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TI2 > Intro to leukaemias > Flashcards

Intro to leukaemias Flashcards

1
Q

Define leukaemia

A

Group of diseases characterised by malignant overproduction of WBCs or their immature precursors

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2
Q

How do leukaemias present?

A
  • Varies between types of leukaemia
  • But typically first presents with symptoms due to loss of normal blood cell production
  • abnormal bruising (reduced platelets)
  • Repeat/abnormal infection
  • Sometimes just anaemia
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3
Q

What are the different classifications of leukaemias?

A
  • Lymphoid - commonly B-cell, rarely T-cell
  • Myeloid - any of the non-lymphocyte blood cell lineage (commonly neutrophils)
  • Acute - undifferentiated, characterised by blast cells
  • Chronic - differentiated leukaemias, characterised by mature WBCs
  • Have ALL, AML, CLL, CML
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4
Q

What genes are involved in leukaemia?

A
  • Activation of oncogenes and inactivation of TSGs
  • Ras, myc, P53
  • Chromosome translocation can generate novel hybrid oncogenes e.g. BCR-ABL in CML, PML-RARA in AML M4
  • Monosomy/trisomy
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5
Q

Is leukaemia clonal?

A

Yes

- mutation in one cell –> clonal haemopoiesis

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6
Q

What risk factors are there for leukaemia?

A
  • Radiation
  • Chemicals
  • Chemo
  • Viruses (one very rare example - HTLV-1)
  • Genetic factors (only CLL)
  • Age - majority elderly
  • Controversial - power lines, nuclear stations, natural background radiation (radon from granite)
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7
Q

What treatment is there for leukaemia?

A
  • Chemo with cytotoxic drugs
  • Stem cell and bone marrow transplant
  • Disease-specific agents, including oncogene targeted drugs
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8
Q

How do we use chemo?

A
  • Combinations of drugs used to kill leukaemic cells
  • optimised for type and subtype of leukaemia
  • Cytotoxic drugs mostly target dividing cells
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9
Q

Gives some examples of chemo treatments

A
  • Cytosine arabinoside (ara-C, Cytarab)
  • Cytosine analogue, interferes with deoxynucleotide synthesis, preventing successful DNA replication -> cell arrests and dies
  • Vincristine
  • Binds to tubulin dimers, inhibiting microtubule formation, blocking the mitotic spindle.
  • Cell fails to undergo mitosis and dies
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10
Q

What are some side effects of chemo?

A
  • Kills normally dividing cells too
  • GI epithelium -> nausea and diarrhoea
  • Hair follicles -> hair loss
  • Loss of fertility (male = temporary and can bank sperm)
  • Haemopoeitic progenitors -> bone marrow suppression
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11
Q

What is SCBMT?

A
  • Stem cell bone marrow transplant
  • Give intense chemo and total body irradiation
  • Wipes out leukaemic cells and normal stem cells
  • reconstitute bone marrow by transplanted stem cells - much more intense
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12
Q

What are some problems with SCBMT?

A
  • Shortage of HLA matched donors

- High mortality of the procedure for older or sicker patients

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13
Q

What is the histology for acute leukaemias?

A
  • All look like immature blast cells
  • Big nuclei, little cytoplasm
  • All the same
  • Large numbers of myeloid blasts (AML) or lymphoblasts (ALL) in bone marrow - hence “undifferentiated leukaemais”
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14
Q

What are the main symptoms of acute leukaemias?

A
  • Typical symptoms due to bone marrow suppression
  • Thrombocytopaenia (lack of platelets) -> purpura, nosebleeds and bleeding gums
  • Neutropaenia -> recurrent infections
  • Anaemia -> weakness, shortness of breath
  • Petechiae - point like bruises
  • candida albicans infecion
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15
Q

How do we diagnose acute leukaemias?

A

Peripheral blood

  • presence of blasts
  • lack of normal cells
  • all at the same stave of maturation
  • Auer rods - only seen in leukamia (rod-like structures in cell)

Bone marrow aspirate
- >30% blasts is diagnostic of acute leukaemia

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16
Q

How do we classify acute leukaemias

A

French-American-British (FAB)

  • based on stage of differentiation arrest and predominant cell type
  • e.g. AML M6 erythroleukaemia

WHO classification

  • similar to FAB, but acute leukaemias with specific chromosome translocations are classified separately
  • e.g. AML with translocation between Chr8 and 21
17
Q

What is the prognosis after treatment?

A
  • Childhood ALL -> >90% long term remission/ cure
  • Adult ALL - poorer prognosis due to different cell of origin and different oncogene mutations
  • AML - >80% long term remission in young adults with aggressive treatment
  • Elderly unable to tolerate aggressive chemo or SCBMT
18
Q

Define chronic leukaemias

A
  • Differentiated leukaemias

- increased numbers of differentiated cells

19
Q

What is CLL?

A
  • Chronic lymphoid leukaemia
  • Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood
  • Also called chronic lymphocytic leukaemia
20
Q

What are the symptoms of CLL?

A
  • Recurrent infections due to neutropaenia and suppression of normal WBC function
  • Anaemia
  • Thrombocytopaenia
  • Lymph nodes enlargement
  • Hepatosplenomegaly
21
Q

What is the treatment and outcome for CLL?

A
  • Controlled by regular chemo to reduce cell numbers
  • Some patient may die in 2 years
  • Most survive much longer (12 years or longer)
22
Q

What are the symptoms of CML?

A
  • anaemia
  • night fever/sweats
  • splenomegaly
23
Q

How do we diagnose CML?

A
  • neutrophilia
  • left shift in blood and bone marrow
  • Presence of philadelphia chromosome
  • BCR-ABL gene rearrangement
24
Q

What is the treatment and course for CML?

A
  • Controlled but not cured by chemo
  • Imantinib - tyrosine kinase inhibitor
  • Survival on treatment usually measured in years, but eventually progresses to accelerated phase and then blast crisis
  • Blast crisis resembles an acute leukaemia
  • Allogenic bone marrow or stem cell transplant curative
  • Autologous transplant sometimes tried (most people >50 cant tolerate)
25
Q

What is the philadelphia chromosome?

A
  • 22q moves to chromosome 9
  • balanced translocation - no loss or gain
  • 95% of CML cases have Ph’
  • Protein forms has end terminus of protein from BCR and rest from ABL
  • ABL is a TK, but activity tightly regulated
  • BCR-ABL protein has unregulated TK activity - switched on constantly
  • Causes proliferation of progenitor cells in the absence of GFs, decreased apoptosis and decreased adhesion to bone marrow stroma
26
Q

How can we use the Ph’ for diagnosis?

A
  • 95% of CML have Ph’ chromosome detectable
  • Among the remaining 5%, some have a BCR-ABL gene rearrangement
  • Cases without this rearrangment require different therapy
  • Use PCR to detect the translocation
  • 1 primer for BCR, 1 for ABL
  • Only get PCR products if BCR and ABL sequences on same RNA molecuele
  • Amplify and detect CML cells at low level
27
Q

What is Imantinib?

A
  • Specific TK inhibitor
  • Inhibits BCR-ABL but not most other TKs
  • Pt driven to get drug approved in 4 years rather than usual 10-15
  • Compared to previous treatments - more remission, greater durability and fewer side effects (some resistance however)

TI2 (20 decks)

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