leukemia DD Flashcards
what are the associated symptoms of leukemia?
- pallor;
- lethargy;
- pharyngitis;
- recurrent infections;
- easy bruising;
- pyrexia;
- night sweats;
- bone pain;
- flu-like symptoms;
- lymphadenopathy;
- splenomegaly;
- hepatomegaly.
what are the 4 major classifications of leukaemia?
- Acute Lymphoblastic Leukaemia (ALL)
- Acute Myeloid Leukaemia (AML)
- Chronic Lymphocytic Leukaemia (CLL)
- Chronic Myeloid Leukaemia (CML)
what is the difference between acute vs chronic leukaemia?
- Acute leukaemia is fast-growing and can progress quickly without treatment
- Acute leukaemia cells multiply before any immune function has developed
- Chronic leukaemia is slow-growing
- Chronic leukaemia cells have immature, limited immune function
how do you classify leukaemia?
- Morphology-Cornerstone, but some share
similar morphology - Immunophenotype-Quantitative determination of cell lineage (e.g. B-, T- or NK-cell)
- Genotype-Specific translocations in
lymphomas
what is the difference between leukaemia and lymphoma?
leukemia is cancer of the blood cells that usually starts in the bone marrow and often travels through the bloodstream
lymphoma is cancer of the lymphatic system that usually originates in lymph nodes or, sometimes, the spleen.
how does immunophenotyping of leukaemia work?
- Malignant cells may show altered morphology
- Immunophenotyping (e.g. by flow cytometry) can identify cell lineage
- CD proteins on cell surface used as markers
- B-Cells have a marker called CD19
what are the risk factors for acute lymphocytic leukaemia?
- Radiation, pesticides, viruses (EBV, HIV) – thought to contribute
- Inherited syndromes
race/ethnicity
what is acute lymphoblastic leukaemia?
Acute lymphoblastic leukaemias are neoplasms of precursor B- and T-cells, called lymphoblasts
* Accumulation of lymphoblasts in bone marrow and peripheral blood
what is the most common type of acute lymphoblastic leukaemia?
Can be malignancy of B-cell (85%) or T-cell (15%) lineage
where does acute lymphoblastic leukaemia originate and spread to?
ALL starts in Bone Marrow, while lymphomas start in lymph nodes and spreads to Bone Marrow
– At diagnosis, malignant cells can be found at both locations – hard to
diagnose leukaemia Vs lymphoma
what investigations are done for ALL?
- Full blood count
– Normochromic normocytic anaemia (normal-sized RBC, normal Hb
content)
– Neutropenia (low neutrophil count)
– Thrombocytopenia (low platelet count)
– WBC count can be increased (>200 x 109), normal, or decreased - Blood film
– Variable number of blast cells - Bone marrow
– Hypercellular, with >20% blasts
how are ALL blast cells characterised?
- Morphology
- Immunological tests
- Cytogenetic analysis
- Blasts are larger than lymphocytes
- Morphology similar to
myeloblasts - Requires immunophenotyping or cytochemical stains
what investigations do you do for ALL?
- Immunophenotype
– Markers of B-cells (CD19) or T-cells (CD7) lineage - Immunoglobulin (B-cell) and TCR (T-cell) genes
– Recombination occurs early in immunoglobulin and T-cell receptor
production, in primary lymphoid tissues (bone marrow / thymus)
– Clonal populations carry the same VDJ rearrangements
– Polyclonal indicates reactive lymphocytes, e.g. due to infection - Molecular genetics
– Detection of cytogenetic abnormalities and mutations, etc.
what is the pathogenesis of ALL?
*Normally the first mutation occurs in the foetus, in early lymphoid
progenitor cells
– Cells continue to undergo alterations in the bone marrow, forming
lymphoblasts (pro-B cells) and prolymphocytes (pre-B cells)
– Germline mutation in <5% of cases
what causes the second genetic event in childhood?
– Potentially associated with childhood infection and exposures (e.g. ionising radiation)
– May be indirectly promoted through abnormal response to a common
infection (i.e. not due to a specific virus), esp. in under-exposed infants
what are the genes involved in ALL?
Genes identified for this disease are directly involved in blood cell proliferation and differentiation
what are the genetic observed in ALL patients?
– Gene variability
– Chromosomal alterations
– Observation of ‘chimeric’ proteins
– Chimera is a hybrid creature from
Greek Mythology
what is the main driver of ALL?
