PathY5 > Acute Leukaemia > Flashcards

Acute Leukaemia Flashcards

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1
Q

What can leukaemia be?

A

Acute/ Chronic
Myeloid/ Lymphoid

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2
Q

What is acute leukaemia?

A

A neoplastic condition characterized by
Rapid onset
Early death if untreated
Immature cells (blast cells)
Bone marrow failure
Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding

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3
Q

Which cells does AML, CML, B-ALL, T-ALL and CLL affect?

A
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4
Q

Which cell is dominant in acute leukaemia?

A

Blast cells

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5
Q

What is the age people get AML?

A

Incidence increases with age- median = 65-70 yrs

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6
Q

How may chromosomes be different in AML?

A
  • Many AMLs have aberrations in chromosome count or structure
  • Such aberrations are recurrent and may be directly involved in the development of cancer
  • Other patients have molecular changes

Chromosome abnormalities include:

  • Duplication (usually trisomy)
  • Loss
  • Translocation
  • Inversion
  • Deletion
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7
Q

What are important anomalies?

A

t(15;17)

t(5;8)

inv(16)

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8
Q

What do inversions and translocations cause in leukaemia?

A

•Altered DNA sequence

–creation of new fusion genes (AML and ALL)

–abnormal regulation of genes (mainly ALL)

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9
Q

What is duplication common in?

A
  • Common in AML
  • Disease hotspots

–+8

–+21 gives predisposition

•Possible dosage affect

–extra copies of proto-oncogenes

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10
Q

What is chromosomal loss and deletion important to?

A
  • Common in AML
  • Disease hotspots

–deletions and loss of 5/5q & 7/7q

  • Possible loss of tumour suppressor genes
  • Alternative explanation ‒ one copy of an allele may be insufficient for normal haemopoiesis
  • Possible loss of DNA repair systems
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11
Q

What Molecular abnormalities in patients with apparently normal chromosomes are common?

A
  • Point mutation – NPM1, CEBPA
  • Loss of tumour suppressor genes
  • Partial duplication – FLT3
  • Cryptic deletion

Don’t need details

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12
Q

Why do blast cells accumulate?

A

There is a block in maturation

Blast cells accumulate

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13
Q

Why do people get AML?

A
  • Familial or constitutional predisposition
  • Irradiation
  • Anticancer drugs
  • Cigarette smoking
  • Unknown
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14
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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15
Q

What are type 1 and type 2 abnormalities in leukaemogenesis in AML?

A

•Type 1 abnormalities

–promote proliferation & survival

•Type 2 abnormalities

–block differentiation (which would normally be followed by apoptosis)

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16
Q

Anti-apoptosis and pro-proliferation

Blocking differentiation and maturation

A

Anti-apoptosis and pro-proliferation

Blocking differentiation and maturation

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17
Q

How does differentiation work?

A

•Transcription factors

–bind to DNA

–alter structure to favour transcription

–regulate gene expression

•If transcription factor function is disrupted, cells cannot differentiate

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18
Q

What is core bidning factor?

A

•Core binding factor

–dimeric transcription factor

–master controller of haematopoiesis

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19
Q

What are the Core Binding Factor Leukaemias?

A

•t(8;21) fuses RUNX1 (encoding CBFα) with RUNX1T1

–15% of adult AML

•inv(16) fuses CBFB with MYH11

–12% of adult AML

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20
Q

What is t(8;21)?

A

With this particular chromosomal abnormality there is some maturation; these are not all blast cells

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21
Q

What does inv(16) do?

A

Again, in this genetic subtype there is some maturation to bizarre eosinophil precursors with giant purple granules

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22
Q

What is Acute promyelocytic leukaemia with t(15;17)?

A
  • A very special type of acute leukaemia
  • The molecular mechanism is understood
  • Molecular treatment can be applied
  • The great majority of patients can now be cured
  • An excess of abnormal promyelocytes
  • Disseminated intravascular coagulation (DIC)
  • Two morphological variants but the same disease

The block in maturation is later

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23
Q

What is this and how is it different to the variant form?

A

t(15;17) classical

Variant looks like this but basic molecular mechanism is the same.

