Introduction to Leukaemias Flashcards
Define leukaemia
(“leuk” = white, “emia” = blood)
Malignant disorders of haematopoietic stem cells characteristically associated with increased no. of white cells in bone marrow or/and peripheral blood
Give examples of leukocytes
Leukocytes consist of many different types of cells including, neutrophils, monocytes, lymphocytes, basophils etc.
What is haematopoiesis?
Process of blood cell formation
What are the 3 lineages of blood cells?
Blood cells are differentiated into 3 different lineages:
- Erythrocytes (RBCs)
- Lymphoid (T/B lymphocytes)
- Myeloid (innate immune response + blood clotting)
Describe features of haematopoietic stem cells
Pluripotent- can give rise to cells of every blood lineage
Self maintaining- a stem cell can divide to produce more stem cells
Describe the development of progenitor cells
Can divide to produce many mature cells
But cannot divide indefinitely
Eventually differentiate and mature
What are multipotent progenitors?
Undifferentiated (multipotent):
Can’t tell difference between progenitors morphologically as they show no characteristics of mature cells
What are unipotent progenitors?
Committed (unipotent):
already committed to what they will become when they generate mature cells
Where does leukaemia stem from?
It is a clonal disease- all the malignant cells derive from a single mutant stem cell.
Outline the incidence rates of leukaemias
31% childhood cases
38% of leukaemia cancer cases occur among people aged 75+
What are the common symptoms of leukaemia?
Varies between types of leukaemia
- Abnormal bruising-commonest
- Repeating abnormal infection
- Sometimes anaemia
What causes the presentation of leukaemia symptoms?
Typically first presents with symptoms due to loss of normal blood cell production
What techniques can we use to characterise leukaemia molecularly and pathophysiologically?
- Cytomorphology
- Immunophenotyping
- NGS
- Fluorescence in situ hybridisation (FISH)
- Flow cytometry
What causes leukaemia?
Exact cause is unclear. Combination of predisposing factors:
- Genetic risk factors
- Lifestyle related risk factors
- Uncertain, unproved or controversial factors
- Environmental factors
What is the genetic risk of inheriting leukaemia?
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
What are the acquired genetic risk factors of leukaemia?
- Oncogene/TSG mutations
- Chromosome aberrations
- Inherited immune problems
What kind of mutations can lead to leukaemia?
Gene mutations of oncogenes (activation) or/and tumour suppressors (inactivation)
Can involve genes common to other malignancies (TP53-Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia
Describe the chromosome aberrations causing leukaemia
- Translocations (e.g. BCR-ABL in CML).
- Numerical disorders (e.g. trisomy 21-Down syndrome).
Which inherited immune system disorders predispose to leukaemia?
e.g. Ataxia-telangiectasia
and Wiskott-Aldrich syndrome
What are the environmental risk factors of leukaemia?
- Radiation exposure
- Chemicals and chemotherapy
- Immune system suppression
How may patients be exposed to radiation?
- acute radiation accidents
- atomic bomb survivors
Describe the chemicals and chemotherapy causing leukaemia?
- Cancer chemotherapy with alkylating agents (e.g. Busulphan)
- Industrial exposure to benzene
Why may patient immune system be suppressed?
e.g. After organ transplant
What are the lifestyle related risk factors for adult cancers?
Smoking
Drinking
Excessive exposure to sun
Overweight
What are the controversial risk factors of childhood leukaemia?
Infections early in life Exposure to electromagnetic fields Mother’s age when child is born Parent’s smoking history Nuclear power stations Foetal exposure to hormones
How is leukaemia classified?
Acute disease
- rapid onset and short but severe course.
Chronic disease
- persisting over a long time.
Describe acute leukaemia
Undifferentiated leukaemia
Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)
How is chronic leukaemia characterised?
Differentiated leukaemia
Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
Describe the epidemiology of acute leukaemia
Mainly children affected
Sudden onset
Lasts weeks - months
WBC count is variable
Outline the chronic leukaemia pidemiology
Affects middle aged - elderly
Insidious onset
Lasting years
High WBC count
Which cells characterise acute leukaemia?
Characterized by large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood
Hard to differ between two cells due to similar morphology
Describe normal maturation of blood cells
Blood cells undergo differentiation and mature
At some point differentiated cells die via different processes (necrosis / apoptosis)
How does maturation differ in acute leukaemia?
