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

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 2. 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

gene variability chromosomal alterations - most common genetic driver chimeric proteins

leukaemia (SD) Flashcards by Sarah Ramsbottom

Sx of leukameia

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

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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

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3 ways to classify leukaemia

morphology
immunophenotype
genotype

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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

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What is immunophenotyping?

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

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CD marker of B cells

CD19
CD20

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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

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what is ALL

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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How to immunophenotype?

flow cytometry

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Are B or T cells most affected?

B cells (85%)

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how to differentiate betwen leukaemia and lymphoma

leukaemia if >25% bone marrow replaced by malignant cells

lymphoma if large lymph nodes

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peak age of ALL incidence

3-7 years

rises again >40yrs

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investigations for ALL

FBC
blood film
bone marrow
immunophenotype
immunoglobulin and TCR genes
molecular genetics

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bone marrow findings in investigations for ALL

hypercellular

with >20% blast cells

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FBC for ALL

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

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neutropenia

low neutrophil count

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thrombocytopenia

low platelet count

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What are blast cells?

large lymphocytes (huge WBCs)

morphology similar to myeoblasts

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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

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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