Introduction To Leukaemia Flashcards
1
Q
- Define Leukaemia?
A
Malignant disorders of haematopoietic stem cells associated with an increased number of white cells in bone marrow or/and peripheral blood.
2
Q
- What two lineages do WBC’s come from?
A
- Lymphoid (T/B lymphocytes) lineage
2. Myeloid (Macrophages,Neutrophils) lineage
3
Q
- Leukaemia is a clonal disease- what does this mean?
A
o Clonal disease where all the malignant cells derive from a single mutant stem cell.
• 1st mutation is pre-leukaemia, 2nd mutation acquisition is full blown leukaemia.
4
Q
- What are HSCs?
A
o Haematopoietic stem cells (HSCs) are self-maintaining (self-renew), pluripotent cells that can give rise to cells of every blood lineage.
5
Q
- What are progenitor cells?
A
o Progenitor cells can divide to produce many mature cells but have a finite lifespan (can’t divide indefinitely) and will eventually differentiate/mature.
6
Q
- Can you tell the morphological difference between precursor cells and undifferentiated (multipotent) cells?
A
can’t tell the morphological differences between them and precursors because they don’t show the characteristics of mature cells.
7
Q
- Can you tell the morphological difference between committed (unipotent) and precursor cells?
A
yes because they are committed to what they will become when they generate mature cells.
8
Q
- How many new cases of leukaemia is there every day?
A
9900
9
Q
- What % of new daily cases are childhood?
A
31%
10
Q
- Between what ages is there a peak rate of leukaemia cancers in?
A
85-89
11
Q
- What % has the incidence rate decreased by since early 1900s
A
18%
12
Q
- How does leukaemia present itself?
A
- Varies between diff leukaemia’s but;
- 1st present with symptoms due to loss of normal blood cell production
- Abnormal Bruising
- Repeating abnormal infection
- Anaemia
13
Q
- What is the Aetiology of leukaemia?
A
Exact cause is unclear but there is a combination of predisposing factors.
14
Q
- Leukaemia is not usually hereditary except for some cases of *** ?
A
Chronic Lymphocytic Leukaemia
15
Q
- In some cases, rare genetic diseases can predispose you to leukaemia , give examples of which diseases?
A
- Fanconi’s anaemia
- Down’s syndrome
16
Q
- What 3 main types of genetic factors can cause leukaemia?
A
- Oncogenes/ Tumour Suppressor
- Chromosome Aberrations
- Inherited immune system issues
17
Q
- Explain how “Oncogenes/Tumour Suppressor genes” can play a genetic factor in leukaemia?
A
Activating mutations of oncogenes and inactivating mutations of tumour suppressor genes, this may involve genes specific to leukaemia or genes that are also common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis).
18
Q
- Explain how “Chromosome aberrations” can play a genetic factor in increasing chances of leukaemia?
A
Translocations (e.g. BCR-ABL in CML) or numerical disorders (e.g. trisomy 21-Down syndrome).
19
Q
- Give 2 examples of inherited immune system problems that might increase risk of leukaemia?-
A
- Ataxia-telangiectasia
- Wiskott-Aldrich syndrome
20
Q
- What are some environmental and lifestyle related risk factors for leukaemia?
A
- Radiation Exposure (radiation accidents or atomic bomb survivors)
- Immunosuppression (after transplant)
- Exposure to chemicals and chemotherapy
- Lifestyle related risk factors (smoking,drinking, overexposure to sun, overweight)
21
Q
- Why might a patient have exposure to chemicals and chemotheraphy?
A
- Cancer chemotherapy with alkylating agents (e.g. Busulphan)
- Industrial exposure to benzene
22
Q
- What are some controversial risk factors (uncertain/unproven) or leukaemia?
A
o Exposure to electromagnetic fields
o Foetal exposure to hormones and infections in early life.
o Mother’s age when child is born and parents’ smoking history.
o Nuclear power stations
23
Q
- What is another name for acute lymphoid leukaemia?
A
Acute Lymphoblastic leukaemia (ALL)
24
Q
- What is another name for chronic lymphoid leukaemia?
A
Chronic Lymphocytic Leukaemia (CLL)
25
25. What are the names given for acute and chronic myeloid leukaemia?
Acute Myeloid Leukaemia=
Acute myeloblastic leukaemia (AML)
Chronic Myeloid Leukaemia =
Chronic granulocytic leukaemia (CML)
26
26. Which age is mostly affected by acute leukaemia or chronic leukaemia?
Acute = Mainly Children
Chronic =Middle Age and Elderly
27
27. What is the difference between acute and chronic leukaemia for "Onset and Duration"
Acute = "Sudden onset, duration weeks-months"
Chronic = "Insidious (gradual) onset, duration years"
28
28. What is the difference between acute and chronic leukaemia for "WBC Count"
Acute = Variable WBC count
Chronic = High WBC Count
29
29. Define acute (rapid onset and short but severe course) leukaemia?
undifferentiated leukaemia characterised by uncontrolled clonal accumulation of immature white blood cells (myeloblasts and lymphoblasts).
30
30. Define chronic (persisting over a long time) leukaemia?
differentiated leukaemia that is characterised by uncontrolled clonal accumulation of mature white blood cells (cytes)
31
31. What percentage of leukaemia's are ALL (acute lymphoblastic leukaemia) and what % are AML (acute myeloblastic leukaemia)
75% of leukaemia’s are ALL and 20% are AML.
32
32. What is meant by undifferentiated leukaemia's? eg ALL and AML?
o large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow/blood.
oMaturation arrest: cells arrest in the blast cell pool so they cannot differentiate to become mature cells.
