leukaemia

Answer 18

Chronic disease: persisting over a long time.

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

Question 19

Compare acute and chronic leukaemia

Answer 19

Acute:

• Mainly in children
• Sudden onset
• Weeks to months duration
• Variable WBC count

Chronic:

• Mainly in middle age and elderly
• Insidious onset
• Years duration
• High WBC count

Question 20

What is the incidence rate of acute leukaemia

Answer 20

• 31% of cancer in children is leukaemia
• Of that 75% is acute lymphoid and 25% are acute myeloid

Question 21

What is acute leukaemia characterised by

Answer 21

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

Question 22

What are the typical symptoms of acute leukaemia due to bone marrow suppression

Answer 22

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

Question 23

How can we treat acute leukaemia

Answer 23

Lymphoblastic:

• Chemotherapy. Long-term side effects are rare

Myeloblastic:

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

Question 24

What is chronic leukaemia characterised by

Answer 24

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

Question 25

What are the symptoms of chronic lymphocytic leukaemia

Answer 25

Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly

Question 26

What are the symptoms of chronic Myeloid/granulocytic leukaemia

Answer 26

Often asymptomatic and discovered through routine blood tests

Question 27

How can we treat chronic lymphocytic leukaemia

Answer 27

Regular chemotherapy to reduce cell numbers

Question 28

How can we treat chronic Myeloid/granulocytic leukaemia?

Answer 28

Targeted therapy: Imatinib

Question 29

What is the BCR-ABL oncogene

Answer 29

• 95% of cases of CML have a detectable Philadelphia chromosome (Ph’)
• There is a break in chromosomes 9 and 22
• The broken sections swap and fuse on the other chromosome
• This brings the ABL and BCR genes together on chromosome 22 causing the Philadelphia chromosome

Question 30

How does this oncogenes cause CML

Answer 30

• 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

Unregulated BCR-ABL= tyrosine kinase activity that causes:
- Proliferation of progenitor cells in the absence of growth factors
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma

Question 31

What are the applications of the BCR-ABL oncogene

Answer 31

• 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

Question 32

How can targeted therapy be used in treating CML

Answer 32

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

• Diagnosis: 95% of cases of CML have a detectable Ph’ chromosome.
• Used for detection of minimal residual disease
• Remission induced in more patients,
  with greater durability and fewer
  side effects
• Some patients become drug resistant

Question 33

How has targeted therapy worked in CML

Answer 33

• Positive outcomes also in the treatment of gastrointestinal stromal tumours and SCLC.