Leukaemia

Question 1

What is leukaemia?

Answer 1

Blood cancer.
‘White blood’- first cases recognised had increased white cell count.
Bone marrow disease- not all patients have abnormal cells in blood.

Question 2

What percentage of cancers are blood cancers?

Answer 2

5%

Question 3

How many people are diagnosed with a blood cancer daily in the UK?

Answer 3

Approximately 60.

Question 4

What is the most common type of cancer in the age bracket 15-24?

Answer 4

Blood cancers (men and women).

Question 5

What is the main cause of cancer death in people aged 1-34 years?

Answer 5

Leukaemia/ blood cancers.

Question 6

What proportion of the UK population will die of leukaemia, lymphoma or myeloma?

Answer 6

1 in 45 people.

Question 7

What does leukaemia result from?

Answer 7

A series of mutations in a single lymphoid or myeloid stem cell.
These mutations lead the progeny of that cell to show abnormalities in proliferation, differentiation or cell survival leading to steady expansion of the leukaemic clone.

Question 8

What is the difference between leukaemia and other cancers?

Answer 8

Most cancers exist as a solid tumour.
It is uncommon for patients with leukaemia to have tumours.
Leukaemic cells replace normal bone marrow cells and circulate freely in the bloodstream.
Haemopoietic and lymphoid cells behave differently from other body cells.
Normal haemopoietic stem cells can circulate in the blood- stem cells and cells derived from them can enter tissues.
Normal lymphoid stem cells recirculate between tissues and blood.

Question 9

What is the equivalent of ‘benign’ and ‘malignant’ leukaemia?

Answer 9

The concepts of invasion and metastasis cannot be applied to cells that normally travel around the body and enter tissues.
Leukaemias that behave in a relatively ‘benign’ manner are chronic- the disease goes on for a long time.
Leukaemias that behave in a ‘malignant’ manner are acute- if not treated, the disease is very aggressive and the patient dies quite rapidly.

Question 10

How is leukaemia classified?

Answer 10

Acute or chronic
Lymphoid or myeloid
Lymphoid can be B or T lineage
Myeloid can be any combination of granulocytic, monocytic, erythroid or megakaryocytic

Question 11

What are the 4 main types of leukaemia?

Answer 11

Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)

Question 12

Why do people get leukaemia?

Answer 12

Results from a series of mutations in a single stem cell.
Some mutations result from identifiable (or unidentifiable) oncogenic influences.
Others are probably random errors- chance events- that occur throughout life and accumulate in individual cells.

Question 13

What important leukaemogenic mutations have been recognised?

Answer 13

Mutation in a known proto-oncogene.
Creation of a novel gene, e.g. a chimaeric or fusion gene.
Dysregulation of a gene when translocation brings it under the influence of the promoter or enhancer of another gene.

Question 14

What factors increase the risk of leukaemia developing or contribute to leukaemogenesis?

Answer 14

Loss of function of a tumour suppressor gene can contribute to leukaemogenesis- this can result from deletion or mutation of the gene.
If there is a tendency to increased chromosomal breaks, the likelihood of leukaemia is increased.
If the cell cannot repair DNA normally, an error may persist whereas in a normal person the defect would be repaired.

Question 15

Give examples of inherited or other constitutional abnormalities that can contribute to leukaemogenesis.

Answer 15

Down’s syndrome
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of tumour-suppressor genes

Question 16

Give examples of identifiable causes of leukaemogenic mutations.

Answer 16

Irradiation
Anti-cancer drugs
Cigarette smoking
Chemicals- benzene

Question 17

What are the differences between acute and chronic myeloid leukaemia?

