Introduction to Leukaemia Flashcards
What is leukaemia
Malignant disorders of haematopoietic stem cells characteristically associated with an increased number of white cells in bone marrow or/and peripheral blood
What are haematopoetic stem cells
Multipotent- can give rise to cells of every blood lineage
Self maintaining- a stem cell can divide to produce more stem cells
What are progenitor cells
Can divide to produce many mature cells
But cannot divide indefinitely
Eventually differentiate and mature
What is the difference between undifferentiated and committed progenitor cells
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
How does leukaemia arise
It is a clonal disease- all the malignant cells derive from a single mutant stem cell
It form sit sown progenitor cells
What is the incidence of leukaemia
The higher incidence rate in the elderly, increases with ageing
Childhood cases are rising now at 31%
what are the initial symptoms of leukaemia
Typically first presents with symptoms due to loss of normal blood cell production:
- Abnormal bruising-commonest
- Repeating abnormal infection
- Sometimes anaemia
How can we clinically diagnose leukaemia and what does each test show
- 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).
How can we diagnose leukaemia pathologically
- Cytomorphology
- Immunophenotyping
- Next-generation sequencing
- Flow cytometry
- Fluorescence in situ hybridation (FISH)
What are the predisposing factors for leukaemia
- Genetic risk factors
- Lifestyle-related
- Uncertain, unproven or controversial factors
- Environmental risk factors
How can genetic risk factors cause disease
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 genetic risk factors that cause leukaemia
- 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).
what environmental risk factors that cause leukaemia
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
what lifestyle-related risk factors that cause leukaemia
- Smoking
- Drinking
- Excessive exposure to sun
- Overweight
what controversial risk factors that cause leukaemia
- 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
What are the 4 types in leukaemia classifaction
- Acute lymphoid leukaemia
- Chronic lymphoid leukaemia
- Acute myeloid leukaemia
- Chronic myeloid leukaemia
Describe acute leukaemia
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)
Describe chronic leukaemia
Chronic disease: persisting over a long time.
Chronic leukaemia:
Differentiated leukaemia
Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
Compare acute and chronic leukaemia
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
What is the incidence rate of acute leukaemia
- 31% of cancer in children is leukaemia
- Of that 75% is acute lymphoid and 25% are acute myeloid
What is acute leukaemia characterised by
Characterized by a large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- “undifferentiated leukaemia”
What are the typical symptoms of acute leukaemia due to bone marrow suppression
- Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.
- Neutropenia: Recurrent infections, fever.
- Anaemia: lassitude, weakness, tiredness, shortness of breath
How can we treat acute leukaemia
Lymphoblastic:
- Chemotherapy. Long-term side effects are rare
Myeloblastic:
- Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant
What is chronic leukaemia characterised by
Characterised by an increase number of differentiated cells -“differentiated leukaemia”
What are the symptoms of chronic lymphocytic leukaemia
Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly
What are the symptoms of chronic Myeloid/granulocytic leukaemia
Often asymptomatic and discovered through routine blood tests
How can we treat chronic lymphocytic leukaemia
Regular chemotherapy to reduce cell numbers
How can we treat chronic Myeloid/granulocytic leukaemia?
Targeted therapy: Imatinib
What is the BCR-ABL oncogene
- 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
How does this oncogenes cause CML
- 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
What are the applications of the BCR-ABL oncogene
- 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
How can targeted therapy be used in treating CML
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
How has targeted therapy worked in CML
- Positive outcomes also in the treatment of gastrointestinal stromal tumours and SCLC.
