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HAEM - Abbie > 11. Acute leukaemia > Flashcards

11. Acute leukaemia Flashcards

1
Q

What are the classifications of leukaemia?

A

There is acute and chronic, and lymphoid and myeloid

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2
Q

What is the clinical presentation of leukaemia?

A

Rapid onset; early death if untreated (weeks or months); immature cells (blasts) - this is the dominant cell; bone marrow failure leading to: anaemia, neutropaenia, thrombocytopaenia

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3
Q

Why do leukaemias arise?

A

The leukaemias arise due to the presence of mutations at various point in the B and T cell lineages

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4
Q

At which level does CML occur?

A

CML occurs at the pluripotent haemopoietic stem cell level because during the chronic phase it is characterised by overproduction of myelocytes, however, when it turns acute, it can then have a lymphoblastic crisis (check notes)

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5
Q

At which level does AML occur?

A

AML can also occur at a pluripotent haemopoietic stem cell level meaning that it present as a myeloid leukaemia but then relapse later on as an acute lymphoid leukaemia. Other AMLs can occur at a multipotent stem cell level or a granulocyte-monocyte precursor level

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6
Q

What happens to the incidence and prognosis of AML with age?

A

Incidence increases with age. Prognosis is worse with increasing age

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7
Q

What percentage of AML patients are adults?

A

40% of patients are adults (mainly older adults)

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8
Q

How does AML occur?

A

Many AMLs have aberrations in chromosome count or structure. These aberrations are recurrent (i.e. many patients with the disease have these abnormalities) and may be directly involved in the development of cancer. Other patients have molecular changes.

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9
Q

How can chromosomes be analysed for AML?

A

Via karyotyping and staining

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10
Q

What are the types of chromosomal abnormalities?

A

Duplication, loss, translocation

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11
Q

What chromosomal abnormality occurs in acute promyelocytic leukaemia (APML)?

A

This is a translocation of t(15;17). The fusion genes produced have the potential to be oncogenic.

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12
Q

What is inversion?

A

When a chromosome breaks in two places and then flips over. This results in two places where chimeric genes could be oncogenic.

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13
Q

What is deletion?

A

Loss of part of a chromosome

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14
Q

In which type of leukaemia is creation of a new fusion gene seen?

A

AML and ALL

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15
Q

In which type of leukaemia is abnormal regulation of genes seen?

A

Mainly ALL e.g. inappropriately switching on a gene

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16
Q

In which type of leukaemia is chromosomal duplication seen in?

A

Common in AML

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17
Q

Which are the two most common chromosomal duplications, giving rise to leukaemia?

A

Two MOST COMMON: +8 and +21 (gives a predisposition to AML (as seen in Down syndrome))

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18
Q

What is the effect of dosage associated with these trisomies (+8 and +21) on leukaemia?

A

There is a possible dosage effect associated with these trisomies (having 3 copies of a proto-oncogene rather than 2 may be the underlying trigger of the leukaemia)

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19
Q

In which types of leukaemia is chromosomal loss or deletion common in?

A

Common in AML

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20
Q

What are examples of chromosomal loss or deletion?

A

Deletion and loss of 5/5q or 7/7q

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21
Q

Why does chromosomal loss or deletion cause leukamogenesis?

A

Due to loss of tumour suppressor gene. One copy of an allele may be insufficient for normal haemopoiesis. Possible loss of DNA repair systems

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22
Q

What are molecular abnormalities in patients with apparently normal chromosomes?

A

Point mutations, loss of function of tumour suppressor genes, partial duplication, cryptic deletion.

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23
Q

What are examples associated with point mutations, resulting in molecular abnormalities??

A

NPM1, CEBPA (both associated with AML). Both have prognostic implications.

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24
Q

What is an example of partial duplication leading to molecular abnormality?

A

FT3 - bad prognostic indicator

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25
Q

What is an example of cryptic deletion?

A

Where a fusion gene forms as a result of a tiny bit of DNA being deleted and the remaining ends joining up.

