Intro to leukaemias Flashcards
1
Q
Define leukaemia
A
Group of diseases characterised by malignant overproduction of WBCs or their immature precursors
2
Q
How do leukaemias present?
A
- Varies between types of leukaemia
- But typically first presents with symptoms due to loss of normal blood cell production
- abnormal bruising (reduced platelets)
- Repeat/abnormal infection
- Sometimes just anaemia
3
Q
What are the different classifications of leukaemias?
A
- Lymphoid - commonly B-cell, rarely T-cell
- Myeloid - any of the non-lymphocyte blood cell lineage (commonly neutrophils)
- Acute - undifferentiated, characterised by blast cells
- Chronic - differentiated leukaemias, characterised by mature WBCs
- Have ALL, AML, CLL, CML
4
Q
What genes are involved in leukaemia?
A
- Activation of oncogenes and inactivation of TSGs
- Ras, myc, P53
- Chromosome translocation can generate novel hybrid oncogenes e.g. BCR-ABL in CML, PML-RARA in AML M4
- Monosomy/trisomy
5
Q
Is leukaemia clonal?
A
Yes
- mutation in one cell –> clonal haemopoiesis
6
Q
What risk factors are there for leukaemia?
A
- Radiation
- Chemicals
- Chemo
- Viruses (one very rare example - HTLV-1)
- Genetic factors (only CLL)
- Age - majority elderly
- Controversial - power lines, nuclear stations, natural background radiation (radon from granite)
7
Q
What treatment is there for leukaemia?
A
- Chemo with cytotoxic drugs
- Stem cell and bone marrow transplant
- Disease-specific agents, including oncogene targeted drugs
8
Q
How do we use chemo?
A
- Combinations of drugs used to kill leukaemic cells
- optimised for type and subtype of leukaemia
- Cytotoxic drugs mostly target dividing cells
9
Q
Gives some examples of chemo treatments
A
- Cytosine arabinoside (ara-C, Cytarab)
- Cytosine analogue, interferes with deoxynucleotide synthesis, preventing successful DNA replication -> cell arrests and dies
- Vincristine
- Binds to tubulin dimers, inhibiting microtubule formation, blocking the mitotic spindle.
- Cell fails to undergo mitosis and dies
10
Q
What are some side effects of chemo?
A
- Kills normally dividing cells too
- GI epithelium -> nausea and diarrhoea
- Hair follicles -> hair loss
- Loss of fertility (male = temporary and can bank sperm)
- Haemopoeitic progenitors -> bone marrow suppression
11
Q
What is SCBMT?
A
- Stem cell bone marrow transplant
- Give intense chemo and total body irradiation
- Wipes out leukaemic cells and normal stem cells
- reconstitute bone marrow by transplanted stem cells - much more intense
12
Q
What are some problems with SCBMT?
A
- Shortage of HLA matched donors
- High mortality of the procedure for older or sicker patients
13
Q
What is the histology for acute leukaemias?
A
- All look like immature blast cells
- Big nuclei, little cytoplasm
- All the same
- Large numbers of myeloid blasts (AML) or lymphoblasts (ALL) in bone marrow - hence “undifferentiated leukaemais”
14
Q
What are the main symptoms of acute leukaemias?
A
- Typical symptoms due to bone marrow suppression
- Thrombocytopaenia (lack of platelets) -> purpura, nosebleeds and bleeding gums
- Neutropaenia -> recurrent infections
- Anaemia -> weakness, shortness of breath
- Petechiae - point like bruises
- candida albicans infecion
15
Q
How do we diagnose acute leukaemias?
A
Peripheral blood
- presence of blasts
- lack of normal cells
- all at the same stave of maturation
- Auer rods - only seen in leukamia (rod-like structures in cell)
Bone marrow aspirate
- >30% blasts is diagnostic of acute leukaemia
16
Q
How do we classify acute leukaemias
A
French-American-British (FAB)
- based on stage of differentiation arrest and predominant cell type
- e.g. AML M6 erythroleukaemia
WHO classification
- similar to FAB, but acute leukaemias with specific chromosome translocations are classified separately
- e.g. AML with translocation between Chr8 and 21
17
Q
What is the prognosis after treatment?
A
- Childhood ALL -> >90% long term remission/ cure
- Adult ALL - poorer prognosis due to different cell of origin and different oncogene mutations
- AML - >80% long term remission in young adults with aggressive treatment
- Elderly unable to tolerate aggressive chemo or SCBMT
18
Q
Define chronic leukaemias
A
- Differentiated leukaemias
- increased numbers of differentiated cells
19
Q
What is CLL?
A
- Chronic lymphoid leukaemia
- Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood
- Also called chronic lymphocytic leukaemia
20
Q
What are the symptoms of CLL?
A
- Recurrent infections due to neutropaenia and suppression of normal WBC function
- Anaemia
- Thrombocytopaenia
- Lymph nodes enlargement
- Hepatosplenomegaly
21
Q
What is the treatment and outcome for CLL?
A
- Controlled by regular chemo to reduce cell numbers
- Some patient may die in 2 years
- Most survive much longer (12 years or longer)
22
Q
What are the symptoms of CML?
A
- anaemia
- night fever/sweats
- splenomegaly
23
Q
How do we diagnose CML?
A
- neutrophilia
- left shift in blood and bone marrow
- Presence of philadelphia chromosome
- BCR-ABL gene rearrangement
24
Q
What is the treatment and course for CML?
A
- Controlled but not cured by chemo
- Imantinib - tyrosine kinase inhibitor
- Survival on treatment usually measured in years, but eventually progresses to accelerated phase and then blast crisis
- Blast crisis resembles an acute leukaemia
- Allogenic bone marrow or stem cell transplant curative
- Autologous transplant sometimes tried (most people >50 cant tolerate)
25
Q
What is the philadelphia chromosome?
A
- 22q moves to chromosome 9
- balanced translocation - no loss or gain
- 95% of CML cases have Ph’
- Protein forms has end terminus of protein from BCR and rest from ABL
- ABL is a TK, but activity tightly regulated
- BCR-ABL protein has unregulated TK activity - switched on constantly
- Causes proliferation of progenitor cells in the absence of GFs, decreased apoptosis and decreased adhesion to bone marrow stroma
26
Q
How can we use the Ph’ for diagnosis?
A
- 95% of CML have Ph’ chromosome detectable
- Among the remaining 5%, some have a BCR-ABL gene rearrangement
- Cases without this rearrangment require different therapy
- Use PCR to detect the translocation
- 1 primer for BCR, 1 for ABL
- Only get PCR products if BCR and ABL sequences on same RNA molecuele
- Amplify and detect CML cells at low level
27
Q
What is Imantinib?
A
- Specific TK inhibitor
- Inhibits BCR-ABL but not most other TKs
- Pt driven to get drug approved in 4 years rather than usual 10-15
- Compared to previous treatments - more remission, greater durability and fewer side effects (some resistance however)
