Leukaemia Flashcards
1
Q
Define leukaemia
A
- A cancer of haemopoietic cells usually associated with increased numbers of white blood cells in the bone marrow or the blood
2
Q
What are the four types of leukaemia
A
- Acute lymphoblastic leukaemia (ALL)
- Acute myeloid leukaemia (AML)
- Chronic myeloid leukaemia (CML)
- Chronic lymphocytic leukaemia (CLL)
3
Q
describe normal blood cell development from a haematopoietic system
A
- Start with haemopoietic stem cell – called a stem cell can divide into lymphoid progenitor or myeloid progenitor
- Lymphoid progenitor differentiates into B and T lymphocyte
- Myeloid progenitor divides into neutrophils, eosinophils, basophils, monocyte, platelets, red cell
- B lymphocytes – have an antibody that is designed to recognise an antigen
4
Q
Where does acute lymphoblastic leukaemia begin
A
- Acute lymphoblastic leukaemia occurs at the lymphoid progenitor stage – stuck at this stage and makes lots of copies of lymphoid progenitor
5
Q
Where does acute myeloid leukaemia begin
A
- Acute myeloid leukaemia occurs at the myeloid progenitor stage - stuck at this stage and makes lots of copies of myeloid progenitor
6
Q
Where does chronic lymphoblastic leukaemia begin
A
- Chronic lymphoblastic leukaemia occurs at naïve B lymphocyte
7
Q
Where does lymphoma begin
A
- Lymphomas occurs at T lymphocyte (happens in the lymph nodes) and B lymphocytes
8
Q
Where does myeloma begin
A
Myeloma occurs at plasma cell – cancer of plasma cells
9
Q
where do blood cells come from
A
- Bone marrow
10
Q
Where do blood cells come from in adults
A
- In adults it is mainly in the hip bone, makes all the cells that float in the peripheral blood
11
Q
What lab tools are diagnosed for haematological malignancies
A
Morphology
- Blood film
- Bone marrow biopsy – look at the bone marrow and see if we are seeing normal development
Immunophenotyped
- Flow cytometry
Genetic and molecular features
- Chromosome abnormalities: G banding and FISH
- Gene point mutations, insertions/deletions: PCR based
12
Q
What does flow cytometry distinguish between
A
- Cancerous from normal tissue
- Different types of haematological malignancies
13
Q
describe how flow cytometry work
A
- Lets say we know CD20 is a marker on a cell surface that is normally in lymphoid cells and not myeloid cells
- Use an antibody that links to CD20 – attached to a fluorescent
- Then the laser would measure the fluorescent
- Picking up how many cells have CD20 on the surface
- Compare to the normal ranges
14
Q
How does G banding (genetic and molecular tests) work and what is it used for
A
- Used to detect chromosomal abnormalities
- Cells are cultured for a short time and then are stopped at metaphase and coloured by Giemsa
15
Q
How does FISH (fluorescence in situ hybridization)
A
- Does not need to be used with cells in metaphase
- Technique using fluorescent probes to detect a specific DNA sequence
- Can identify chromosomal translocations or gains or losses of regions in the genome
- Need to know what your looking for whereas cytogentics you can see what abnormalities are there
16
Q
What is a mutation
A
Change in the DNA sequence
17
Q
What does a mutation do
A
- If the change affects the protein sequence and function of the translated protein can contribute to disease cancer
18
Q
How are mutations detected
A
- Detected by sequencing technologies
19
Q
What is acute leukaemia characterised by
A
- Characterised by the accumulation of large numbers of undifferentiated cells called blasts in the bone marrow
- Block in differentiation
- These blasts rapidly overwhelm normal blood cells and then spill into the peripheral blood
20
Q
What are the two types of acute leukaemia
A
acute myeloid leukaemia
acute lymphoid leukaemia
21
Q
What are the signs and symptoms of acute leukaemias: AML, ALL
A
- Signs and symptoms of bone marrow failure
- anaemia = tiredness, shortness of breath
- WCC – infections if low or leucostasis if high, the blood viscous sticky/cloggy causing problems with smooth blood flow in vessels leading to stroke/confusion
- Low platelets – bleeding and bruising
- Aggressive/fast growing/fatal if untreated
22
Q
What causes acute myeloid leukaemia (AML)
