Concepts in Malignant Haematology and Acute Leukaemia Flashcards
** on every card with exam knowledge **
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Name the 5 processes which are important in the normal kinetics of haempoiesis.
- Self-renewal.
- Proliferation.
- Differentiation or lineage commitment.
- Maturation.
- Apoptosis.
** What techniques/methods can be used to identify normal (more mature) cells? **
** Morphology ** - blood count and film
Cell surface antigens – (glycophorin A would indicate red cells)
* Enzyme expression – (myeloperoxidase, an enzyme, would indicate it is a neutrophil)
The presence of the cell surface antigen glycophorin A would indicate?
Red cells
The presence of what enzyme would suggest that the cell was a neutrophil?
Myeloperoxidase
What techniques are used to identify morphology of cells?
Blood count and blood film
** How can we identify normal progenitor/stem cells? **
Immunophenotying
What does immunophenotyping look at?
Cell surface antigens e.g CD34
What is the problem with identifying normal progenitor/stem cells?
They are more difficult to recognise as they – microscopically – look the same.
How else (apart from immunophenotyping) can we identify normal progenitor/stem cells?
- Cell culture assays.
* Animal models (not practical in routine diagnostic practice).
** What cell surface antigen do haemopoietic stem cells express? **
CD34
What is malignant haemopoiesis characterised by?
Malignant haemopoiesis is usually characterised by:
- Increased numbers of abnormal + dysfunctional cells
- Loss of normal activity
** Increased numbers of abnormal + dysfunctional cells ** is seen in?
Malignant haemopoiesis
Acute leukaemias is a malignancy which affects haemopoiesis
T
Lymphomas are a malignancy which affects immune function
T
Malignant haemopoiesis arises due to ONE OR MORE of which 4 things?
- Increased proliferation.
- Lack of differentiation.
- Lack of maturation.
- Lack of apoptosis.
** Proliferation of abnormal progenitors (precursors) with block in differentiation /maturation ** what condition is this?
Acute leukaemia e.g acute myeloid leukaemia
Describe acute leukaemia.
** Proliferation of abnormal progenitors (precursors) with block in differentiation /maturation **
There is lots of abnormal proliferation with no maturation
Give an example of an acute leukaemia.
Acute myeloid leukaemia
What is the bone marrow filled with in acute leukaemia.
Bone marrow is filled up with primitive cells which proliferate excessively.
The cells are primitive as there is a block of maturation so they cannot divide
Describe the histological appearance of chronic myeloid leukaemia.
Although there is an increase in proliferation, maturation is occurring normally i.e. there are lots of different cell types
Describe the histological appearance of acute myeloid leukaemia.
There is an increase in proliferation, but failure to mature.
Describe chronic myeloproliferative disorders e.g chronic myeloid leukaemia.
Proliferation of abnormal progenitors but NO differentiation/maturation block
** What causes haematological malignancies? **
- Genetic, epigenetic and environmental factors
- Somatic mutations in regulatory genes – driver mutations vs passenger mutations
- Recurrent cytogenetic abnormalities
What are driver mutations?
Mutations in genes which regulate/drive growth
What is a clone?
Population of cells derived from a single parent cell
What are passenger mutations?
Mutations which reflect the noise of mutations which the cell is exposed to
What does the single parent cells (that makes a clone) have?
A genetic marker (driver mutation or chromosomal change) that is shared by the daughter cells.
Can clones diversify?
Yes, but they contain a similar genetic ‘backbone.’
** Normal haemopoiesis is polyclonal **
T
** Malignant haemopoiesis is usually monoclonal **
T
What do driver mutations do? When are these selected?
Confer growth advantage on the cells, and are selected during the evolution of the cancer.
What do passenger mutations do?
Do not confer growth advantage, but happen to be present in an ancestor of the cancer cell when it acquired one of its drivers.
What, observed in 10% of people older than 65y/o without a blood disorder, can predict the risk of haem malignancy subsequently?
Somatic mutations.
Outline how the different types of haematological malignancies are categorised.
- Based on lineage.
- Based on developmental stage (precursor) within lineage.
- Based on anatomical site involved.
Based on lineage, what can haematological malignancies be?
- Myeloid – granulocytes, platelets, erythrocytes, monocytes
* Lymphoid – B cell, T cell, NK cell
Based on lineage, what can haematological malignancies be?
- Myeloid – granulocytes, platelets, erythrocytes, monocytes
* Lymphoid – B cell, T cell, NK cell
Based on anatomical site involved, what can haematological malignancies be?
- Blood involvement: a leukaemia.
2. Lymph node involvement: a lymphoma.
What can chronic lymphocytic leukaemia involve?
Blood + Lymph nodes
What is a myeloma?
A plasma cell malignancy in marrow.
A malignancy under the term ‘myeloid’ can involve what?
- Granulocytes
- Platelets
- Erythrocytes
- Monocytes
A malignancy under the term ‘lymphoid’ can involve what?
- B cells
- T cell
- NK cell
Acute leukaemia and high-grade lymphoma (1)
Vs
Chronic leukaemia and low-grade lymphoma (2)
Which is more aggressive?
1
What are the histological features of an aggressive cancer?
- Large cells with high nuclear-cytoplasmic ratio.
- Prominent nucleoli.
- Rapid proliferation.
What is the main feature of clinical aggression?
Rapid progression of symptoms
- Open chromatin – smooth and active
Acute leukaemias (in contrast to chronic leukaemias) present with failure of normal bone marrow function
T
Acute leukaemia are usually problems with more primitive precursors
T
Describe acute leukaemia.
A rapidly progressive CLONAL malignancy of the marrow/blood with maturation defects
What is acute leukaemia defined as (in terms of scientific parameters)?
