intro to leukaemia Flashcards
define leukaemia
malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood
haematopoietic stem cells
multipotent = can give rise to cells of every blood lineage
self maintaining = stem cell can divide to produce more stem cells
describe progenitor cells
can divide to produce many mature cells
cannot divide indefinitely
eventually differentiate and mature
2 types of progenitor cells
undifferentiated = cannot tell the difference between them morphologically because they don’t show characteristics of mature cells
committed = already committed as to what they will become when they generate mature cells
leukaemia presentation
varies between types of leukaemia
first presents with symptoms due to loss of normal blood cell production
- abnormal bruising commonest
- repeating abnormal infection
- sometimes anaemia
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 = taken from pelvic bone and results compared with PB
lumbar puncture = to determine if the leukaemia has spread to the cerebral spinal fluid
molecular and pathophysiological characterisation
cytomorphology immunophenotying next generation sequencing flow cytometry fluorescence in situ hybridisation
aetiology
exact cause is unclear
combination of predisposing factors
- genetic risk factors
- lifestyle related risk factors
- uncertain, unproven or controversial factors
- environmental factors
genetic risk factors
not usually hereditary
some rare genetic diseases may predispose to leukaemia e.g. fanconi’s anaemia, Down’s syndrome
genetic risk factors 2
gene mutations involving oncogenes or/and tumour suppressors
- involve genes common to other malignancies or specific to leukaemia
chromosome aberrations:
- translocations
- numerical disorders
- inherited immune system problems
environmental risk factors
radiation exposure
- acute radiation accidents
- atomic bomb survivors
exposure to chemicals and chemotherapy
- cancer chemotherapy with alkylating agents
- industrial exposure to benzene
immune system suppression
- after organ transplant
lifestyle related risk factors
for adult cancers:
- smoking
- drinking
- excessive exposure to sun
- overweight
controversial risk factors
possible links to childhood leukaemia:
- exposure to electromagnetic fields
- nuclear power stations
- infections early in life
- foetal exposure to hormones
- parents smoking history
- mothers age when child is born
classification of leukaemia
lmyphoid =
- acute = acute lymphoid leukaemia
- chronic lymphoid leukaemia
myeloid =
- acute myeloid leukaemia
- chronic myeloid leukaemia
classification
acute disease = rapid onset and short but severe course
acute leukaemia:
- undifferentiated leukaemia
- characterised by uncontrolled clonal and accumulation of immature white blood cells
classification 2
chronic disease: persisting over a long time
chronic leukaemia:
- differentiated leukaemia
- characterised by uncontrolled clonal and accumulation of mature white blood cells
describe acute leukaemia
characterised by a large number of lymphoblasts or myeloid blasts in bone marrow and blood “ undifferentiated leukaemia”
acute leukaemia 2
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 lymphoblastic leukaemia
- prevalence = commonest cancer of childhood
- origin = cancer of immature lymphocytes
- classification = B cell and T cell leukaemia
- treatment = chemotherapy, long term side effects are rare
- outcome = 5 year event-free survival of 87% in 2010. 1 out 10 ALL patients relapse. remission in 50% of them after second chemotherapy treatment of bone marrow transplant
adult ALL = poorer prognosis because disease presents different cell of origin and different oncogene mutations
acute myeloblastic leukaemia
- prevalence = 70 children aged over 16 diagnosed in Uk every year
- origin = cancer of immature myeloid white blood cells
- classification = based on FAB system m0-m7
- treatment = chemotherapy, monoclonal antibodies, allogenic bone marrow transplant
- outcome = 5 year event-free survival of 50-60%
chronic leukaemia
characterised by an increase number of differentiated cells = differentiated leukaemia
chronic leukaemia 2
prevelance = 3800 new cases diagnosed in UK every year
origin = large numbers of mature lymphocytes in bone marrow and peripheral blood
symptoms = recurrent infections due to neutropenia, suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomagaly
treatment = regular chemotherapy to reduce cell numbers
outcome = 5 year event free survival of 83%. many patients survive > 12 years
chronic leukaemia 3
prevalence = 742 new cases diagnosed in UK every year
origin = large numbers of mature myeloid white blood cells
symptoms = often asymptomatic and discovered through routine blood tests
diagnosis = very high white cell count in blood and bone marrow, presence of Philadelphia chromosome
treatment = targeted therapy = imatinib
outcome = 5 year event free survival of 90%. eventually progresses to accelerated phase and then blast crisis = allogeneic bone marrow transplant
describe BCR-ABL oncogene
95% of cases of CML have a detectable Philadelphia chromosome
BCR = encodes a protein that needs to be continuously active
ABL = encodes a protein tyrosine kinase whose activity is tightly regulated
BCR-ABL = protein has consititutive protein tyrosine kinase activity
BCR-ABL oncogene
unregulated BCR-ABL = tyrosine kinase activity that causes:
proliferation of progenitor cells in absence of growth factors
decreased apoptosis
decreased adhesion to bone marrow storm
applications:
diagnosis = 95% cases of CML have detectable Ph’ chromosome
applications of 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
BCR-ABL oncogene - targeted therapy
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