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24
Q

Summarise leukaemogenesis in AML

A

•Transcription factor dysregulation

–not sufficient alone to cause leukaemia

–further genetic hits are required

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25
What are the type 1 and 2 abnormalities genes in APML?
•Type 1 abnormalities –FLT3 -ITD •Type 2 abnormalities –t(15;17) PML-RARA
26
What are the type 1 and 2 abnormality genes in Leukaemogenesis in CBF leukaemias?
•Type 1 abnormalities –Sometimes mutated KIT •Type 2 abnormalities –Mutation affecting function of CBF
27
How do you know if it is AML or ALL?
–Cytological features –Cytochemistry –Immunophenotyping
28
Which one is AML?
Top Granules/ Auer rods
29
What stains are used in cytochemistry?
Myeloperoxidase Non specific esterase Sudan black B positive reactions = myeloid
30
How do ALL and AML differ in cytochemistry?
Cytochemical stain AML/ ALL Myeloperoxidase + (Gr)/ - Sudan black + (Gr)/ - Non-specific esterase + (Mo)/ -
31
What do you do if you can’t tell if it is AML or ALL?
Immunophenotyping * Cell surface and cytoplasmic antigens * Flow cytometry * Immunocytochemistry * Immunohistochemistry
32
How do we use immunohistochemistry?
Positive reaction with a monoclonal antibody
33
What is the difference between ALL and AML immunophenotype?
ALL: –Precursor-B-cell: CD19, CD20, TdT, CD10 +/- –B-cell: CD19, CD20, surface Ig –T-cell: CD2, CD3, CD4, CD8,TdT AML: MPO, CD13, CD33, CD14, CD15 glycophorin (E), platelet antigens Both: CD34, CD45, HLA-DR
34
What are the clinical features of AML?
* Bone marrow failure * Anaemia * Neutropenia * Thrombocytopenia * Local infiltration * Splenomegaly * Hepatomegaly * Gum infiltration (if monocytic) * Lymphadenopathy (only occasionally) * Skin, CNS or other sites
35
What happens in acute monocytic leukaemia?
•Skin infiltration, gum infiltration & organomegaly
36
What does CNS disease happen in?
•CNS disease –Particularly with monocytic differentiation (also ALL)
37
What's another reason to get DIC?
APML
38
When do renal problems happen?
•Hyperviscosity if WBC is very high, retinal haemorrhages, retinal exudates
39
How do you use blood film in AML?
–Usually diagnostic: circulating blasts –Auer rods (proves myeloid) –ALL versus AML (if no granules or Auer rods how do you tell?) Immunophenotyping –“Aleukaemic” leukaemia If there are no leukaemic cells in in the blood you need a bone marrow aspirate
40
How do you do bone marrow aspirate in AML?
Bone marrow from femur
41
How are cytogenetics/ molecular studies used in AML?
•Cytogenetic studies –All newly diagnosed patients •Molecular studies and FISH –Selected patients •Why? –Prognostic value – Helps select treatment
42
What are the risk subgroups in AML cytogenetics?
43
Summarise diagnostic tools in AML
* Blood count and film\* * Bone marrow morphology\* * Immunophenotyping * Cytogenetic analysis * Molecular studies \* With or without cytochemistry
44
What is supportive care in AML?
–Red cells –Platelets –Fresh frozen plasma/ cryoprecipitate if DIC –Antibiotics –Long line –Allopurinol, fluid and electrolyte balance
45
Why is chemo used?
* Damages DNA * Normal stem cells –often quiescent –checkpoints allow repair of DNA damage •Leukaemia cells –continuously dividing –lack of cell cycle checkpoint control
46
Why is combination chemo good?
•Combination chemotherapy –different mechanisms of action –synergy –non-overlapping toxicity
47
How is chemo used for AML?
* Mainly cell cycle specific drugs * 4‒5 courses * remission induction × 2 * consolidation × 2‒3 * About 6 months of therapy * Consider transplantation if poor prognosis
48
How is prognosis determined in AML?
* Patient characteristics * Morphology * Immunophenotyping * Cytogenetics * Genetics * Response to treatment
49
What is ALL incidence?
