Leukaemia Flashcards
What is the most common cancer in the 15-24 age group?
- Cancers of the blood
Where does the problem exist in leukaemia?
- Bone marrow (not all patients have abnormal cells in the blood)
What does leukaemia result from?
- A series of mutations in a single lymphoid or myeloid stem cell
- These mutations lead to progeny of that cell to show abnormalities in proliferation, differentiation or cell survival leading to steady expansion of the leukaemic clone
Which cells can be affected in leukaemia?
- Pluripotent haematopoietic stem cell
- Myeloid stem cell
- Lymphoid stem cell
- Pre-B lymphocyte
- Pre-T lymphocyte
What are the equivalent terms for ‘benign’ and ‘malignant’ in terms of leukaemia?
- Leukaemias that behave relatively benignly are CHRONIC
- Leukaemias that behave in a malignant manner are ACUTE– the disease is very aggressive
What are the four main types of leukaemia?
- Acute lymphoblastic leukaemia
- Acute myeloid leukaemia
- Chronic lymphocytic leukaemia
- Chronic myeloid leukaemia
Explain the significance of the terms acute lymphoblastic leukaemia and chronic lymphocytic leukaemia
- In ALL the cells are immature – they are lymphoblasts
- In CLL the cells are mature lymphocytes
What are the important leukaemogenic mutations that have been recognised?
- Mutation in a known proto-oncogene
- Creation of a novel gene e.g. chimeric or fusion gene
- Dysregulation of a gene when translocation brings it under the influence of a promoter or enhancer of another gene
- Loss of TSG gene function
- Improper DNA repair
State some inherited or other constitutional abnormalities that can contribute to leukaemogenesis
- Down syndrome
- Chromosomal fragility syndromes
- Defects in DNA repair
- Inherited defects in tumour suppressor genes
What are some identifiable causes of leukaemogenic mutations?
- Irradiation
- Anti-cancer drug
- Cigarette smoking
- Chemicals e.g. benzene
What type of cell is seen in abundance in acute myeloid leukaemia?
- Myelobasts - immature myeloid cells – the cells continue to proliferate but they no longer mature so there is a build up of myeloblasts in the bone marrow, which spread to the blood
Explain how acute leukaemia leads to bone marrow failure
- The leukaemic cells crowd out the normal cells in the bone marrow leading to a decrease in the production of other end cells e.g. granulocytes such as basophils and eosinophils and neutrophils, monocytes, megakaryocytes derived cells such as platelets
What do the responsible mutations normally affect in AML?
- Transcription factors – 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
- This leads to changes in cell kinetics and cell functions
What do the responsible mutations normally affect in CML?
- A gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus
- The protein encoded may be a membrane receptor or a cytoplasmic protein
Describe the nature of the leukaemic cells in CML
- These are mature lymphocytes – their cell kinetics and function are not as seriously affected as they are in AML but…
- The cells do become 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
How is the production of end cells affected in AML and CML?
- AML – decrease in the production of end cells
- CML – increase in the production of end cells
What are the metabolic effects of leukaemic cell proliferation?
- Hyperuricaemia
- Renal failure
- Weight loss
- Low grade fever
- Sweating
How can leukaemia cause proliferation of the gums?
- Infiltration of leukaemic cells and monocytes can lead to inflammation of the gums
- There will be small haemorrhages due to thrombocytopenia
Which type of leukaemia increases the risk of intraventricular haemorrhage and why?
- Acute promyelocytic leukaemia (APML) – this is associated with DIC so the platelet count and fibrinogen are low leading to increased risk of fatal haemorrhage
What does epidemiology suggest that B-lineage acute lymphoblastic leukaemia may result from?
- It may result from delayed exposure to a common pathogen or conversely lack of exposure to a protective pathogen may increase the risk
What can leukaemias in infants and young children result from?
- Irradiation in utero
- In utero exposure to certain chemicals
1) What are the clinical features of acute lymphoblastic leukaemia and what is do they all result from?
2) Why do these happen more in acute lymphoblastic leukaemia than chronic lymphocytic leukaemia?
1)
- Bone pain
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Thymic enlargement
- Testicular enlargement
- These all result from the accumulation of abnormal cells
2)
- The accumulation of abnormal cells happens more in acute forms of leukaemia, where you get large amounts of the precursor cells for example in acute myeloid leukaemia, you get a build up of lots of myeloblasts
What are some clinical haematological features of acute lymphoblastic leukaemia that are to do with end-cell production and describe further how it results in these symptoms?
- Ultimately, all are to do with crowding out of normal cells in the bone marrow in acute lymphoblastic leukaemia, resulting in reduced end-cell product formation
- The cells produced by the bone marrow include erythroid lineage cells, granulocytes (basophils, eosinophils and neutrophils) and platelets. Thus you can work out the symptoms from this
- Caused by anaemia – fatigue, lethargy, pallor, breathlessness
- Caused by neutropenia / low eosinophils / low basophils– fever and other features of infection
- Caused by thrombocytopenia – bruising, petechiae, bleeding
Give one other haematological finding that happens with acute lymphoblastic leukaemia that is not to do with the reduced end-cell production of bone marrow products
- Leucocytosis of lymphoblasts in the blood
What investigations are performed in acute lymphoblastic leukaemia?
- Blood count and film
- Check of liver function and renal function and uric acid
- Bone marrow aspirate
- Cytogenetic/molecular analysis
- Chest X-ray - check for thymic enlargement and signs of pneumonia
- Immunophenotyping to see what type of cells are involved
What are the uses of cytogenetic and molecular genetic analysis in ALL?
- Useful for managing the individual patient because it gives us information about prognosis
- Permits the discovery of leukaemogenic mechanisms
What are the implications of hyperdiploidy in the cytogenetic analysis of ALL?
- Good prognosis
What features of the cytogenetic analysis are associated with a poor prognosis?
- Chromosomal translocations resulting in the formation of a bad fusion gene
What translocation causes ALL? State the fusion gene
- Translocation between chromosome 12 and chromosome 21
- Fusion gene: ETV6-RUNX1 on chromosome 12
What technique is used to detect the fusion genes in ALL?
- Fluorescence in situ hybridisation (FISH)
What are the treatment options for ALL?
- Supportive: red cells, platelets, antibiotics
- Systemic chemotherapy
- Intrathecal chemotherapy - important because often leukaemic cells can enter CSF and thus avoid systemic chemotherapy and then result in relapse
What is event-free survival?
- Survival without any relapse event having happened
