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PHAM02 > leukaemia (SD) > Flashcards

leukaemia (SD) Flashcards

1
Q

Sx of leukameia

A

pallor
lethargy
pharyngitis
recurrent infections
easy bruising
pyrexia
night sweats
bone pain
flu-like sx
lymphadenopathy
splenomegaly
hepatomegaly

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2
Q

acute vs chronic

A

ACUTE
- fast growing
- can progress quickly without Tx
- cells multiply before any immune function has devleoped
- more common in young children
- sudden onset
- develops in weeks/months
- variable WBC count

CHRONIC
- slow growing
- cells have immature, limited immune function
- middle aged/elderly
- insidious
- develops over years
- high WBC count

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3
Q

3 ways to classify leukaemia

A
  1. morphology
  2. immunophenotype
  3. genotype
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4
Q

difference between leukaemia and lymphoma

A

leukaemia = cancer of blood cells, starts in bone marrow

lymphoma = cancer of lymphatic system, starts in lymph nodes or spleen and SPREADS to bone marrow

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5
Q

What is immunophenotyping?

A

used to ID CD proteins on cell surface which are used as markers

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6
Q

CD marker of B cells

A

CD19
CD20

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7
Q

risk factors for ALL

A

radiation, pesticides, viruses (EBV, HIV)

inherited syndromes (Down syndrome, Fanconi anemia, Bloom syndrome, ataxia telangiectasia and Nijmegen breakdown syndrome)

rase/ethnicity - more common in Caucasians

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8
Q

what is ALL

A

acute lymphoblastic leukaemia

neoplasms of precursor B and T cells, called lymphocytes

accumulation of lymphoblasts in bone marrow and peripheral blood

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9
Q

How to immunophenotype?

A

flow cytometry

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10
Q

Are B or T cells most affected?

A

B cells (85%)

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11
Q

how to differentiate betwen leukaemia and lymphoma

A

leukaemia if >25% bone marrow replaced by malignant cells

lymphoma if large lymph nodes

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12
Q

peak age of ALL incidence

A

3-7 years

rises again >40yrs

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13
Q

investigations for ALL

A
  • FBC
  • blood film
  • bone marrow
  • immunophenotype
  • immunoglobulin and TCR genes
  • molecular genetics
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14
Q

bone marrow findings in investigations for ALL

A

hypercellular

with >20% blast cells

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15
Q

FBC for ALL

A
  • normochromic normocytic anaemia (normal sized RBC, normal Hb content)
  • neutropenia
  • thrombocytopenia
  • WBC count can be increased/normal/decreased
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16
Q

neutropenia

A

low neutrophil count

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17
Q

thrombocytopenia

A

low platelet count

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18
Q

What are blast cells?

A

large lymphocytes (huge WBCs)

morphology similar to myeoblasts

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19
Q

pathogenesis of ALL

A
  1. first mutation occurs in the foetus in early lymphoid progenitor cells
  • cells continue to undergo alterations in bone marrow, forming lymphoblasts and prolymphocytes
  • germline mutation in <5% of cases
  1. 2nd genetic event occurs in childhood
  • could be associated with childhood infection and exposures (ionising radiation)
  • may be promoted through abnormal response to a common infection esp in under exposed infants
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20
Q

genetics in ALL

A
  • gene variability
  • chromosomal alterations - most common genetic driver
  • chimeric proteins
21
Q

What is aneuploidy?

A

gain or loss of whole chromosomes

22
Q

types of aneuploidy

A

hyperdiploid = >50 chromosomes, good prognosis

hypodiploid = <44 chromosomes, poor prognosis

23
Q

most common genetic driver for ALL

A

chromosomal abnormalities

24
Q

example of a chromosomal translocation

A

ETV6-RUNX1

25
Q

What do chromosomal translocations do?

A

they create fusion genes that drive oncogenesis

26
Q

How to detect chromosonal abnormalities?

A

FISH

fluorescence in situ hybridisation

27
Q

most common fusion gene in B-ALL

A

ETV6-RUNX1

28
Q

ETV6-RUNX1 fusion gene

A

ETV6 = recruits transcriptional repressors

RUNX1 = regulates transcription during haematopoiesis

fusion gene leads to transcriptional silencing of RUNX1 targets and deregulation of haematopoieis

not sufficient to drive leukaemia alone

29
Q

BCR gene

A

breakpoint cluster region

30
Q

What is the Philadelphia chromosome?

A

fusion of BCR and ABL1 genes onto the chromosome of each other

ABL-1 is a
- proto-oncogene
- (non receptor) tyrosine kinase
- roles in cell proliferation, survival or death and migration
- activity limited by protein domain encoded by exon 1

fusion leads to loss of exon 1 and turns ABL into an oncogene

31
Q

How does BCR-ABL1/Philadelphia positive cause leukaemia?

A

activates tyrosine kinase signalling

through activation of:
- Jak-Stat
- MAPK

causes cell growth, migration, differentiation

inhibits apoptosis mechanisms - p53, inhibits caspsases

32
Q

What is used first line to treat philadelphia positive ALL?

A

TKIs - imatinib

33
Q

Treatment for imatinib resistance (in Ph+ ALL)?

A

alternate TKIs
- dasatinib
- ponatinib

34
Q

How does methotrexate work?

A

it blocks pyrimidine/purine biosynthetic pathway and the proliferation of B cells by interfering with DNA synthesis, repair and replication

suppresses the immune system

35
Q

Tx for ALL relapse?

A

Rituximab

36
Q

Rituximab MOA

A
  • binds to cell surface protein CD20 on B cells
  • anti-CD20 B-cell depleter
  • mostly specific to B cells, some T cells
  • 3 MOA:
    1. antibody dependent cell mediated toxicity via Fc region
    2. complement mediated cell lysis
    3. induction of apoptosis
  • depletes CD20+ B cells by binding to the CD20 antigen expressed on the B cell suraface
  • blockade of CD20 leads to B cell death via apoptosis and lysis
37
Q

Repeated Tx of Rituximab?

A

patients progress after approx 36 months ans need repeat treatment

38
Q

Other cancers that Rituximab is used in?

A

lymphoma

39
Q

response rate of Rituximab

A

80%

40
Q

What is CD20?

A

a cell marker on B cells during B cell differentiation

41
Q

What is CD19?

A

cell marker on B cells

plays a role in maintaining the balance between humoral, antigen-induced response and tolerance induction

Tx target

42
Q

What does PD-L1 do?

A

prevents tumour cells from ‘evading’ the immune system

43
Q

Therapy to target CD19?

A

Blinatumomab

44
Q

Therapy to target CD20?

A

Rituximab

45
Q

Blinatumomab

A

tatgets CD19

BiTE - bispecific T cell engaging antibodies

one part of the drug binds to CD3 on T cell

2nd part on drug binds to CD19 on the B cell (target cell)

BiTE directs T cells to the B cell and assists T cell activaiton

46
Q

BiTE therapy?

A

bi-specific T cell engaging antibodies

47
Q

What is CAR-T cell therapy?

A

chimeric antigen receptor T cells

T cells removed from patients own blood

genitically engineered T cells that target CD19 B cells

48
Q

What is prognosis of ALL determined by?

A

cytogenetic abnormality causing the disease

(ETV6-RUNX1, hypodiploid, hyperdiploid, BCR-ABL all good prognosis)

49
Q

Repeated Tx of Rituximab?

A

patients progress after approx 36 months ans need repeat treatment

PHAM02 (32 decks)

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