There is an arrest in blast cell pool
Cells unable to differentiate and mature
⇒ lack of mature cells in blood
⇒ excess blast cells
Why do we see high numbers of immature cells in acute leukaemia?
Balance between new cells and cell death is broken
High levels of proliferation in blast cells and lack of mature cells ⇒ causes acute leukaemia
What causes the acute leukaemia symptoms?
Typical symptoms due to bone marrow suppression
Outline the acute leukaemia symptoms
Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.
Neutropenia: Recurrent infections, fever.
Anaemia: lassitude, weakness, tiredness, shortness of breath.
What are the 3 methods of diagnosis of leukaemia?
- Peripheral blood blasts test (PB)
- Bone marrow test/biopsy (BM)
- Lumbar puncture
How does a peripheral blood blasts test diagnose leukaemia?
Checks for the presence of blasts and cytopenia
> 30% blasts are suspected of acute leukaemia
When is Lumbar puncture used?
To determine if leukemia has spread to CSF
How is a bone marrow test carried out?
taken from pelvic bone and results compared with PB
Describe the prevalence of acute lymphoblastic leukaemia (ALL)
Commonest cancer of childhood (overall still not very common)
What is the origin of acute lymphoblastic leukaemia (ALL)?
Cancer of immature lymphocytes (lymphoblasts or blasts)
How is ALL classified?
B-cell & T-cell leukaemia
How is ALL treated?
Chemotherapy. Long term side effects are rare
What is the general outcome of ALL treatment?
5 year event-free survival (EFS) of 87% in 2010
1 out of 10 ALL patients relapse
Remission in 50% percent of them after second chemotherapy treatment or bone marrow transplant.
Why is Adult ALL prognosis poorer than in children?
Disease presents different cell of origin and different oncogene mutations
Outline the prevalence of acute myeloblastic leukaemia (AML)
70 children aged ≤16 y/o diagnosed in the UK every year (very rare)
What is the origin of acute myeloblastic leukaemia (AML)?
Cancer of immature myeloid white blood cells.
What is the treatment available for AML?
Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant.
Describe the prognosis of AML patients
5 year event-free survival (EFS) of 50-60%
Describe the prevalence of chronic lymphoblastic leukaemia (CLL)
3,800 new cases diagnosed in UK annually (average diagnosis age= 70)
What is the origin of chronic lymphoblastic leukaemia?
Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood
What are the symptoms of CLL?
- Recurrent infections due to neutropenia + lymphocyte function suppression
- Anaemia
- Thrombocytopenia
- Lymph node enlargement
- Hepatosplenomegaly.
What is the available treatment for CLL?
Regular chemotherapy to reduce cell numbers
What is the prognosis of CLL?
5 year event-free survival (EFS) of 83%. Many patients survive >12 years
What is the prevalence of chronic myeloid leukaemia (CML)?
742 new cases diagnosed in UK every year (peak rate = 85-89y/o)
What is the origin of chronic myeloid leukaemia (CML)?
Large numbers of mature myeloid white blood cells
What are the symptoms of CML?
Often asymptomatic and discovered through routine blood tests
How is CML diagnosed?
Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome
What treatments are there for CML?
Targeted therapy: Imatinib*
Describe the prognosis of CML patients
5 year event-free survival (EFS) of 90%
Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant
What is the defining chracteristic of CML?
95% of cases of CML have a detectable Philadelphia chromosome (Ph’)
What causes the presence of the philadelphia chromosome?
This is the result of a balanced translocation in t(9;22)(q34;q11)
Describe the translocation producing the philadelphia chromosome
Translocation brings together 2 small pieces of chromosomes that form a new smaller chromosome BCR-ABL ‘philadelphia’ chromosome
Where is the BCR gene normally found?
BCR is present in normal Chr.22
Where is ABL gene normally located?
ABL present in an oncogene on Chr.9
What induces the translocation to occur?
When the two chromosomes are in close proximity of one another, BCL promoter starts regulating ABL proto-oncogene expression
What is the consequence of philadelphia chromosome formation?
BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity
What is the effect of the BCR-ABL unregulated tyrosine kinase activity?
- Proliferation of progenitor cells in absence of GFs
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma
What is imatinib?
Small molecule inhibitor that targets Abl –CML treatment
What is the role of imatinib?
- Inhibits BCR-ABL but not most other tyrosine kinases
- Causes apoptosis of CML cells
- Remission induced in more patients, with greater durability and fewer side effects
- Some patients become drug resistant