A
- Associated with T(15:17) fusion of PML and RARA
23
Q
Who does acute myeloid leukaemia (AML) tend to affect
A
– occurs in older people
24
Q
Describe the presentation of acute myeloid leukaemia (AML)
A
Usually presents with Disseminated intravascular coagulation or thrombocytopenia
Bone marrow failure
- Neutropenia, fever, pneumonia, fungal infection, thrombocytopenia, bleeding, anaemia
Infiltration
- Hepatomegaly, splenomegaly, gum hypertrophy, skin involvement, CNS involvement (rare)
Elevated white blood cell - Blasts from the bone marrow spilling into the peripheral blood
- Causes leukostasis(headache, stroke, confusion)
Bone pain
– blasts rapidly dividing in the bone marrow
25
How do you diagnose acute myeloid leukaemia (AML)
- abnormal FBC – low haemoglobin or high, or low Whtie Cell Count /low platelets
- Blast cells can be found in the peripheral blood
- Diagnosis depends on the bone marrow biopsy, immunophenotyping and molecular methods - AUER RODS are present in the bone marrow biopsy
- raised urate and LDH
- clotting (AMPL- can cause abnormal clotting)
- Immunophenotyping (flow cytometry)– CD34+ (marker of immature myeloid cell)
- Cryogenics – 7q – abnormalities on chromosome 7
- Mutations FLT3
26
what does acute myeloid leukaemia (AML) look like in a blood film and on a biopsy
- Elongated structures – grouping of granules
| - Auer rods present on a biopsy
27
How do you treat acute myeloid leukaemia (AML)
- Anaemia = blood transfusion
- Thrombocytopenia = platelet transfusion
- Neutropenia (need to be treated ASAP if temperature) = prophylactic antibodies and prompt treatment of neutropenic sepsis (temperature greater than 30 degrees, neturophils) with broad spectrum antibiotics
- Tumour lysis (renal failure, high potassium, high urate, high phosphate, low calcium); fluids = allopurinol, rasburicase
- Lecuostasis(really high white cell count): emergency venesection or leucopharesis
Currently
- Intensive chemotherapy
- Allogenic stem cell transplant
28
what do cytogenetics matter in acute myeloid leukaemia (AML)
- These matter in terms of progressive free survival years
- Thus they impact the abnormalities on outcome in AMP
Patietns are risk stratified based on cytogenetics and mutations
- Good risk – 4 cycles of intensive chemotherapy
- Intermediate/poor risk – chemotherapy to remission then allogenic transplant
29
What does it mean for treatment if patients have good cytogenetics versus poor cytogenetics in acute myeloid leukaemia (AML)
- Good risk – 4 cycles of intensive chemotherapy
| - Intermediate/poor risk – chemotherapy to remission then allogenic transplant
30
What chemotherapy is used for acute myeloid leukaemia (AML)
- Has been no new drugs for standard AML since 1960s and 1970s
- usually a combination of daunorubicin and cytarabine - anti metabolites interfere with DNA synthesis
31
what cells are affected by chemotherapy for Acute myeloid leukaemia
Affects cells that have a high turnover
- Leukaemia cells
- Normal cells such as hair cells
- cells of the gut and intestinal tract
- Bone marrow
32
What are the two treatment options for Acute myeloid leukaemia (AML)
- Chemotherapy
| - Allogenic bone marrow transplant
33
what do you do with the bone marrow cells will having chemotherapy
- Auto – give back your own stem cells - Mainly used in myelomas and lymphomas – use heavy chemo to wipe out the bone marrow
- Allo – give back someone’s elses stem cells – can be used as treatments for acute leukaemia’s.- use someone elses stem cells
34
What are the two types of allogenic transplant (treatment for Acute myeloid leukaemia (AML))
- Myeloablative
| - reduced intensity
35
describe the two types of allogenic transplant (treatment for Acute myeloid leukaemia (AML))
- Myeloablative – wipe out BM completely
- Reduce intensity: make some room in BM for new stem cells – don’t wipe out BM completlety, just give some chemotherapy – kill the tumour cells, immune reaction against residual tumour cells
36
How does an allogenic transplant work
Allogeneic transplant works via immune reaction against residual tumour cells (though conditioning chemoradiotherapy can help kill AML cells).