33
33. Typical symptoms of AML or ALL are due to the bone marrow suppression, what are some typical symptoms?
1. Thrombocytopenia (platelet deficiency): purpura (bruising), epistaxis (nosebleed), bleeding from gums.
2. Neutropenia (neutrophil deficiency): Recurrent infections, fever.
3. Anaemia: lassitude (lack of energy), weakness, tiredness, shortness of breath.
34
34. To diagnose ALL or AML , a peripheral blood blast test (PB) could be done, how does this work?
check for presence of blasts and cytopenia (acute leukaemia >30% blasts).
35
35.To diagnose ALL or AML , a bone marrow test/ biopsy (BM) could be done, how does this work?
taken from pelvic bone and results compared with PB.
36
36. What is the purpose of doing a lumbar puncture on a ALL /AML patient?
to determine if the leukaemia has spread to the cerebral spinal fluid (CSF).
37
37. What is more common: ALL or AML?
ALL is not very common but AML is very rare , so ALL out of the two
38
38. For both ALL and AML , state the PREVALENCE:
ALL:
Prevalence: commonest cancer of childhood.
AML:
Prevalence: most common in over 75 year old
39
39. For both ALL and AML , state the ORIGIN:
ALL:
Cancer of immature lymphocytes (lymphoblasts/blasts).
AML:
Cancer of immature myeloid white blood cells.
40
40. For both ALL and AML , state the CLASSIFICATION:
ALL:
B-cell & T-cell leukaemia
AML:
based on FAB system (French-American-British): M0-M7.
41
41. For both ALL and AML , state the TREATMENT:
ALL:
Chemotherapy (long term side effects are rare).
AML:
Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant.
42
42. For both ALL and AML , state the OUTCOME after treatment:
ALL:
• 5 year event-free survival (EFS) of 87% in 2010.
• 1 out of 10 ALL patients relapse- remission in 50% of these after 2nd chemotherapy treatment or bone marrow transplant.
AML:
5 year event-free survival (EFS) of 50-60%.
43
43. Why is there a poorer prognosis in Adult ALL?
poorer prognosis because disease presents different cell of origin and different oncogene mutations
44
44. What is chronic leukaemia characterised by?
Characterised by an increase number of differentiated cells -“differentiated leukaemia”.
45
45. What is more common out of the two:
-Chronic Lymphocytic leukaemia (CLL)
-Chronic Myeloid Leukaemia (CML)
???
CLL is more common
| CML is rare
46
46. For both CLL and CML state the PREVALENCE?
CLL:
3,800 new cases diagnosed in the UK every year (average diagnosis age= 70).
CML:
742 new cases diagnosed in the UK every year (peak rate = 85-89y/o).
47
47. For both CLL and CML state the ORIGIN?
CLL:
Large numbers of mature (clonal) lymphocytes.
CML:
Large numbers of mature myeloid white blood cells
48
48. For both CLL and CML state the SYMPTOMS?
CLL:
Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly.
CML:
Often asymptomatic and discovered through routine blood tests.
49
49.For both CLL and CML state the TREATMENT?
CLL:
Chemotherapy to reduce cell numbers
CML:
Targeted therapy: Imatinib.(cancer growth blocker- tyrosine kinase inhibitor)
50
50 .For both CLL and CML state the OUTCOME after treatment?
CLL:
5 year event-free survival (EFS) of 83%. Many patients survive >12 years.
CML:
: 5 year event-free survival (EFS) of 90%.
o Eventually progresses to accelerated phase and then blast crisis (>30% of cells are blast).- allogeneic bone marrow transplant.
51
51. How do we diagnose CML?
very high white cells count (neutrophilia) and presence of Philadelphia chromosome.
52
52. What % of CML cases have a detectable Philadelphia chromosome?
95%
53
53. What translocation results in a philadelphia chromosome?
Balanced translocation between chromosomes 9 and 22 - t(9;22)(q34;q11).
Normal Chromosome 9 (with ABL gene)
Normal Chromsome 22 (With BCR gene)
Chromosomes break, chromosome 9 is unchanged, chromosome 22 has both ABL and BCR gene and therefore is now a Philadelphia chromosome
54
54. What does the BCR and ABL genes encode?
o BCR encodes a protein that needs to be continuously active and ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition).
55
55. oBCR-ABL protein causes constitutive (unregulated) protein tyrosine kinase activity which causes what three things:
1. Proliferation of progenitor cells in the absence of growth factors
2. Decreased apoptosis
3. Decreased adhesion to bone marrow stroma.
56
56. What are some clinical applications of the BCR-ABL oncogene?
* 95% of cases of CML have a detectable Ph' chromosome that allows diagnosis (by FISH which uses fluorescent probes).
* Detection of minimal residual disease (small no of cancer cells remaining after treatment).
* Therapy using drugs that specifically inhibit BCR-ABL. e.g. Imatinib (Glivec®, STI571). Cases negative for BCR-ABL require different therapy.
57
57. What is Imatinib and how does it work?
* Imatinib is a small molecule inhibitor (competitor of ATP for the small pocket) that specifically targets ABL –CML treatment.
* It inhibits BCR-ABL (but not other tyrosine kinases) which causes apoptosis of chronic myeloid leukaemia (CML) cells.
* Remission induced in more patients, with greater durability and fewer side effects.
* Some patients become drug resistant.
* Also used for lung cancers and gastrointestinal tumours.
58
58. Compare Targeted therapies vs chemotherapy?
Targeted Therapies:
- Design to interact with their targets
- Act on specific molecular targets associated with cancer
- Cytostatic (inhibit cell growth without directly killing cells).
- Many are oral agents
Chemotherapy:
- Identified because they kill cells
- Act on all rapidly dividing cells (cancerous and normal)
- Cytotoxic (kill cells)
- Mainly intravenous, some oral agents
