Concepts in Malignant Haematology Flashcards
normal haemopoiesis?
stem cells > multipotent progenitors > oligolineage progenitors > mature cells
what kinetic events occur during haemopoiesis?
self-renewal proliferation differentiation/lineage commitment maturation apoptosis
how can normal, mature non-lymphoid cells be identified?
via morphology
- cell surface antigens (e.g glycophorin A = red cells)
- enzyme expression (myeloperoxidase = neutrophils)
what are the non-lymphoid cells?
red cells (erythrocytes)
platelets
granulocytes (neutrophils, basophils, eosinophils)
macrophages
how can normal progenitor cells/stem cells be identified?
cell surface antigens (immunophenotyping eg CD34)
cell culture assay
animal models
malignant haemopoiesis is characterised by what?
increased numbers of abnormal and dysfunctional cells
loss of normal activity (loss of normal haemopoiesis in leukaemia or loss of immune function in certain lymphoma)
what problems can occur in haemopoiesis?
increased proliferation
lack of differentiation
lack of maturation
lack of apoptosis
describe bone marrow aspirate in acute leukaemia
proliferation of abnormal progenitors with block in differentiation/maturation
describe bone marrow aspirate in chronic myeloproliferative disorders (e.g chronic myeloid leukaemia)
proliferation of abnormal progenitors
but no block of differentiation/maturation
what causes haematological malignancy?
genetic, epigenetic and environmental interaction
somatic mutations in regulatory genes(driver/passenger genes)
recurrent cytogenic abnormalities (e.g deletions, chromosomal translocations etc) can contribute but not usually causal
usually multiple “hits” rather than single event
driver mutations can select “clones”, what are clones?
population of cells derived from a single parent cell
this parent cells has a genetic marker that is chared by all daughter cells
clones can diversify but contain similar genetic backbone
clones in normal haemopoiesis vs malignant haemopoiesis?
normal = polyclonal malignant = monoclonal
what is a driver mutation?
a mutation that gives a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction. Driver mutations tend to cause clonal expansions.
how do driver mutations cause cancer?
they confer a growth advantage on the cells and are selected during the evolution of the cancer
what is a passenger mutation?
AKA hitchhiker mutation
doesn’t confer a growth advantage but can still be associated with clonal expansion as it occurs on the same genome as the driver mutation
what are types of haematological malignancies based on?
lineage
developmental stage (precursor) within lineage
anatomical site involved
types of haematological malignancy based on lineage?
myeloid
lymphoid
examples of haematological malignancy based on developmental stage?
cancer of lymphocyte precursor = acute lymphoblastic anaemia
cancer of mature lymphocytes = chronic lymphocytic leukaemia
cancer of mature plasma cell (branch of B cell) = myeloma
types of haematological malignancy based on anatomical site involved?
blood involvement = leukaemia
lymph node involvement with lymphoid malignancy = lymphoma
(however chronic lymphocytic leukaemia can involve blood and lymph nodes)
which is more histologically and clinically more aggressive, acute leukaemias/high grade lymphomas or chronic leukaemias/low grade lymphomas?
acute leukaemias and high grade lymphomas
what features on histology indicate aggressive cancer?
large cells with high nuclear:cytoplasmic ratio
prominent nucleoli
rapid proliferation
clinical features of aggressive cancer?
rapid progression of symptoms
acute leukaemias, in contrast to chronic, present with failure of normal bone marrow function
what myeloid cancers occur at stem cell stage?
chronic myeloid leukaemia
chronic myeloproliferative disorders
what myeloid cancers occur at multipotent progenitor stage?
acute myeloid leukaemia
what lymphoid cancer can occur at multipotent progenitor stage?
acute lymphoblastic leukaemia
what lymphoid cancer can occur at mature cell stage?
lymphomas
chronic lymphocytic anaemia
myeloma of plasma cells
describe pathology of acute laeukaemia
rapidly progressive clonal malignancy of the marrow/blood with maturation defects
defined as an excess of “blasts” (>20%) in either the peripheral blood or bone marrow
decrease/loss of normal haemopoietic reserve
types of acute leukaemia?
acute myeloid leukaemia (AML)
acute lymphoblastic leukaemia (ALL)
ALL is a malignant disease of which cells?
primitive lymphoid cells (lymphoblasts)
most common childhood cancer?
ALL
clinical presentation of ALL?
features of marrow failure (anaemia, infection, bleeding)
leukaemic effects (high blood cell counts with obstruction of circulation, involvement of areas outside blood/marrow)
bone pain
who is AML more common in?
elderly (>60)
can be de novo or secondary to something else
presentation of AML?
similar to ALL
subgroups may have characteristic presentation (DIC, gum infiltration etc)
investigations for acute leukaemia?
blood count and film
coagulation screen
bone marrow aspirate
blood film in acute leukaemia?
reduction in normal cells
presence of abnormal cells (high nuclear:cytoplasmic ratio etc)
characteristic feature found in cells in acute myeloid leukaemia on blood film?
auer rod (pale area/line/blob/slit? at edge of cell)
what features do you look for on bone marrow aspirate?
morphology
immunophenotyping (are there lineage-specific proteins on cell surface?)
cyto/molecular genetics
trephine (piece of bone) - better assessment of cellularity and helpful if aspirate not great
definitive diagnosis to differentiate between AML and ALL?
immunophenotyping
even though cells from AML and ALL look alike, they express lineage associated proteins
curative treatment of acute leukaemia?
multi-agent chemo
other options include targeted treatments with kinase inhibitors and allogeneic stem cell transplant in select patients
how is multi agent chemo given in ALL?
can last up to 2-3 years
different phases of treatment with different intensity
targeted treatment in certain subsets
how is multi-agent chemo given in AML?
intensive
2-4 cycles (5-10 days chemo then 2-4 weeks recovery)
prolonged hospital stay
targeted treatments in subsets
what is a hickman line?
long term IV line inserted through the chest and SVC > right atrium
has port for easy connection of drips and syringes
problems with marrow suppression from chemo?
anaemia
neutropenia (main problem as can cause infections which are severe and long lasting)
thrombocytopenia (bleeding problems)
what type of bacteria can cause fulminant life threatening sepsis in neutropaenic patients?
gram -ve
other complications of chemo?
nausea and vomiting hair loss liver/renal dysfunction tumour lysis syndrome infection late effects such as infertility, cardiomyopathy in anthracyclines)
how is bacterial infection in chemo managed (important)?
broad spectrum antibiotics as soon as neutropenic fever occurs
(cover gram -ves in particular)
what suggests a fungal infection in chemo? (important)
prolonged neutropenia and persisting fever unresponsive to anti-bacterial agents
how effective is treatment in acute leukaemia?
many people go into remission
however remission might not last depending on type of acute leukaemia and many relapse
some patients will also die of treatment related toxicity
definition of remission?
<5% marrow blasts with recovery of normal haemopoiesis
cure rates in acute leukaemia
childhood ALL = 85-90%
adult ALL = 30-40
adult AML = 40-50
elderly AML = 10% or less
