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review haem > Haem: Acute Leukaemia > Flashcards

Haem: Acute Leukaemia Flashcards

1
Q

Which cell level does CML mutations tend to occur in?

A

Pluripotent haematopoietic stem cell

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2
Q

Which cell level does AML tend to occur in?

A

Pluripotent haematopoietic stem cell or multipotent myeloid stem cell

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3
Q

List some types of chromosomal abnormalities that can occur

A
  • Duplications
  • Loss
  • Translocation
  • Inversion
  • Deletion
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4
Q

How can altered DNA sequence lead to leukaemia?

A
  • By the creation of a fusion gene (AML and ALL)
  • By abnormal regulation of genes (mainly ALL)
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5
Q

Which chromosomal duplications are most commonly associated with AML?

A

chr 8 and chr 21 (hence the predisposition seen in Down syndrome)
Duplication means extra copies of proto-oncogenes

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6
Q

How might chromosomal deletion be oncogenic in AML

A

Loss of tumour suppressor genes or DNA repair genes
(common in AML, specifically deletions in chr 5 and chr 7)

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7
Q

List some molecular abnormalities that an occur in apparently normal chromosomes.

A
  • 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)
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8
Q

Describe the epidemiology of AML

A

Incidence increases with age

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9
Q

Describe the basic pathogenesis of AML

A

Block in the maturation of granulocytes leads to abnormal proliferation of blast cells

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10
Q

List some risk factors for AML.

A
  • Familial
  • Constitutional (e.g. Down syndrome)
  • Anti-cancer drugs
  • Irradiation
  • Smoking
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11
Q

What are type 1 and type 2 abnormalities with regards to leukaemogenesis?

A
  • 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

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12
Q

What is the main role of transcription factors?

A
  • 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
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13
Q

Give an example of how disruption of a transcription factor can lead to leukaemogenesis.

A
  • 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
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14
Q

Which chromosomal aberration causes APML?

(Acute Promyelocytic leukaemia)

A

Translocation 15;17

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15
Q

What is a complication of APML? Why does this occur?

A
  • Haemorrhage - this is because APML is associated with DIC and hyperactive fibrinolysis
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16
Q

Name the fusion gene that is responsible for APML.

A

PML-RARA

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17
Q

What is the difference in the maturity of cells in AML vs APML?

A

Block in maturation occurs later in the granulocyte lineage in APML, hence the proliferation of promyelocytes

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18
Q

Which microscopic feature is pathognomonic of myeloid leukemias?

A

Auer rods

19
Q

In what way are the promyelocytes in APML considered ‘abnormal’ histologically?

A

They contain multiple Auer rods

20
Q

Describe how the variant version of APML is different from the original version.

A
  • The variant form has granules that are below the resolution of a light microscope
  • They also tend to have bilobed nuclei
21
Q

Give a type 1 and type 2 mutation for APML.

A
  • Type 1: FLT3-ITD
  • Type 2: PML-RARA
22
Q

Give a type 1 and type 2 mutation for CBF leukaemias.

A
  • Type 1: sometimes mutated KIT
  • Type 2: mutations affecting function of CBF
23
Q

Which stain can be used to distinguish myeloid leukaemias from other leukaemias?

A

Myeloperoxidase

24
Q

List the clinical features of AML.

A

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

25
Q

Outline the tests that may be used to diagnose AML.

A
  • Blood film (DIAGNOSTIC) - can see circulating blast cells
  • Bone marrow aspirate
  • Cytogenetic studies (done in EVERY patient)
  • Molecular studies and FISH
26
Q

What is the significance of cytogenetic and molecular analysis in AML

A

Prognostic value and guides treatment

27
Q

What is aleukaemia leukaemia?

A

When there are no leukaemic cells in the peripheral blood but the bone marrow has been replaced

28
Q

Outline the treatment for AML.

A

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

29
Q

Describe the chemotherapy regime in AML

A
  • Combination chemotherapy is ALWAYS used
  • Usually given as 4-5 courses: 2x remission induction + 2/3x consolidation
  • Treatment usually lasts around 6 months
30
Q

List some determinants of prognosis in AML.

A
  • Patient characteristics
  • Morphology
  • Immunophenotyping
  • Cytogenetics
  • Genetics
  • Response to treatment
31
Q

How is AML differentiated from ALL

A

Immunophenotyping: identifies cell surface and cytoplasmic antigens
* Flow cytometry
* Immunocytochemistry
* Immunohistochemistry

32
Q

Describe the epidemiology of ALL

A

Peak incidence in childhood (most common childhood malignancy)

33
Q

Outline the clinical features of ALL.

A

Systemic symptoms

Bone marrow failure
* Anaemia
* Neutropenia
* Thrombocytopenia

Local infiltration
* Lymphadenopathy
* Splenomegaly
* Hepatomegaly
* Bone marrow
* Testes, CNS

34
Q

What is seen on peripheral blood smear and BM biopsy in ALL?

A

Lymphoblasts

35
Q

What is a key difference in the origin of B-lineage and T-lineage ALL?

A
  • B-lineage starts in the bone marrow
  • T-lineage can start in the thymus (which may be enlarged)
36
Q

List some possible leukaemogenic mechanisms in ALL.

A

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

37
Q

List some investigations used in the diagnosis of ALL.

A
  • FBC and blood film
  • Bone marrow aspirate
  • Immunophenotyping
  • Cytogenetic/molecular analysis
38
Q

Why is immunophenotyping important in ALL

A
  • Differentiate between AML and ALL (treated differently)
  • Differentiate between B cell and T cell lineage (treated differently)
39
Q

Why is cytogenetic/molecular analysis important in ALL

A

Prognosis and treatment guidance:
* Philidephia chr positive ALL requires imatinib
* Treatment must be tailored to prognosis

40
Q

What are the general principles of ALL treatment

A

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)

41
Q

What are the four phases of chemotherapy for ALL?

A
  • Remission induction
  • Consolidation and CNS therapy
  • Intensification
  • Maintenance
42
Q

How long does chemotherapy for ALL usually take? Why is it longer in boys?

A

2 years for girls, 3 years for boys

Longer in boys because the testes are a site of accumulation of lymphoblasts

43
Q

Who receives CNS-directed chemotherapy? How can this be given?

A
  • 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
44
Q

Give 2 examples of targeted molecular treatments in ALL

A

Tyrosine kinase inhibitors for Ph-positive ALL
Rituximab for CD20 positive ALL

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