Answer 17

In AML, cells continue to proliferate but they no longer mature so there is: a build-up of the most immature cells- myeloblasts or ’blast cells’- in the bone marrow with spread into the blood; failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets (for 2 reasons).
In AML, the responsible mutations usually affect transcription factors so that the transcription of multiple genes is affected.
Often the product of an oncogene prevents the normal function of the protein encoded by its normal homologue.
Cell behaviour is profoundly disturbed.
In CML, the responsible mutations usually affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus.
The protein encoded may be either a membrane receptor or a cytoplasmic protein.
In CML, cell kinetics and function are not as seriously affected as in AML.
However, the cell becomes independent of external signals, there are alterations in the interaction with stroma and there is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively.
Whereas in AML there is a failure of production of end cells, in CML there is increased production of end cells.

Question 18

What are the differences between acute and chronic lymphoid leukaemia?

Answer 18

Acute lymphoblastic leukaemia has an increase in very immature cells- lymphoblasts- with a failure of these to develop into mature T and B cells.
In chronic lymphoid leukaemia, the leukaemic cells are mature, although abnormal, T cells or B cells.

Question 19

How does leukaemia cause the disease characteristics?

Answer 19

Accumulation of abnormal cells leading to:
-leukocytosis
-bone pain (if acute)
-hepatomegaly
-splenomegaly
-lymphadenopathy (if lymphoid)
-thymic enlargement (if T lymphoid)
-skin infiltration
Metabolic effects of leukaemic cell proliferation:
-hyperuricaemia and renal failure
-weight loss
-low grade fever
-sweating
Crowding out of normal cells leading to:
-anaemia
-neutropaenia
-thrombocytopaenia
Loss of normal immune function as a result of loss of normal T cell and B cell function- a feature of chronic lymphoid leukaemia.

Question 20

What is the epidemiology of acute lymphoblastic leukaemia?

Answer 20

Peak incidence is between 2-8 year olds. Largely a disease of children.
B-lineage ALL may result from delayed exposure to a common pathogen, or early exposure to pathogens protects.
Evidence relates to family size (bigger is better), new towns (mixing populations is bad), socioeconomic class (higher is worse), early social interactions, variations between countries.
In infants and young children, may result from:
-irradiation in utero
-in utero exposure to certain chemicals ? Baygon, ? Dipyrone
-? Epstein-Barr virus infection
Rarely ALL results from exposure to a mutagenic drug.

Question 21

What are the clinical features of acute lymphoblastic leukaemia?

Answer 21

Resulting from accumulation of abnormal cells:
-bone pain
-hepatomegaly
-splenomegaly
-lymphadenopathy
-thymic enlargement
-testicular enlargement
Resulting from crowding out of normal cells:
-fatigue, lethargy, pallor, breathlessness (caused by anaemia)
-fever and other features of infection (caused by neutropaenia)
-bruising, petechiae, bleeding (caused by thrombocytopaenia)

Question 22

What are the haematological features of acute lymphoblastic leukaemia?

Answer 22

Leukocytosis with lymphoblasts in the blood
Anaemia (normocytic, normochromic)
Neutropaenia
Thrombocytopaenia
Replacement of normal bone marrow cells by lymphoblasts

Question 23

What investigations are performed if acute lymphoblastic leukaemia is suspected?

Answer 23

Clinical history and physical examination
Blood count and film
Check of liver and renal function and uric acid
Bone marrow aspirate
Cytogenetic/molecular analysis
Chest x-ray
Immunophenotyping

Question 24

Why is cytogenetic/molecular genetic analysis important in acute lymphoblastic leukaemia?

Answer 24

Useful for managing the individual patient because it gives information about prognosis.
Advances knowledge of leukaemia because it has permitted the discovery of leukaemogenic mechanisms.

Question 25

What are the leukaemogenic mechanisms in acute lymphoblastic leukaemia?

Answer 25

Translocation leading to formation of a fusion gene.
Dysregulation of a proto-oncogene by juxtaposition of it to the promoter of another gene, e.g. a T cell receptor gene.
Point mutation in a proto-oncogene.

Question 26

How is acute lymphoblastic leukaemia treated?

Answer 26

Supportive:
-red cells
-platelets
-antibiotics
Systemic chemotherapy
Intrathecal chemotherapy