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YR5 Haematology > Acute Leukaemia > Flashcards

Acute Leukaemia Flashcards

1
Q

Give 4 features of acute leukaemia

A

Rapid onset

Early death if untreated

Immature cells (blast cells) replace normal tissue

BM failure:

  • Anaemia: Fatigue, pallor, breathlessness
  • Neutropenia: Infections
  • Thrombocytopenia: Bleeding
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2
Q

What are features of acute myeloid leukaemia?

A

Increases with age

Prognosis worse with increasing age

40% of adults cured

Aberrations in Chr count/ structure

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3
Q

Which chromosomal translocations are associated with acute myeloid leukaemia?

A

t(15;17)

t(5;8)

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4
Q

Which chromosomal inversion is associated with acute myeloid leukaemia?

A

Inv (16)

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5
Q

What results from chromosomal translocations and inversions in acute leukaemia?

A

Altered DNA sequence

Creation of new fusion gene (AML + ALL)

Abnormal regulation of genes (mainly ALL)

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6
Q

What is the association between chromosomal duplication and AML?

A

Common in AML

Disease hotspots: +8 and +21 give predisposition

Possible dosage effect: extra copies of proto-oncogenes

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7
Q

Distinguish between an oncogene and protooncogene

A

Onco: Can contribute to neoplastic condition

Proto: potential to develop into oncogene

Most people use the term oncogene to describe both

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8
Q

What is the association between chromosomal loss or deletion and AML?

A

Common in AML

Disease hotspots: Deletions + loss of 5/5q + 7/7q

Possible loss of tumour suppressor genes.

Alternative explanation: 1 copy of an allele may be insufficient for normal haemopoiesis. Possible loss of DNA repair systems.

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9
Q

What are the molecular abnormalities in patients with apparently normal chromosomes which can result in AML?

A

Point mutation: NPM1, CEBPA

Loss of tumour suppressor genes

Partial duplication: FLT3

Cryptic deletion

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10
Q

Where does the block in maturation usually arise in AML?

A

Between myeloblast + pro-myelocyte

Proliferation continues

Increased blasts

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11
Q

What are 5 risk factors for AML?

A

Familial or constitutional predisposition

Irradiation

Anticancer drugs

Cigarette smoking

Unknown

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12
Q

What is leukaemogenesis in AML?

A

Multiple genetic hits

At least 2 interacting molecular defects

Synergise to give leukaemic phenotype

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13
Q

What are the two types of abnormalities in leukaemogenesis in AML?

A

Type 1: Promote proliferation + survival.

Type 2: Block differentiation (which would normally be followed by apoptosis).

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14
Q

How is differentiation affected in AML?

A

Transcription factors:

Bind to DNA

Alter structure to favour transcription

Regulate gene expression

If TF function is disrupted, cells can’t differentiate.

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15
Q

What can be seen in t(8,21) AML?

A

Some maturation; not all blast cells.

Failure of adequate differentiation, not complete block

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16
Q

What can be see in inv(16), t(16;16) AML?

A

Some maturation to bizarre eosinophil precursors with giant purple granules.

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17
Q

What can be seen in acute promyelocytic leukaemia with t(15;17)?

A

Excess of abnormal promyelocytes.

Disseminated intravascular coagulation (DIC).

2 morphological variants but the same disease.

Molecular mechanism is understood, thus molecular tx can be applied.

Majority of patients can be cured.

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18
Q

What are the two types of abnormalities in acute promyelocytic leukaemia?

A

T1: FLT3 -ITD

T2: t(15;17) PML-RARA

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19
Q

What are abnormalities in leukaemogenesis in CBF leukaemias?

A

T1: Sometimes mutated KIT

T2: Mutation affecting function of CBF

(core binding factor)

20
Q

What is the difference between cytochemistry between AML and ALL?

A

AML: Stain +ve for Myeloperoxidase (Gr), Sudan black (Gr) + Non-specific esterase (Mo)

ALL: -ve

21
Q

What can be used if cytochemistry does not differentiate between AML and ALL?

A

Immunophenotyping:

Cell surface and cytoplasmic antigens

  • Flow cytometry
  • Immunocytochemistry: antibodies to cells on slide
  • Immunohistochemistry: antibodies to tissue sections
22
Q

What immunophenotypes are associated with ALL?

A

B-cell: CD19, CD20, TdT, CD10 +/-

T-cell: CD2, CD3, CD4, CD8, TdT

(TdT only in immature blast cells)

23
Q

What immunophenotypes are associated with AML?

A

MPO (Myeloperoxidase)

CD13

CD33

CD14

CD15

Glycophorin (Erythroid)

Platelet antigens

24
Q

What immunophenotypes are associated with both ALL and AML?

