intro to leukaemia

Question 1

define leukaemia

Answer 1

malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood

Question 2

haematopoietic stem cells

Answer 2

multipotent = can give rise to cells of every blood lineage

self maintaining = stem cell can divide to produce more stem cells

Question 3

describe progenitor cells

Answer 3

can divide to produce many mature cells
cannot divide indefinitely
eventually differentiate and mature

Question 4

2 types of progenitor cells

Answer 4

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

Question 5

leukaemia presentation

Answer 5

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

Question 6

diagnosis

Answer 6

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

Question 7

molecular and pathophysiological characterisation

Answer 7

cytomorphology 
immunophenotying 
next generation sequencing 
flow cytometry 
fluorescence in situ hybridisation

Question 8

aetiology

Answer 8

exact cause is unclear
combination of predisposing factors

• genetic risk factors
• lifestyle related risk factors
• uncertain, unproven or controversial factors
• environmental factors

Question 9

genetic risk factors

Answer 9

not usually hereditary

some rare genetic diseases may predispose to leukaemia e.g. fanconi’s anaemia, Down’s syndrome

Question 10

genetic risk factors 2

Answer 10

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

Question 11

environmental risk factors

Answer 11

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

Question 12

lifestyle related risk factors

Answer 12

for adult cancers:

• smoking
• drinking
• excessive exposure to sun
• overweight

Question 13

controversial risk factors

Answer 13

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

Question 14

classification of leukaemia

Answer 14

lmyphoid =

1. acute = acute lymphoid leukaemia
2. chronic lymphoid leukaemia

myeloid =

1. acute myeloid leukaemia
2. chronic myeloid leukaemia

Question 15

classification

Answer 15

acute disease = rapid onset and short but severe course

acute leukaemia:

• undifferentiated leukaemia
• characterised by uncontrolled clonal and accumulation of immature white blood cells

Question 16

classification 2

Answer 16

chronic disease: persisting over a long time

chronic leukaemia:

• differentiated leukaemia
• characterised by uncontrolled clonal and accumulation of mature white blood cells

Question 17

describe acute leukaemia

Answer 17

characterised by a large number of lymphoblasts or myeloid blasts in bone marrow and blood “ undifferentiated leukaemia”

Question 18

acute leukaemia 2

Answer 18

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

Question 19

acute lymphoblastic leukaemia

Answer 19

1. prevalence = commonest cancer of childhood
2. origin = cancer of immature lymphocytes
3. classification = B cell and T cell leukaemia
4. treatment = chemotherapy, long term side effects are rare
5. 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

Question 20

acute myeloblastic leukaemia

Answer 20

1. prevalence = 70 children aged over 16 diagnosed in Uk every year
2. origin = cancer of immature myeloid white blood cells
3. classification = based on FAB system m0-m7
4. treatment = chemotherapy, monoclonal antibodies, allogenic bone marrow transplant
5. outcome = 5 year event-free survival of 50-60%

Question 21

chronic leukaemia

Answer 21

characterised by an increase number of differentiated cells = differentiated leukaemia

Question 22

chronic leukaemia 2

Answer 22

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

Question 23

chronic leukaemia 3

Answer 23

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

Question 24

describe BCR-ABL oncogene

Answer 24

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

Question 25

BCR-ABL oncogene

Answer 25

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

Question 26

applications of BCR-ABL oncogene

Answer 26

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

Question 27

BCR-ABL oncogene - targeted therapy

Answer 27

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