* Peak incidence in childhood * Most common childhood malignancy * 85% of children cured * Prognosis worse with increasing age
50
What are the clinical features of ALL?
* Bone marrow failure — effects of * Anaemia * Neutropenia * Thrombocytopenia * Local infiltration * Lymphadenopathy (± thymic enlargement) * Splenomegaly * Hepatomegaly * Testes, CNS, kidneys or other sites * Bone (causing pain)
51
What are the pathological features of ALL?
* Peripheral blood * Anaemia * Neutropenia * Thrombocytopenia * Usually lymphoblasts * Bone marrow and other tissues * Lymphoblast infiltration * Lymphoblasts may be B-lineage or T-lineage * B-lineage –Starts in the bone marrow •T-lineage –Can start in the thymus and thymus may be enlarged •There are quite different genetic defects in B-lineage and T-lineage ALL
52
What are the genetic features of ALL?
* As for AML, prognosis is very dependent on cytogenetic/genetic subgroups, particularly for B-lineage ALL * Hyperdiploidy, t(12;21), t(1;19) — good prognosis * t(4;11), hypodiploidy — poor prognosis * t(9;22) — improved prognosis with tyrosine kinase inhibitors
53
In ALL, what are the Leukaemogenic mechanisms?
•Proto-oncogene dysregulation –chromosomal translocation * Fusion genes * Wrong gene promoter * Dysregulation by proximity to T-cell receptor (TCR) or immunoglobulin heavy chain loci * Unknown – hyperdiploidy
54
Philadelphia (Ph) positive — previously poor prognosis
Philadelphia (Ph) positive — previously poor prognosis
55
How do you diagnose ALL?
* 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
56
* Why does immunophenotype matter * Why does cytogenetic/molecular genetic category matter?
•Why does immunophenotype matter –AML and ALL are treated very differently –T-lineage (15%) and B-lineage (85%) ALL may be treated differently •Why does cytogenetic/molecular genetic category matter? –Ph-positive need imatinib –Treatment must be tailored to the prognosis
57
What is the treatment of ALL?
•Specific therapy –systemic chemotherapy –CNS-directed therapy •Supportive care –blood products –antibiotics –general medical care
58
What is supportive care in ALL?
* Central venous catheter * Red blood cell and platelet transfusions * Broad spectrum antibiotics for fever * Prophylaxis for Pneumocystis jirovecii infection * Hyperuricaemia: hydration, urine alkalinization and allopurinol or rasburicase * Hyperphosphataemia; aluminum hydroxide, calcium * Hyperkalemia: fluids, diuretics * Extreme leukocytosis (WBC \> 200 × 109/l): leukapheresis * Sometimes haemodialysis
59
What is chemo for ALL?
* Induction cycle * Intensification/consolidation cycles * Early intrathecal chemotherapy for all (to treat occult CNS disease) * Prolonged continuation/maintenance phase * Two to three years of therapy * Special measures for poor prognosis
60
What is CNS therapy?
* Intrathecal chemotherapy even if initial LP is negative (6‒8 treatments) * More frequent, intensive and prolonged intrathecal chemotherapy for patients with lymphoblasts in CSF * Systemic chemotherapy that penetrates CNS (e.g. high dose cytarabine) Cranial irradiation now less frequently used
61
Why is cranial irradiation used less frequently?
* It causes cognitive impairment * Now that more children are cured thinking about long term morbidity of treatment is increasingly important
62
What is ALL prognosis after treatment?
• * Children: 5-year disease-free survival 80% * Adults: 5-year disease free survival 30‒40%
63
What are the outcomes by cytogenetic subgroups?
64
A 3-year-old girl develops pain in her legs and is found to have generalised lymphadenopathy and a palpable spleen. Her blood count shows WBC 35.4 × 109/l, Hb 77 g/l and platelet count 85 × 109/l. The most likely diagnosis is ## Footnote 1. Acute lymphoblastic leukaemia 2. Chronic lymphocytic leukaemia 3. Acute myeloid leukaemia 4. Chronic myeloid leukaemia
?
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