Introduction to Leukaemias Flashcards
Define leukaemia
Leukaemia (“leuk” = white, “emia” = blood): “malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood.”
can be classified according to cell linage (lymphoid or myeloid) and degree of terminal differentiation (acute or chronic).
Pluripotent definition
Pluripotent- can give rise to cells of every blood lineage
Self maintaining
Self maintaining- a stem cell can divide to produce more stem cells
Features of progenitor cells
Can divide to produce many mature cells
But cannot divide indefinitely
Eventually differentiate and mature
Compare unipotent w/multipotent
Progenitor cells- Undifferentiated (multipotent): you cannot tell the difference between them morphologically because they do not show the characteristics of mature cells.
Progenitor cells- Committed (unipotent): already committed as to what they will become when they generate mature cells
Leukaemia derived from
- It is a clonal disease- all the malignant cells derive from a single mutant stem cell.
Describe presentation of leukaemia
- Typically first presents with symptoms due to loss of normal blood cell production
Abnormal bruising-commonest
Repeating abnormal infection
Sometimes anaemia
Describe diagnosis of leukaemia
Molecular and pathophysiological characterisation
Cytomorphology Immunophenotyping Next Generation Sequencing (NGS) Flow cytometry Fluorescence in situ Hybridation (FISH)
Describe aetiology of leukaemia
Genetic risk factors Uncertain, unproven or controversial factors Environmental risk factors Lifestyle-related risk factors
Explain genetic factors of 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
Describe the effect of gene mutations on leukaemia
Gene mutations involving oncogenes (activation) or/and tumour suppressors (inactivation)
- Involving genes common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia.
Describe the effect of chromosome abberations on leukaemia
Chromosome aberrations:
Translocations (e.g. BCR-ABL in CML).
Numerical disorders (e.g. trisomy 21-Down syndrome).
Describe the effect of immune system problems on leukaemia
Inherited immune system problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).
Describe the environmental risk factors for 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
Describe lifestyle-related risk factors for leukaemia
For some adult cancers: Smoking Drinking Excessive exposure to sun Overweight
Describe the controversial risk factors for leukaemia
(Possible link to childhood leukaemia)
Exposure to electromagnetic fields Infections early in life Mother’s age when child is born Nuclear power stations Parent’s smoking history Foetal exposure to hormones
Define an acute disease
Acute disease: rapid onset and short but severe course
Describe features of
acute leukaemia
Undifferentiated leukaemia
Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)
Define a chronic disease
Chronic disease: persisting over a long time
Describe features of
chronic leukaemia
Chronic leukaemia:
Differentiated leukaemia
Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
Describe classification of leukaemia
LYMPHOID:
Acute = Acute Lymphoblastic Leukaemia (ALL)
Chronic = Chronic Lymphocytic Leukaemia
(CLL)
MYELOID:
Acute = Acute Myeloblastic Leukaemia (AML)
Chronic = Chronic Granulocytic Leukaemia
(CML)
Compare acute vs chronic leukaemia
Acute first then chronic
Age = children vs middle/elderly
Onset = sudden vs insidious
Duration = weeks/months vs years
White Blood Cells (WBC) count = variable vs high
Describe how you can characterize acute leukaemia
Characterized by a large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- “undifferentiated leukaemia”.
= maturation arrest
Acute leukaemia symptoms
Typical symptoms due to bone marrow suppression:
Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.
Neutropenia: Recurrent infections, fever.
Anaemia: lassitude, weakness, tiredness, shortness of breath.
Acute leukaemia diagnosis
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).
Describe prevalence of acute lymphoblastic leukaemia (ALL)
- Prevalence: Commonest cancer of childhood (overall still not very common).
Describe origin of acute lymphoblastic leukaemia (ALL)
- Origin: Cancer of immature lymphocytes (lymphoblasts or blasts)
Describe classification of ALL
- Classification: B-cell & T-cell leukaemia.
Describe treatment of ALL
- Treatment: Chemotherapy. Long term side effects are rare.
Describe outcome of ALL
- Outcome: 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.
- Adult ALL- poorer prognosis because disease presents different cell of origin and different oncogene mutations.
Describe prevalence of acute myeloblastic leukaemia (AML)
- Prevalence: 70 children aged ≤16 y/o diagnosed in the UK every year (very rare).
Describe origin of AML
- Origin: Cancer of immature myeloid white blood cells.
Describe classification of AML
- Classification: based on FAB system (French-American-British): M0-M7.
Describe treatment of AML
- Treatment: Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant.
Describe outcome of AML
- Outcome: 5 year event-free survival (EFS) of 50-60%.
Describe how you can characterise chronic leukaemia
Characterised by an increase number of differentiated cells -“differentiated leukaemia”.
Describe prevalence of chronic lymphocytic leukaemia (CLL)
- Prevalence: 3,800 new cases diagnosed in the UK every year (average diagnosis age= 70).
Describe origin of CLL
- Origin: Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood.
Describe symptoms of CLL
- Symptoms: Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly.
Describe treatment of CLL
- Treatment: Regular chemotherapy to reduce cell numbers.
Describe outcome of CLL
- Outcome: 5 year event-free survival (EFS) of 83%. Many patients survive >12 years.
Describe prevalence of chornic myeloid leukaemia
- Prevalence: 742 new cases diagnosed in the UK every year (peak rate = 85-89y/o).
Describe origin of CML
- Origin: Large numbers of mature myeloid white blood cells.
CML - symptoms
- Symptoms: Often asymptomatic and discovered through routine blood tests.
CML - diagnosis
- Diagnosis: Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome.
CML - treatment
- Treatment: Targeted therapy: Imatinib.
CML - outcome
- Outcome: 5 year event-free survival (EFS) of 90%. Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant.
CML - feature of most cases
- 95% of cases of CML have a detectable Philadelphia chromosome (Ph’)
Balanced translocation t(9;22)(q34;q11)
BCR-ABL Oncogene structure
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
BCR-ABL Oncogene - applications
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
BCR-ABL Oncogene - targeted therapy
Imatinib (Glivec®, STI571) is a small molecule inhibitor that targets Abl –CML treatment
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
Targeted therapy vs chemotherapy
Targeted Therapies: Design to interact with their targets Act on specific molecular targets associated with cancer Cytostatic Many are oral agents
Chemotherapy: Identified because they kill cells Act on all rapidly dividing cells (cancerous and normal) Cytotoxic Mainly intravenous, some oral agents
