Haem: Acute Leukaemia Flashcards
Which cell level does CML mutations tend to occur in?
Pluripotent haematopoietic stem cell
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 can occur
- Duplications
- Loss
- Translocation
- Inversion
- Deletion
How can altered DNA sequence lead to leukaemia?
- By the creation of a fusion gene (AML and ALL)
- By abnormal regulation of genes (mainly ALL)
Which chromosomal duplications are most commonly associated with AML?
chr 8 and chr 21 (hence the predisposition seen in Down syndrome)
Duplication means extra copies of proto-oncogenes
How might chromosomal deletion be oncogenic in AML
Loss of tumour suppressor genes or DNA repair genes
(common in AML, specifically deletions in chr 5 and chr 7)
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)
Describe the epidemiology of AML
Incidence increases with age
Describe the basic pathogenesis of AML
Block in the maturation of granulocytes leads to abnormal proliferation of blast cells
List some risk factors for AML.
- Familial
- Constitutional (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 differentation (this would normally be followed by apoptosis)
NOTE: leukaemogenesis in AML requires multiple genetic hits i.e. a type 2 abnormality alone would not be enough to cause leukaemia
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
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 with CBF leading to the formation of a fusion gene that drives leukaemia
- The fusion transcription factor binds to co-repressors leading to a differentiation block
- Inversion of chromosome 16 also affects CBF in a similar way
Which chromosomal aberration causes APML?
(Acute Promyelocytic leukaemia)
Translocation 15;17
What is a complication of APML? Why does this occur?
- Haemorrhage - this is because APML is associated with DIC and hyperactive fibrinolysis
Name the fusion gene that is responsible for APML.
PML-RARA
What is the difference in the maturity of cells in AML vs APML?
Block in maturation occurs later in the granulocyte lineage in APML, hence the proliferation of promyelocytes
Which microscopic feature is pathognomonic of myeloid leukemias?
Auer rods
In what way are the promyelocytes in APML considered ‘abnormal’ histologically?
They contain multiple Auer rods
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
- 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
Which stain can be used to distinguish myeloid leukaemias from other leukaemias?
Myeloperoxidase
List the clinical features of AML.
Systemic symptoms - Bone marrow failure:
- Anaemia - pallor, fatigue
- Neutropaenia - infection
- Thrombocytopaenia - bleeding
Local infiltration:
- Splenomegaly
- Hepatomegaly
- Gum infiltration (if monocytic)
- Lymphadenopathy (occasionally)
- CNS, skin or other sites
DIC
Hyperviscosity (if WCC is very high) - retinal haemorrhages and exudates
Outline the tests that may be used to diagnose AML.
- Blood film (DIAGNOSTIC) - can see circulating blast cells
- Bone marrow aspirate
- Cytogenetic studies (done in EVERY patient)
- Molecular studies and FISH
What is the significance of cytogenetic and molecular analysis in AML
Prognostic value and guides treatment
What is aleukaemia leukaemia?
When there are no leukaemic cells in the peripheral blood but the bone marrow has been replaced
Outline the treatment for AML.
Chemotherapy
BM transplant if treatment resistant
Supportive (important for patient to survive chemo)
- Red cells
- Platelets
- FFC/cryoprecipitate in DIC
- Antibiotics
- Allopurinol (prevent gout)
- Fluid and electrolyte balance
Describe the chemotherapy regime in AML
- Combination chemotherapy is ALWAYS used
- Usually given as 4-5 courses: 2x remission induction + 2/3x consolidation
- Treatment usually lasts around 6 months
List some determinants of prognosis in AML.
- Patient characteristics
- Morphology
- Immunophenotyping
- Cytogenetics
- Genetics
- Response to treatment
How is AML differentiated from ALL
Immunophenotyping: identifies cell surface and cytoplasmic antigens
- Flow cytometry
- Immunocytochemistry
- Immunohistochemistry
Describe the epidemiology of ALL
Peak incidence in childhood (most common childhood malignancy)
Outline the clinical features of ALL.
Systemic symptoms
Bone marrow failure
- Anaemia
- Neutropenia
- Thrombocytopenia
Local infiltration
- Lymphadenopathy
- Splenomegaly
- Hepatomegaly
- Bone marrow
- Testes, CNS
What is seen on peripheral blood smear and BM biopsy in ALL?
Lymphoblasts
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
- Fusion genes
- Wrong gene promotor
- Dysregulation due to proximity to TCR or Ig heavy chain loci
- Hyperdiploidy - mechanism unknown
List some investigations used in the diagnosis of ALL.
- FBC and blood film
- Bone marrow aspirate
- Immunophenotyping
- Cytogenetic/molecular analysis
Why is immunophenotyping important in ALL
- Differentiate between AML and ALL (treated differently)
- Differentiate between B cell and T cell lineage (treated differently)
Why is cytogenetic/molecular analysis important in ALL
Prognosis and treatment guidance:
- Philidephia chr positive ALL requires imatinib
- Treatment must be tailored to prognosis
What are the general principles of ALL treatment
Specific therapy
- Systemic chemotherapy
- CNS-directed therapy
- Targeted molecular therapy
- BM transplant
Supportive care
- Blood products
- Antibiotics
- General medical care (central line, gout management, hyperkalaemia management, sometimes dialysis)
What are the four phases of chemotherapy for ALL?
- Remission induction
- Consolidation and CNS therapy
- Intensification
- Maintenance
How long does 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
Give 2 examples of targeted molecular treatments in ALL
- Tyrosine kinase inhibitors for Ph-positive ALL
- Rituximab for CD20 positive ALL
