leukaemia (SD) Flashcards
Sx of leukameia
pallor
lethargy
pharyngitis
recurrent infections
easy bruising
pyrexia
night sweats
bone pain
flu-like sx
lymphadenopathy
splenomegaly
hepatomegaly
acute vs chronic
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
3 ways to classify leukaemia
- morphology
- immunophenotype
- genotype
difference between leukaemia and lymphoma
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
What is immunophenotyping?
used to ID CD proteins on cell surface which are used as markers
CD marker of B cells
CD19
CD20
risk factors for ALL
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
what is ALL
acute lymphoblastic leukaemia
neoplasms of precursor B and T cells, called lymphocytes
accumulation of lymphoblasts in bone marrow and peripheral blood
How to immunophenotype?
flow cytometry
Are B or T cells most affected?
B cells (85%)
how to differentiate betwen leukaemia and lymphoma
leukaemia if >25% bone marrow replaced by malignant cells
lymphoma if large lymph nodes
peak age of ALL incidence
3-7 years
rises again >40yrs
investigations for ALL
- FBC
- blood film
- bone marrow
- immunophenotype
- immunoglobulin and TCR genes
- molecular genetics
bone marrow findings in investigations for ALL
hypercellular
with >20% blast cells
FBC for ALL
- normochromic normocytic anaemia (normal sized RBC, normal Hb content)
- neutropenia
- thrombocytopenia
- WBC count can be increased/normal/decreased
neutropenia
low neutrophil count
thrombocytopenia
low platelet count
What are blast cells?
large lymphocytes (huge WBCs)
morphology similar to myeoblasts
pathogenesis of ALL
- 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
- 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
genetics in ALL
- gene variability
- chromosomal alterations - most common genetic driver
- chimeric proteins
What is aneuploidy?
gain or loss of whole chromosomes
types of aneuploidy
hyperdiploid = >50 chromosomes, good prognosis
hypodiploid = <44 chromosomes, poor prognosis
most common genetic driver for ALL
chromosomal abnormalities
example of a chromosomal translocation
ETV6-RUNX1
What do chromosomal translocations do?
they create fusion genes that drive oncogenesis
How to detect chromosonal abnormalities?
FISH
fluorescence in situ hybridisation
most common fusion gene in B-ALL
ETV6-RUNX1
ETV6-RUNX1 fusion gene
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
BCR gene
breakpoint cluster region
What is the Philadelphia chromosome?
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
How does BCR-ABL1/Philadelphia positive cause leukaemia?
activates tyrosine kinase signalling
through activation of:
- Jak-Stat
- MAPK
causes cell growth, migration, differentiation
inhibits apoptosis mechanisms - p53, inhibits caspsases
What is used first line to treat philadelphia positive ALL?
TKIs - imatinib
Treatment for imatinib resistance (in Ph+ ALL)?
alternate TKIs
- dasatinib
- ponatinib
How does methotrexate work?
it blocks pyrimidine/purine biosynthetic pathway and the proliferation of B cells by interfering with DNA synthesis, repair and replication
suppresses the immune system
Tx for ALL relapse?
Rituximab
Rituximab MOA
- 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
Repeated Tx of Rituximab?
patients progress after approx 36 months ans need repeat treatment
Other cancers that Rituximab is used in?
lymphoma
response rate of Rituximab
80%
What is CD20?
a cell marker on B cells during B cell differentiation
What is CD19?
cell marker on B cells
plays a role in maintaining the balance between humoral, antigen-induced response and tolerance induction
Tx target
What does PD-L1 do?
prevents tumour cells from ‘evading’ the immune system
Therapy to target CD19?
Blinatumomab
Therapy to target CD20?
Rituximab
Blinatumomab
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
BiTE therapy?
bi-specific T cell engaging antibodies
What is CAR-T cell therapy?
chimeric antigen receptor T cells
T cells removed from patients own blood
genitically engineered T cells that target CD19 B cells
What is prognosis of ALL determined by?
cytogenetic abnormality causing the disease
(ETV6-RUNX1, hypodiploid, hyperdiploid, BCR-ABL all good prognosis)
Repeated Tx of Rituximab?
patients progress after approx 36 months ans need repeat treatment