37
how can you harvest bone marrow cells
- Collect from the bone marrow – done under GA
| - Or can give someone GCSF
38
How does G-CSF work
- Given to the donor or patient subcut for 4 days – collect day +5
- Mobilises CD34+ stem cells into peripheral blood
- Collected by leucaphresis
- No GA
- No evidence of late haem effects for donors
39
What does survival depend on in AML
- Depends to cytogenic risk group
40
How many patents survive AML
- 50% of children and young adults can expect a long-term cure
- Less than 10% of patients over 70 can expect a long-term remission
41
What is acute promyelocytic leukaemia (AMPL)
- Subtype of AML
42
What is the characteristic of acute promyelocytic leukaemia (AMPL)
- Characteristic morphology of cells (hypergranular promyelocytes)
43
What is the presentation of acute promyelocytic leukaemia (AMPL)
- Present with abnormal clotting – sevre bleeding or clots
44
What causes acute promyelocytic leukaemia (AMPL)
- T15:17 – fusion of PML and RARA to generate PML-RARA oncoprotein
45
How do you treat acute promyelocytic leukaemia (AMPL)
- Treatment involves ATRA/Arsenic/anthracyclines
| - Very treatable with remission rates of greater than 90%
46
What is a Hickman line and when is it used
- Need to do lots of blood tests
- They go into the larger veins and can stay in or weeks and months
- Look for clots and infections
47
What is acute lymphoblastic leukaemia (ALL)
- Malignancy of lymphoid cells affecting either B or T lymphocytes cell lineage, arresting maturation and promoting uncontrolled proliferation of immature blast cells
48
Who does acute lymphoblastic leukaemia (ALL) occur in
- Most common childhood cancer
| - Peak indigence 2-4 years
49
What are the signs and symptoms of acute lymphoblastic leukaemia (ALL)
General
- Lerthary
- Bone pain
- Anorexia
Marrow failure
- Neutropenia and resultant infection due to thrombocytopenia
Infiltration
- hepatomegaly, splenomegaly, lymphadenopathy, testicular swelling
- Thrombocytopenia and bleeding
- Anaemia
CNS involvement
- Cranial nerve palsies and meningism
Lymphadenopathy
- Mediastinal – SVC obstruction
Abdominal Organomegaly
CNS involvement
50
How do you diagnose Acute lymphoblastic leukaemia (ALL)
- Abnormal full blood count – low haemophibic/high or low WCC/low platelets
- Blast cells on blood film and bone marrow
- Renal function
- Blood film
- Bone marrow biopsy
- Immunophenotyping – CD34+, TdT
- Cytogenetics
- Mutations
51
What is the treatment for Acute lymphoblastic leukaemia (ALL)
- Remission induction – killed most of the cells – vincristine, prednisolone, daunorubicin, asparaginase
- Consolidation – various combiantions of hcemotherapuetic agents
- CNS directed therapy – high dose systemic and intrathecal methotrexate – drugs that penetrate the BBB
- Maintenance therapy – vincristine, prednisolone, mercaptopurine and methotrexate for 2-3 years
52
What is the response of treatment for Acute lymphoblastic leukaemia (ALL)
Childhood ALL
- Greater than 95% achieve remission
- Greater than 80% remain in remission
- Treatment is now stratified on basis of initial presenting features and speed of response
Adult
- Lower remission rate (80%) with long term remission of only 20-40%
- May need allogenic bone marrow transplant
53
What provides diagnostic and prognostic information in Acute lymphoblastic leukaemia (ALL)
ALL cytogenetics
| - Provides important diagnostic and prognostic information
54
Name the chronic leukaemias
- Chronic myeloid leukaemia (CML)
| - Chronic lymphocytic leukaemia (CLL)
55
What is Chronic lymphocytic leukaemia (CLL)
- Proliferation of small mature B lymphocytes in the BM and PB
56
Who does Chronic lymphocytic leukaemia (CLL) present in
- Median age of presentation is 65-70 years
| - Incidence = 5-9/100,000
57
What are the signs and symptoms of Chronic lymphocytic leukaemia (CLL)
Symptoms
- Often none, presenting as surprise finding on routine FBC
- Could have weight loss, night sweats, anorexia if severe
Signs
- Enlarged rubbery non-tender nodes
- Splenomegaly
- Hepatomegaly
58
How do you diagnose Chronic lymphocytic leukaemia (CLL)
- FBC – lymphocytosis and anaemia
- Blood film = Smudge cells (also known as smear cells)
- Autoimmune haemolysis
- Marrow infiltration = haemoglobin decreases, neutrophils decreased, platelets decreased
59
In a white cell count what cell is raised in Chronic lymphocytic leukaemia (CLL)
Lymphocytes
60
What does a blood film look like in Chronic lymphocytic leukaemia (CLL)
- Lots of small mature lymphocytes with monomorphic appearance
- Smear cells – artefact produced by smear
61
What are the indications of treatment for Chronic lymphocytic leukaemia (CLL)
- Some patients may just be observed initially
Indications for treamtnet
- Progressive marrow failure
- Massive LN/organomealgy
- Systemic symptoms
- Autoimmune cytopenias: haemolysis(AIHA), platelets (ITP)
62
What is the treatment for Chronic lymphocytic leukaemia (CLL)