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26
Q

In AMLs, what does a block in maturation lead to?

A

Excess of blast cells. These cells have an advantage over the normal cells leading to gradual replacement of the normal cells.

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27
Q

Why do people get AML?

A

Familial or constitutional predisposition (e.g. Down syndrome); irradiation; anticancer drugs; cigarette smoking; unknown

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28
Q

In leukaemogenesis in AML, which genetic changes occur?

A

Multiple genetic hits are required. At least 2 interacting molecular defects. Synergise to give leukaemic phenotype.

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29
Q

What are type 1 abnormalities in AML?

A

Promote proliferation and survival (anti-apoptosis)

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30
Q

What are type 2 abnormalities in AML?

A

Block differentiation (which would normally be followed by apoptosis). This leads to an accumulation of blast cells.

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31
Q

Transcription factors are very important in differentiation as they:

A

Bind to DNA; alter structure to favour transcription; regulate gene expression

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32
Q

What can disruption of transcription factor function result in?

A

Can result in failure of differentiation

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33
Q

What is an example of a mutation which disrupts transcription factor function and how?

A

Mutation of the Core Binding Factor (CBF). CBF is a dimeric transcription factor (CBF-beta and CBF-alpha). These are master controllers of haemopoiesis. RUNX1 codes for CBF-alpha. Translocation of 8;21 fuses RUNX1 with RUNX1T1. This leads to the formation of a fusion transcription factor which binds to co-repressors rather than co-activators, which leads to the differentiation block. There is a partial block of differentiation. This process drives leukaemia.

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34
Q

Apart from translocation of 8;21, which other mutation affects CBF and how?

A

Inversion of chromosome 16. The inversion fuses CBF-beta to MYH11 to form a fusion product that cannot bind to the DNA sequence and leads to an arrest in differentiation.

35
Q

What is dominant negative effect and how is it related to leukaemia?

A

Dominant-negative (DN) mutants represent an important class of mutation in which a mutant receptor interferes with the function of the wild-type (WT) version of the receptor. In the examples of CBF (RUNX1/RUNX1T1 and CBF-beta/MYH11), there is only one chromosome that is abnormal, however, in leukaemias we tend to see a dominant negative effect which is when a single abnormal chromosome dominates over the normal one.

36
Q

What is acute promyelocytic leukaemia (APML) caused by? And what does it form?

A

Caused by a translocation between chromosomes 15 and 17. This forms a PML-RARA fusion gene.

37
Q

Why does the PML-RARA fusion gene lead to abnormal promyelocytes?

A

The promyelocytes are abnormal because they contain multiple Auer rods

38
Q

What is the variant form of APML like?

A

There are TWO morphological variants but they are the same disease. There is a variant form of APML where the granules are still present but they are below the resolution of a light microscope so you can’t see all of them. This variant form is characterised by bilobed nuclei.

39
Q

How does APML present?

A

This type of leukaemia causes haemorrhage (e.g. sudden-onset bruising or bleeding)

40
Q

Why can most patients with APML be cured?

A

The molecular mechanism is understood and a molecular treatment can be applied to great effect

41
Q

What is APML characterised by?

A

Excess of abnormal promyelocytes

42
Q

Why does APML present with bleeding?

A

The reason they present with bleeding is because this type of leukaemia is characterised by DIC and hyperactive fibrinolysis

43
Q

What is an important contributor to leukaemogenesis?

A

Transcription factor dysregulation

44
Q

Is transcription factor dysregulation sufficient on its own to cause leukaemia?

A

It is NOT sufficient on its own to cause leukaemia. Further genetic hits are required (e.g. chromosomal translocation, loss of genetic material, localised mutations in DNA).

45
Q

Which Type 1 mutation causes leukaemogenesis in APML?

A

FLT3-ITD

46
Q

Which Type 2 mutation causes leukaemogenesis in APML?

A

PML-RARA

47
Q

Which Type 1 mutation causes leukaemogenesis in CBF leukaemias?

