Haem: Acute Leukaemia Flashcards
Define Leukaemia
Uncontrolled proliferation of immature white blood cells - accumulating in bone marrow or blood. Leukaemia arises due to the presence of mutations at various points in B and T cell lineages
Different from lymphomas as lymphomas typically form solid tumours in lymph nodes, thymus and spleen
Outline the types of classifications of Leukaemias
Acute v Chronic
Lymphoid v Myeloid
Characteristics of acute leukaemias
- Rapid onset
- Early death if untreated (weeks, months)
- Immature cells (blasts)
- Bone marrow failure –> anaemia, neutropenia (infections), thrombocytopenia (bleedings)
Which cell level does CML tend to occur in?
Pluripotent haematopoietic stem cell
During the chronic phase it is characterised by overproduction of myelocytes (granulocyte precursors). Over the period where the leukaemic cells are proliferating more rapidly this increases the risk of furthter mutations to occur. If they do occur this causes CML to turn into an Acute crisis.
Which cell level does AML tend to occur in?
Pluripotent haematopoietic stem cell or multipotent myeloid stem cell
List some types of chromosomal abnormalities that are associated with AML.
- Duplications
- Loss
- Translocation
- Inversion
- Deletion
Describe the incidence of AML in terms of age. How does it differ from ALL.
AML: Incidence increases with age (prognosis worsens with age and 40% of patients are adults)
ALL: Childhood cancer
How can mutations that lead to Leukaemia arise
- Majority due to aberrations in chromosome count or structure
- Other patients may have molecular changes (with apparently normal chromosomes)
How can altered DNA sequence lead to leukaemia?
Duplication:
* potential dosage effect - increased copies of proto-oncogenes
Inversion or Translocation:
* By the creation of a fusion gene
* By abnormal regulation of genes
Chromosomal loss
* loss of tumour suppressor gene
* possible loss of DNA repair systems
Which chromosomal duplications are most commonly associated with AML?
8 and 21 (there is a predisposition seen in Down syndrome)
List some molecular abnormalities that an occur in apparently normal chromosomes.
- Point mutations —> Loss of function of tumour suppressor genes
- Partial duplication
- Cryptic deletion (formation of a fusion gene by deletion of a small section of DNA)
List some risk factors for AML.
- Familial
- Constitutional predisposition (e.g. Down syndrome)
- Anti-cancer drugs
- Irradiation
- Smoking
What are type 1 and type 2 abnormalities with regards to leukaemogenesis?
- Type 1: promote proliferation and survival (anti-apoptosis)
- Type 2: block differentiation (leading to blast cell accumulation)
Leukaemogenesis in AML REQUIRES multiple genetic hits (at least one of each type)
What is the main role of transcription factors?
- They bind to DNA, alter the structure to favour transcription and, ultimately, regulate gene expression
- Disruption of transcription factors can result in failure of differentiation (type 2 abnormality)
Give an example of how disruption of a transcription factor can lead to leukaemogenesis.
- Core binding factor (CBF) is the master controller of haemopoiesis
- Translocation 8;21 fuses RUNX1 leading to the formation of a fusion gene that drives leukaemia
- The fusion transcription factor binds to co-repressors rather than co-activators leading to a differentiation block
- Inversion of chromosome 16 also affects CBF in a similar way
What is APML?
Similar leukaemia to AML however development arrest occurs later down the cell line (in promyelocytes - which are granulocyte precursors)
Which chromosomal aberration causes APML?
Translocation 15;17
What is a characteristic feature of APML? Why does this occur?
- Acute Sudden onset Haemorrhage - this is because APML is associated with DIC and hyperactive fibrinolysis
Name the fusion gene that is responsible for APML.
PML-RARA
In what way are the promyelocytes in APML considered ‘abnormal’?
They contain multiple Auer rods (as they are hyper granular)
Describe how the variant version of APML is different from the original version.
- The variant form has granules that are below the resolution of a light microscope - hence are not seen in light microscopy!
- They also tend to have bilobed nuclei
Give a type 1 and type 2 mutation for APML.
- Type 1: FLT3-ITD
- Type 2: PML-RARA
Give a type 1 and type 2 mutation for CBF leukaemias.