An excess of ‘blasts’ (≥20%) in either the peripheral blood or bone marrow
What is there a decreased/loss of in acute leukaemia?
Decrease/loss of normal haemopoietic reserve – because of the block in maturation, normal red cells, neutrophils and platelets do not appear.
What are the 2 main types of acute leukaemia?
- Acute myeloid leukaemia
* Acute lympoblastic leukaemia
Compare AML to ALL.
AML is more aggressive and involves the bone marrow
What is ALL a disease of?
Primitive lymphoid cells (lymphoblasts)
What is the name for primitive lymphoid cells?
Lymphoblasts
What is the - MOST COMMON CHILDHOOD CANCER (30-40 cases/million)?
ALL
ALL is the most common ….
Childhood cancer
What is the clinical presentation of ALL due to?
Marrow failure …
- Anaemia (low red cells)
- Infections (low neutrophils)
- Bleeding (low platelets)
** What are the important leukaemia effects to be aware of in ALL? **
- High count with obstruction of circulation
- Involvement of areas outside the marrow and blood (extramedullary) e.g. CNS, testis
- BONE PAIN !!!!!
What symptom is a big indicator that someone has ALL?
BONE PAIN !!!!
Who gets AML?
> 60 yo
How can AML arise?
Either ‘de novo’ or secondary to another cancer.
What can the presentation of AML be similar to? Why?
ALL - also associated with marrow failure
Some subgroups of AML may have a characteristic presentation. Give examples (2).
- Coagulation defect – called DIC.
* Gum infiltration – the type that affects monoblasts.
What are the 3 main Ix’s done for acute leukaemia?
- Blood count and film
- Coagulation screen
- Bone marrow aspirate
What will a blood count of someone with acute leukaemia show?
- Anaemia
- Thrombocytopenia
- Neutropenia
BUT might have a high white cell count because of lots of immature cells.
What will a blood film of someone with acute leukaemia show?
- Reduction in normal cells.
- Presence of abnormal cells.
- The abnormal cells (‘blasts’) have a high nuclear:cytoplasmic ratio.
Apart from the 3 main Ix’s for acute leukaemia, what other investigations are also very important?
- Morphology – what do the cells look like?
* Immunophenotyping – are there lineage specific proteins on the cell surface
In what condition are ‘AUER RODS’ seen?
In AML - acute myeloid leukaemia
What is the importance of doing a coagulation screen in someone with suspected acute leukaemia?
Some acute leukaemias are associated with DIC which can cause life-threatening bleeding
NOTE: when taking a bone marrow aspirate from an adult remember to locate which bones in the adult have marrow e.g axial skeleton and long bones
T
Where can bone marrow in an adult be found?
Axial skeleton + long bones
** What is required for a DEFINITE diagnosis of acute leukaemia (i.e ALL vs AML)? **
** IMMUNOPHENOTYPING **
Why is the diagnosis between AML and ALL so important?
Because the treatments are very different
What is the treatment of acute leukaemia?
Multi-agent chemotherapy
Hickman line – used to give chemotherapy
Describe the treatment of ALL.
Different phases of treatment of varying intensity (induction, consolidation, intensification, maintenance).
Also, targeted treatments in certain subsets
How long can treatment of ALL last?
2-3 years
Describe the treatment of AML.
Normally intensive.
Between 2-4 cycles of chemotherapy (5-10days of chemo, followed by 2-4weeks of recovery).
Prolonged hospitalisation.
What are the 3 main problems associated with the suppression of bone marrow?
- Anaemia
- Neutropenia – infection from a gram -ve organism usually
- Thrombocytopenia – bleeding, purpura, petechiae (plt <20 x 109)
What kind of infection do people with bone marrow suppression usually get?
Gram -ve
Is the gram -ve infection in people with bone marrow suppression usually from them or the environment?
Them - usually bowel bacteria
What can a gram -ve infection cause in people with bone marrow suppression?
Fulminant life-threatening sepsis in neutropenic patients
What should you do if you suspect that someone with bone marrow suppression has a gram -ve infection?
TREAT WITH ABX ASAP - do not wait for culture results
To get bleeding, petechiae, and purpura what must your platelet count be?
plt <20 x 109)
What causes bleeding, petechiae, and purpura?
Thrombocytopenia
Outline the 4 main complications of treatment of acute leukaemia (i.e chemo).
- Nausea and vomiting
- Hair loss
- Liver, renal dysfunction
- Tumour lysis syndrome
This usually occurs during the first course of treatment
** When should you suspect a bacterial infection in someone with bone marrow suppression? **
- Suspect this as soon as a neutropenic fever onsets
** What should you do if you suspect someone with bone marrow suppression has a bacterial infection? **
Give empirical treatment with broad spectrum antibiotics (particularly covering gram -ve organisms) as soon as neutropenic fever
** When should you suspect a fungal infection in someone with bone marrow suppression? **
If there is prolonged neutropenia and persisting fever even after giving antibiotics you should start to suspect this
Although bacterial infections are more common, patients are also susceptible to fungal infections
T
What patients mostly get protozoa infection?
ALL therapy patients
Give 2 examples of late effects of bone marrow suppression.
- Loss of fertility.
* Cardiomyopathy with anthracyclines.
What is remission defined as?
<5% marrow blasts with recovery of normal haemopoiesis
Many patients go into remission
T
Unfortunately remissions may not durable depending on the type of acute leukaemia and
many patients will relapse
T
Patients NEVER die of treatment related toxicity
F - some of them do :(
What do molecular ‘targeting’ with kinase inhibitors treat?
ALL with the PHILADEPHIA chromosome.
What is the final Tx of someone with ALL?
Allogenic stem cell transplantation in select patients