A

Sometimes mutated KIT

48
Q

Which Type 2 mutation causes leukaemogenesis in CBF leukaemias?

A

Mutation affecting function of CBF

49
Q

What are cytological features differentiating AML and ALL?

A

In AML there are fine speckled granules. Auer rods are pathognomonic of myeloid neoplasms (see notes)

50
Q

What cytochemistry differentiates AML and ALL?

A

Stain for myeloperoxidase (enzyme present in myeloid cells). Other similar stains include Sudan Black and non-specific esterase. NOTE: these are NOT used much any more

51
Q

How can immunophenotyping be used to differentiate AML and ALL?

A

This involves looking at antigens on the surface of the cell or within the cytoplasm. This can be done in various ways. 1. Flow cytometry. By looking at the abundance of various antigens present in the sample, you can determine the lineage. 2. Immunocytochemistry 3. Immunohistochemistry

52
Q

What are the antigens seen in immunophenotyping ALL?

A

Pre-cursor B-cell: CD19, CD20, TdT, CD10 +/-.
B cell: CD19, CD20, surface Ig.
T cell: CD2, CD3, CD4, CD8, TdT.

53
Q

What are the antigens seen in AML?

A

MPO, CD13, CD33, CD14, CD15, glycophorin (E), platelet antigens

54
Q

What antigens are seen in AML and ALL?

A

CD34, CD45, HLA-DR

55
Q

What are clinical features of AML due to bone marrow failure, local infiltration and hyperviscosity?

A

Bone marrow failure: anaemia (fatigue, pallor); neutropaenia (infection may be severe and life-threatening e.g. septic shock, renal failure, DIC), thrombocytopaenia (bruising, bleeding, petechiae or ecchymoses, DIC).

Local infiltration: splenomegaly; hepatomegaly; gum infiltration (if monocytic); lymphadenopathy (occasionally); skin, CNS or other sites (can cause cranial nerve palsies).

Hyperviscosity if WBC is very high: can cause retinal haemorrhages or retinal exudates.

56
Q

Why does APML cause haemorrhage instead of vascular obstruction?

A

APML tends to cause haemorrhage as opposed to vascular obstruction because fibrinolysis is upregulated

57
Q

How is AML diagnosed?

A

Blood film, bone marrow aspirate, cytogenetic studies (ALL newly diagnosed patients), molecular studies and FISH (in some patients)

58
Q

Why is blood film done in AML diagnosis?

A

Usually diagnostic (presence of circulating blasts). Auer rods (suggestive of myeloid). Could help differentiate between AML and ALL (presence of granules) - however, immunophenotyping is the key.

59
Q

What is aleukaemic leukaemia?

A

This is when there are NO leukaemic cells in the peripheral blood but the bone marrow has been replaced

60
Q

What results in cytogenetic studies suggest a good risk?

A

t(15;17), t(8:21), inv(16)/t(16;16)

61
Q

What results in cytogenetic studies suggest a poor risk?

A

-5, del 5, -7, 3q-, 11q23, complex karyotype

62
Q

What results in cytogenetic studies suggest intermediate risk?

A

Normal karyotype, other chromosomal abnormalities.

63
Q

Why do molecular studies and FISH?***

A

This enables sub-classification of the acute myeloid leukaemia and adds prognostic value and aids treatment decisions (?)

64
Q

What is the treatment of AML?

A

Chemotherapy and supportive care: red cells, platelets, FFP/cryoprecipitate if DIC, ABx, long line, allopurinol, fluid and electrolyte balance (last three to prevent gout).

65
Q

What are the principles of AML treatment?

A
  1. Damage the DNA of the leukaemic cells. 2. Leave the normal stem cells unaffected. 3. Combination chemotherapy is ALWAYS used because: different mechanisms of action, synergy, non-overlapping toxicity. 4. Drugs are mainly cell-cycle specific. 5. Given in 4-5 courses: remission induction x 2 and consolidation x 2-3. 6. treatment goes on for around 6 months. 7. Consider transplantation if poor prognosis.
66
Q

Why have the results of AML treatment improved?