- Type 1: sometimes mutated KIT
- Type 2: mutations affecting function of CBF
Outline the diagnostic pathway for the differentiation of myeloid leukaemias to lymphoid
Differentiate form other types of leukaemia by:
- Cytological features: 1) fine speckled granules in cytoplasm 2) Auer rodes (pathognomic of myeloid leukaemias)
- Cytochemistry stains (no longer used as much)
- Immunophenotyping - best way to determine lymphoid from myeloid
* Flow cytometry
Which microscopic feature is pathognomonic of myeloid leukemias?
Auer rods
Which stain can be used to distinguish myeloid leukaemias from other leukaemias?
Myeloperoxidase
List the clinical features of AML.
- Bone marrow failure (anaemia, neutropaenia, thrombocytopaenia)
- Local infiltration (splenomegaly, hepatomegaly, gum infiltration, lymphadenopathy, CNS, skin)
- Hyperviscosity if WBC is very high (can cause retinal haemorrhages and exudates)
Outline the tests that may be used to diagnose AML.
- Blood film (looking for Auer rides or granules - if neither use immunophenotyping to determine AML vs ALL)
- Bone marrow aspirate
- Cytogenetic studies (done in EVERY patient)
- Molecular studies and FISH (in some patients - adds prognostic value and aids treatment decisions)
What is aleukaemia leukaemia?
When there are no leukaemic cells in the peripheral blood but the bone marrow has been replaced
Outline the supportive care given for AML.
- Red cells
- Platelets
- FFC/cryoprecipitate in DIC
- Antibiotics
- Allopurinol (prevent gout)
- Fluid and electrolyte balance
What are the principles of treatment of AML?
CHEMOTHERAPY:
* Damage the DNA of cells continuously dividing that lack cell cycle checkpoint control (leukaemia cells)
* Combination chemotherapy is ALWAYS used
* Usually given as 4-5 courses (2x remission induction + 2/3x consolidation)
* Treatment usually lasts around 6 months - consider bone marrow transplantation if poor prognosis
List some determinants of prognosis in AML.
- Patient characteristics
- Morphology
- Genetics
- Immunophenotyping
- Cytogenetics
- Response to treatment
Outline the incidence in regards to age in ALL
peak incidence in childhood (commonest childhood malignancy) however prognosis is worse with increasing age.
Outline the clinical features of ALL.
Bone marrow failure
Local infiltration
* lymphadenopathy (a differing clinical picture from AML and ALL involves Lymphocytes which are commonly found in the lymph nodes
* splenomegaly
* hepatomegaly
* Testes, CNS
* Bones (resulting in bone pain - usually a differentiating sign of ALL vs AML)
What is a key difference in the origin of B-lineage and T-lineage ALL?
- B-lineage starts in the bone marrow
- T-lineage can start in the thymus (which may be enlarged)
List some possible leukaemogenic mechanisms in ALL.
Protooncogene dysregulation due to chromosomal abnormalities (resulting in fusion genes, altered gene promoters, hyperploidy)
List some investigations used in the diagnosis of ALL.
- FBC and blood film (anaemia, neutropoenia, throbocytponoea, lymphoblasts)
- Bone marrow aspirate –> 20% blast cells
- Immunophenotyping (crucial for AML vs ALL and also differentiation of L or B cell lineage - as they are treated very differently)
- Cytogenetic/molecular analysis (this is important as if Philadelphia chromosome +ve then treatment requires imatinib)
What are the four phases of chemotherapy for ALL?
- Remission induction
- Systemic and CNS therapy
- Intensification
- Maintenance
How long does systemic chemotherapy for ALL usually take? Why is it longer in boys?
2 years for girls // 3 years for boys
Longer in boys because the testes are a site of accumulation of lymphoblasts
Who receives CNS-directed chemotherapy? How can this be given?
- All patients should receive CNS-directed chemotherapy
- This can be given intrathecally or a high dose of chemotherapy could be given such that it penetrates the BBB
Outline the supportive care for ALL.
- Blood products
- Antibiotics
- General medical care (central line, gout management, hyperkalaemia management, sometimes dialysis)