A

CD34 (Immature)

CD45 (Common leukocyte antigen)

HLA-DR

25
Q

What are 8 clinical features of AML?

A

Bone marrow failure:

Anaemia: pallor, fatigue

Neutropenia: infection: septic shock

Thrombocytopenia: bleeding, DIC

Local infiltration:

Splenomegaly

Hepatomegaly

Gum infiltration (if monocytic)

Lymphadenopathy (occasionally, ALL>AML)

Skin, CNS, other sites

26
Q

How is AML diagnosed?

A

Blood film:

  • Usually diagnostic: circulating blasts
  • Auer rods (proves myeloid)
  • “Aleukaemic” leukaemia: If no leukaemic cells in in blood, need a BM aspirate.
  • Cytogenetic studies
  • +/- Molecular studies + FISH
27
Q

Give 4 characteristics of ALL

A

Peak incidence in childhood.

Most common childhood malignancy.

85% of children cured.

Prognosis worse with increasing age.

28
Q

What are 8 clinical features of ALL?

A

Bone marrow failure:

Anaemia

Neutropenia

Thrombocytopenia

Local infiltration:

Lymphadenopathy (± thymic enlargement)

Splenomegaly

Hepatomegaly

Testes, CNS, kidneys, other sites

Bone (causing pain)

29
Q

What are 6 pathological features of ALL?

A

Peripheral blood:

Anaemia

Neutropenia

Thrombocytopenia

Usually lymphoblasts

BM + other tissues:

Lymphoblast infiltration

Lymphoblasts may be B-lineage or T-lineage

30
Q

How do the genetic factors contribute to the prognosis of ALL?

A

Prognosis very dependent on cytogenetic/ genetic subgroups, esp. for B-lineage ALL.

Hyperdiploidy, t(12;21), t(1;19) = good

t(4;11), hypodiploidy = poor

t(9;22) = improved with tyrosine kinase inhibitors

31
Q

What are the leukaeomogenic mechanisms of ALL?

A

Proto-oncogene dysregulation: chr translocation

  • Fusion genes
  • Wrong gene promoter
  • Dysregulation by proximity to T-cell receptor (TCR) or immunoglobulin heavy chain loci

Unknown: hyperdiploidy

32
Q

How is ALL diagnosed?

A

Clinical suspicion

Blood count + film

BM aspirate

Immunophenotyping

Cytogenetic/ molecular genetic analysis

Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen

33
Q

From which cells do the leukaemias arise?

A

AML: Pluripotent haematopoeitic, multipatent myelolid, GM precursor

CML: Pluripotent haematopoeitic (potential for lymphoid differentiation)

B ALL: cells committed to B lineage

T ALL: cells committed to T lineage

CLL: Mature B cells

34
Q

Summarise the leukaemogenesis in AML

A

Multiple genetic hits: Chr translocation, loss of genetic material, mutation of genes

Proliferation + survival encouraged

Differentiation blocked

Cells don’t die normally

35
Q

Name 2 cytological features of AML

A

Auer rods

Granules

36
Q

What ocular manifestation may arise in AML?

A

Retinal haemorrhages + retinal exudates if WBC is very high due to hyperviscosity

37
Q

How can you tell ALL versus AML if there are no granules or Auer rods circulating? Why is the result important?

A

Immunophenotyping

AML + ALL are treated v differently

T (15%) + B (85%) ALL may be treated differently

38
Q

From which site is a bone marrow aspirate taken?

A

Posterior superior iliac crest

39
Q

Describe the treatment of AML

A

Supportive: Red cells, Platelets, FFP, Abx, Long line, Allopurinol, Fluids

Chemo

Targeted molecular therapy

Transplantation

40
Q

Why is allopurinol given to patients being treated for AML?

A

Due to precipitation of uric acid once tumour cells start to break down

41
Q

How does chemotherapy preferentially target leukaemic cells?

A

Normal stem cells often quiescent + checkpoints allow repair of DNA damage

Leukaemic cells continuously dividing + lack of cell cycle checkpoint control

42
Q

What molecular targeted therapy is available for acute promyelocytic leukaemia?

A

All-trans-retinoic acid (ATRA)

Arsenic trioxide (A2O3)

43
Q

How do B and T lineage ALL pathological features differ?

A

B: starts in BM

T: can start in thymus, thymus may be enlarged

44
Q

Why does cytogenetic/ molecular genetic category matter in diagnosis of ALL?

A

Ph +ve need Imatinib

Tx must be tailored to prognosis

45
Q

Describe the treatment of ALL

A

Systemic chemo

CNS-directed therapy

Molecular targeted tx

Transplantation

Supportive: blood products, abx

YR5 Haematology (20 decks)

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