Most genetic drivers of ALL are chromosomal abnormalities
* Aneuploidy – gain or loss of whole chromosomes
– Hyperdiploid (>50 chromosomes) = good prognosis
– Hypodiploid (<44 chromosomes) = poor prognosis
– ‘Normally’ – 46 chromosome (23 from each parent)
* Chromosomal translocations - can can create fusion genes (e.g. ETV6-
RUNX1) that drive oncogenesis
* These chromosomal abnormalities can be detected by fluorescence in situ
hybridisation (FISH)
what is the most common B-all?
ETV6-RUNX1 fusion gene
* Previously known as TEL-AML1
* ETV6 – recruits transcriptional repressors
* RUNX1 – regulates transcription during
haematopoiesis
what does fusion gene lead to?
transcriptional silencing of
RUNX1 targets and deregulation of
haematopoiesis, but not sufficient to drive
leukaemia alone
what is the philadelphia chromosome?
- entire snap of chromosomes
- can be +ve or -ve
- chromosome 9 and 22- two proteins- ABL1- protooncogene- BCR is a protein of unknown function
- ABL on one chromosome and BCR on another – snap and switch ends
- Fuse
- Consequence- protooncogene axon 1- is the regulatory portion- what switches it on and off- when it snaps and fuse back axon 1 is missing- so abl1 becomes oncogene .
what is ABL1?
it is a proto-oncogene
– (non-receptor) Tyrosine kinase
– Roles in cell proliferation, survival or
death, migration.
– Activity limited by protein domain
encoded by exon 1
what is fusion?
Loss of exon 1 turns ABL
into an oncogene
what is the effect of constitutively activated tyrosine kinase signalling?
Jak-stat
MAPK
what does fusion inhibit?
- p53
- Inhibits Caspases
what is the prognosis of ALL?
- Risk stratification by cytogenetics
- Development of new drugs
- Adaptation of treatment (duration and intensity)
what is the prognosis determined by?
Prognosis is predominantly determined by the cytogenetic abnormality driving the disease (good, intermediate, poor)
what is the ALL treatment?
asparaginase
cyclophosphamide
cytarobine
danorubicin
dexamethasone
doxorubicin
methotrexate
6-mercaptopurine
vincristine
what is used in philidephpia positive patients?
targeted therapy= TKI- imatinib
blocks site of atp binding
how can patients become resistant to imatinib?
multiple pathways:
- epigenetic
-amplification, duplication
-kinase domain mutations
-importer/exporter
- serum protein binding
what happens if imatinib resistance occurs?
If this occurs use alternate TKIs Dasatinib and ponatinib effective against Philadelphia + ALL
how does methotrexate work?
Methotrexate blocks the pyrimidine/Purine biosynthetic pathway and the proliferation
of B-cells by interfering with DNA synthesis, repair, and replication
what do you give for relapsed ALL?
Rituximab
how does Rituximab work?
- Rituximab binds to the cell-surface
protein CD20 on B-cells
– Largely specific to B-cells (& some T-
cells)
– Lost during differentiation
what are the 3 mechanisms of actions of rituximab?
A. Antibody-dependent cell-mediated
toxicity (via Fc region)
B. Complement-mediated cell lysis
C. Induction of apoptosis
what is the patient progress with rituximib?
- Patients progress (36 months on average)
and require repeat treatment
can also be used for lymphoma
what is CD20?
CD20 is a cell marker on B Cells during B cell differentiation
what does rituximab do to CD20?
Rituximab specifically depletes CD20+ B cells by binding to the CD20 antigen
expressed on the cell surface
what happens if you block CD20?
Blockade of CD20 leads to B cell death (via apoptosis and lysis), used in many
diseases that are autoimmune and cancer (e.g. lymphoma, ALL)
what is the role of CD19?
- CD19 = cell marker on B-Cells
- CD19 plays a critical role in
maintaining the balance between
humoral, antigen-induced response
and tolerance induction - CD19 is Targeted for treatment
what is the purpose of PD-l1?
- Discussed in previous
lectures - Prevents tumour cells from
“evading” the immune
system - Recall Hallmarks of cancer
– Immune Evasion
how does BITE work?
Bispecific T-cell engaging
antibodies (BiTEs)
* One variable fragment binds the
CD3 T-cell co-receptor
* The second fragment binds a
protein on the target cell (CD19)
* The BITE directs T-cells to the B-
Cells and assists T cell activation
what is Car-T cell therapy?
Chimeric antigen receptor
(CAR) T cells
* Genetically Engineered T cells
that target CD19 B-cells
* T-Cells removed from patients
own blood
put back in when geentically alt
