Introduction To Leukaemia

Question 1

Define Leukaemia

Answer 1

A clonal disease where all the malignant cells derive from a signal mutant stem cell

Question 2

What are haematopoeitic stem cells (HSCs)?

Answer 2

Multi-potent - 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 are undifferentiated (Multipotent) progenitor cells?

Answer 4

You cannot tell the difference between them and differentiated cells morphologically because they do not show characteristics of mature cells

Question 5

What are committed progenitor cells (unipotent)?

Answer 5

Already committed as to what they will become when they generate mature cells

Question 6

What are the first symptoms present in leukaemia?

Answer 6

Abnormal bruising commonest

Repeating abnormal infection

Sometimes anaemia

• caused by loss of normal blood cell production

Question 7

How is leukaemia diagnosed?

Answer 7

Peripheral blood blast test (PB)
- to check for present of blast and cyopeinia.
- >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 leukaemia has spread to the cerebral spinal fluid (CSF)

Question 8

How is leukaemia characterised molecularly and pathophysiologically?

Answer 8

Cytomorphology

Immunophenotyping

Next generation sequencing (NGS)

Flow cytometry

Fluorescence in situ hybridisation (FISH)

Question 9

What is the aetiology (cause) of leukaemia?

Answer 9

Exact cause if unclear but thought to be a combination of predisposing factors

Genetic risk + environmental factors

Question 10

Describe the genetic risk factors of leukaemia

Answer 10

NOT usually hereditary (except for some cases of chronic lymphocytic leukaemia (CLL)

Some rare genetic diseases may predispose to leukaemia (eg. Down syndrome)

Gene mutations involving oncogene activation or/and tumour suppressor deactivation (could involve genes common to other malignancies or specific to leukaemia)

Chromosome aberrations (translocations or numerical chromosomal disorders)

Inherited immune system problems (eg. Ataxia)

Question 11

Describe the environmental risk factors of leukaemia.

Answer 11

Radiation exposure
- acute radiation accidents
- atomic bomb survivors

Exposure to chemicals and chemotherapy
- cancer chemotherapy with alkylating agents
- industrial exposure to benzene

Immune system suppression
- after organ transplant

Question 12

Describe the lifestyle related risk factors of leukaemia in adults

Answer 12

Smoking

Drinking

Excessive exposure to sun

Overweight

Question 13

Describe the controversial risk factors of childhood leukaemia

Answer 13

Exposure to electromagnetic fields

Infections early in life

Mothers age when child is born

Nuclear power stations

Parents smoking history

Foetal exposure to hormones

Question 14

What are the 2 types of acute leukaemia?

Answer 14

Acute lymphoid leukaemia (ALL)

Acute myeloid leukaemia (AML)

Question 15

What are the 2 types of chronic leukaemia?

Answer 15

Chronic lymphoid leukaemia (CLL)

Chronic Myeloid Leukaemia (CML)

Question 16

What is a acute disease?

Answer 16

Rapid onset and short but serevre course

Question 17

What is acute leukaemia?

Answer 17

Undifferentiated leukaemia

Characterised by uncontrolled clonal and accumulation of immature white blood cells (myoblast and lymphoblast) in bone marrow and blood.

Question 18

What is chronic leukaemia?

Answer 18

Differentiated leukaemia

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

Question 19

How is a patient with acute leukaemia classified?

Answer 19

Age is Mainly children

Sudden onset

Duration of weeks to months

WBC count variable

Question 20

How is a patient with chronic leukaemia classified?

Answer 20

Age is middle aged and elderly

Onset insidious

Duration is years

WBC count is high

Question 21

What are the typical symptoms of acute leukaemia?

Answer 21

Due to bone marrow suppression

Thrombocytopenia - purpura (bruising), epistaxis (nosebleed), bleeding from gums

Neutropenia - recurrent infections, fever

Anaemia: lassitude, weakness, tiredness, shortness of breath

Question 22

What is acute lymphoblastic leukaemia (ALL)?

Answer 22

Prevalence: Commonest cancer of childhood

Origin: cancer of immature lymphocytes

Classification: B cell and T cell leukaemia

Treatment: chemotherapy. Long term side effects are rare

Outcome: 1/10 of ALL patients relapse. Remission is 50% after the second chemotherapy treatment or bone marrow transplant.

Question 23

What is acute myeloblastic leukaemia (AML)?

Answer 23

Prevalence: 70 children < 16 years old diagnosed every year in the UK. (Very rare)

Origin: cancer of immature myeloid white blood cells

Classification: based on FAB system (French American British)

Treatment: chemotherapy, monoclonal antibodies, allogenic bone marrow transplant.

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

Question 24

What is chronic lymphocytic leukaemia?

Answer 24

Prevalence: 3800 new cases in uk every year

Origin: large numbers of mature lymphocytes in bone marrow and peripheral blood

Symptoms: recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, lymph node enlargement, hepatosplenomegaly

Treatment: Regular chemotherapy to reduce cell numbers

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

Question 25

What is chronic Myeloid leukaemia (CML)?

Answer 25

Prevalence: 742 new cases diagnosed in the UK every year

Origin: large numbers of mature myeloid white blood cells

Symptoms: often asymptomatic and discovered through routine blood tests

Diagnosis: very high white cells count in blood and bone marrow, presence of Philadelphia chromosome

Treatment: targeted therapy

Outcome: EFS of 90%. Eventually progress to accelerated phase and then blast crisis.

Question 26

What is the BCR ABL oncogene?

Answer 26

A gene which is usually present on chromosome 22.

After translocation of chromosome 22 and chromosome 9, the Philadelphia chromosome forms.

95% of cases of CML detect Philadelphia chromosome

Question 27

What is the function of BCR?

Answer 27

A proto oncogene that Encodes a protein that needs to be continuously active

Question 28

What is the function of ABL?

Answer 28

A proto-oncogene that Encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)

Question 29

What is the function of the BCR-ABL protien?

Answer 29

Has constitutive protein tyrosine kinase activity

Question 30

What are the consequences of unregulated BCR-ABL in the bone marrow?

Answer 30

Tyrosine kinase activity causes:

• proliferation of progenitor cells in the abscence of growth factors
• decreased apoptosis
• decreased adhesion to bone marrow stroma

Question 31

How can the BCR ABL oncogene be applied?

Answer 31

In diagnosis- 95% of cases of CML have a detectable Ph chromosome.

Detection of minimal residue disease

Therapy - Drugs that specifically inhibit BCR-ABL

Question 32

How is targeted therapy used to treat leukaemia?

Answer 32

Imatinib is a small molecule inhibitor that targets specifically Abi-CML treatment

Remission induced in more patients, with greater durability and fewer side effects

Some patients become drug resistant

ALSO HAS A POSITIVE OUTCOME WHEN IT COMES TO TREATING GASTROINTESTINAL STROMAL TUMOURS ANS SCLC