- No benefit in treating early stage disease – can just be oberevd
- Autoimmune complications (haemolytic anaemia) treated with steroids
- Alkylating agents – chlorambucil – used less commonly as first line
- Purine analogues – fludarabine
- Combination chemotherapy – FCR
- Rituximab is an anti- CD20 mAb – on surface of lots of B lymphocytes
- Supportive care (immunisations/blood transfusions/treatment of infections)
63
What are the poor prognostic features of Chronic lymphocytic leukaemia (CLL)
- Lymphocytes doubling time = less than 12 months
- Certain chromosomal changes
- Mutations or deletions of the tumour suppressor gene TP53
64
What does a bone marrow biopsy look like in Chronic lymphocytic leukaemia (CLL) and what does a blood film look like in CLL
Bone marrow Biopsy = full of CLL cells
Blood film = Smudge cells (also known as smear cells)
65
do people get symptoms with Chronic lymphocytic leukaemia (CLL)
- 80% of the patients diagnosed are asymptomatic – detected on routine FBC
66
What is chronic myeloid leukaemia (CML)
- Characterised by an uncontrolled clonal proliferation of myeloid cells
67
What are the signs and symptoms of chronic myeloid leukaemia
Symptoms
- Weight loss
- Tiredness
- Fever
- Sweats
- Gout – due to purine breakdown
- Bleeding – platelet dysfunction
- Abdominal discomfort – splenic enlargement
Signs
- Splenomegaly
- Hepatomegaly
- Anaemia
- Bruising
68
What are the three phases of chronic myeloid leukaemia present (CML)
- Chronic phase 3-5 years
- Accelerated phase 3-6 months
- Blast crisis – 3 months
- Death
69
What is the treatment of chronic myeloid leukaemia present (CML)
- Imatinib (Glivec) - Tyrosine kinase inhibitor
| - Novel small molecular inhibitor of bcr-abl; highly tumour specific
70
What mutation causes chronic myeloid leukaemia present (CML)
- discovery of t(9;22) (Philadelphia chromosome)
- Nearly all cases involve this translocation of chromosomes 9 and 22
- Called bcr-abl fusion gene
- Overacting kinase
- ABL protein is a tyrosine kinase (an enzyme that adds phosphate groups – phosphorylation)
- After the fusion, oncoprotein has uncontrolled tyrosine kinase activity
71
What is the name of the chromosome responsible for chronic myeloid leukaemia present (CML)
t(9;22) (Philadelphia chromosome)
72
What is myelodysplasic syndrome
* Ineffective production (or "dysplasia") of blood cells.
* Problem with hematopoietic stem cells in bone marrow so they end up making faulty (dysplastic) red cells, neutrophils and platelets (myeloid lineage)
73
What are the symptoms of myelodysplasic syndrome
• Patients can develop severe anaemia, neutropenia and thrombocytopenia requiring blood transfusions. (bone marrow failure).
74
Who does myelodysplasic syndrome usually effect
• Usually in elderly >65
75
How do you diagnose myelodysplasic syndrome
• Diagnosis with blood film, bone marrow biopsy, cytogenetics.
76
What is the prognosis of myelodysplasic syndrome
• Prognosis depends on type and severity.
77
How do you treat myelodysplasic syndrome
• Supportive treatment-transfusions, treat infections, newer drugs-azacytadine (DNA demethylating agent) and bone marrow transplant.
78
what disease can myelodysplasic syndrome transform to
• Can transform to AML
79
What differentiates AML from ALL
AML - this has Auer rods present in it
80
What are the complications of AML
- Predisposition to infection
- chemotherapy causes plaza rate levels to rise from tumour lysis so give allopurinol with chemotherapy and keep well hydrates with IV fluids
- leukostasis may occur if there is a raised WCC count
81
What are the types of acute lymphoblastic leukaemia
- Common ALL – CD10 present (75%)
- T cell ALL (20%)
- B cell ALL (5%)
82
What are the complications of CLL
- Warm Autoimmune haemolysis
- Increased infection due to hypogammaglobulinaemia – leading to recurrent infections
- Marrow failure
- Transformation to high grade lymphoma (Richter’s transformation)
83
What is Richter's transformation
This occurs when leukaemia cells enter the lymph node and change into high grade fast growing non-hodgkin's lymphoma
84
What are the indications that Richter's transformation has taken place
Indicated by
- Lymph node swelling
- fever without infection
- weight loss
- night sweats
- nausea
- abdominal pain
85
What do tests show in chronic myeloid leukaemia
- Increase in granulocytes at different stages of maturation +/- thrombocytosis
- Decreased leukocyte alkaline phosphatase
- Increased neutrophils, monocytes, basophils, eosinophils
- Reduced haemoglobin
- Increased urate, Increase B12
- Bone marrow hypercellular
86
List the main differences between acute and chronic leukaemias
Acute
- Acute onset
- Happens within weeks
- ALL = only in children
- Come from the most immature cells
- Bear no resemblance to the mature cells
Chronic
- Years without any symptoms at all
- Slow onset of disease
- Resemble the mature cells a little bit more