A

Better supportive care; identification of poor prognosis groups; specific treatment for APML

67
Q

What are the determinants of prognosis in AML?

A

Patient characteristics; morphology; immunophenotyping; cytogenetics; genetics; response to treatment

68
Q

Who does ALL tend to occur in?

A

Peak incidence in childhood. MOST COMMON childhood malignancy

69
Q

What is the prognosis of ALL?

A

85% of children are cured. Prognosis is worse with increasing age.

70
Q

What are clinical features of ALL?

A

Bone marrow failure. Local infiltration: lymphadenopathy (+/- thymic enlargement), splenomegaly, hepatomegaly, testes, CNS, kidneys or other sites; bone (causing pain)

71
Q

What are the pathological features of ALL in peripheral blood and bone marrow?

A

Peripheral blood (blood film): anaemia, neutropaenia, thrombocytopaenia, usually lymphoblasts.

Bone marrow: lymphoblastic infiltration - these may be B- or T-lineage.

72
Q

Where do B-lineage and T-lineage ALL start?

A

B-Lineage ALL starts in the bone marrow; T-Lineage ALL can start in the Thymus (which may be enlarged). NOTE: quite different genetic defects will cause B- and T-lineage ALL.

73
Q

ALL prognosis is very dependent on cytogenetic/genetic subgroups (particularly for B-lineage). What suggests a good prognosis?

A

Hyperdiploidy, T(12;21), T(1;19)

74
Q

ALL prognosis is very dependent on cytogenetic/genetic subgroups (particularly for B-lineage). What suggests a poor prognosis?

A

T(4;11), hypodiploidy

75
Q

ALL prognosis is very dependent on cytogenetic/genetic subgroups (particularly for B-lineage). What suggests a good prognosis with tyrosine kinase inhibitors?

A

T(9;22). This is the Philadelphia chromosome

76
Q

What are the leukaemogenic mechanisms in ALL?

A

Proto-oncogene dysregulation by chromosomal translocation: fusion genes, wrong gene promoter, dysregulation by proximity to T cell receptor immunoglobulin heavy chain loci. Unknown mechanism in hyperdiploidy.

77
Q

How is ALL diagnosed?

A

Clinical suspicion; blood count and film; bone marrow aspirate; immunophenotyping; cytogenetic/molecular genetic analysis; blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen.

78
Q

Why is it important to do immunophenotyping in ALL?

A

Particularly important because AML and ALL are treated very differently. Moreover, B-lineage and T-lineage are treated very differently.

79
Q

Why do cytogenetic/molecular genetic analysis in ALL?

A

Philadelphia chromosome positive needs imatinib. Treatment is tailored to prognosis (intensify treatment if bad prognosis).

80
Q

What are the principles of ALL treatment?

A

Specific therapy: systemic chemotherapy (2-3 years of therapy, induction and consolidation); CNS-directed therapy (e.g. intrathecal). Supportive care: blood products, antibiotics (broad-spectrum for fever, prophylaxis for PCP prevention), general medical care (CVC, hyperuricaemia/hyperkalaemia management, sometimes haemodialysis).

81
Q

Why do boys need longer systemic chemotherapy?

A

Boys need to be treated for longer because the testes are a site of accumulation of lymphoblasts

82
Q

Who is CNS-directed therapy done for ALL and how?

A

This is done in ALL patients even if initial LP is negative (6-8 treatments). This can also be done by giving high-dose chemotherapy so that it penetrates the BBB. (NOTE: Cranial irradiation used to be used but has been abandoned because it causes damage to the brain)

83
Q

What is the prognosis for ALL?

A

Children: 5-year disease-free survival of 80%. Adults: 5-year disease-free survival of 30-40%

84
Q

What might sudden-onset bleeding be?

A

May be APML so get a blood count and a coagulation screen

HAEM - Abbie (16 decks)

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