Haematology 2: Acute Leukaemias Flashcards
Which acute leukaemia is an emergency ?
APML
What translocation causes Acute promyelocytic leukaemia (APML) ?
T(15;17) (PML-RARA)
Which leukaemia is more common in patients with Down’s syndrome ?
AML
What signs is characteristic in APML ?
Sudden onset Haemorrhage (bruising and bleeding)
DIC + Hyperfibrinolysis
Which feature is characteristic of APML on microscopy ?
Multiple auer rods
What does the variant of APML without auer rods look like on microscopy ?
Promyelocytes with Bilobed nuclei
Which 2 stains are possitive in AML but not In ALL ?
Myeloperoxidase stain
Sudan black B stain
Which anaemia causes Gum infiltration ?
Monocytic AML
List 5 signs of AML ?
Anaemia- SOB, Pallor
Neutropenia- infections
Thrombocytopenia- easy bruising and bleeding, petichiae, ecchymoses, DIC
Local infiltration - hepatosplenomegaly, gum infiltration, lymphadenopathy, skin, CNS
Hyperviscocity if WBC is high
What is the most important diagnostic test for Leukaemias ?
Immunophenotyping
What is the most common leukaemia in childhood ?
ALL
List 5 signs of ALL ?
Anaemia- SOB, pallor Neutropenia- infections Thrombocytopenia- Easy bruising, bleeding Lymphadenopathy Hepatosplenomegaly
Which drug is used to treat CML or ALL with the Philadelphia chromosome abnormality ?
Tyrosine kinase inhibitor- Imatinib
list features of acute laeukaemia
rapid onset
early death if untreated
immature cells (blasts)
bone marrow failure - anaemia, thrombocytopenia, neutropaenia
features of AML
incidence increases with age
many AMLs have aberrations in chromosome count or structure
abberations are recurrent
what types of chromosomal abnormalities are seen in AML
duplication loss translocation - t(15;17) in APML (acute promyelocytic leukaemia inversion deletion altered DNA sequence
what chromosomes are commonly duplicated in AML
+8 and +21 (predisposition as seen in Down’s syndrome)
what chromosomal losses are common in AML
deletion or loss of 5/5q or 7/7q
- may be a loss of a tumour suppressor gene
- one copy of an allele may be insufficient for normal haemopoiesis
- loss of DNA repair systems
what molecular abnormalities may be present in someone with apparently normal chromosomes in AML
point mutations - NPM1, CEBPA
loss of function of TS genes
partial duplication
cryptic deletion
risk factors for AML
familial or constitutional predisposition ( Down syndrome)
irradiation
anticancer drugs
cigarettes
describe leukaemogenesis in AML
need multiple genetic hits
type 1 abnormalities - promote proliferation and survival (anti-apoptosis)
type 2 abnormalities - block differentiation - accumulation of blast cells
differentiation - disruption of TF function
describe how a translocation in core binding factor can lead to AML
CBF = dimeric TF
translocation 8;21 fuses RUNX + RUNX1T1
fusion transcription factor formed
drives leukaemia by causing a differentiation block
describe how an inversion of chromosome 16 can cause AML
inv (16,) t(16;16)
the inversion fuses CBF-beta to MYH11 to form a fusion product that cannon bind DNA sequence - arrests differentiation
what is APML
acute promyelocytic leukaemia
causes haemorrhage (acute onset bruising and bleeding)
excess abnormal promyelocytes
characterised by DIC and hyperactive fibrinolysis
two morphological variants
translocation chr 15 + 17
= PML-RARA fusion gene
the promyelocytes are abnormal because they contain multiple AUER RODS
variant form - bilobed nuclei
summarise leukaemogenesis in AML... --- --- dysregulation is important but not -- to cause leukaemia further genetic hits required -- and -- encouraged -- is blocked
transcription factor dysregulation is important but not sufficient to cause leukaemia further genetic hits required proliferation and survival encouraged differentiation is blocked
cytological features of AML
fine speckled granules
auer rods
cytochemistry for AML
stain for myeloperoxidase
immunophenotyping for AML
looking at antigens on the cell surface/within the cytoplasm done by: - flow cytometry - immunocytochemistry - immunohistochemistry
how is AML diagnoses
blood film - auer rods, immunophenotyping,
bone marow aspirate
cytogenetic studies t(15;17), t(8;21), inv (16)/t(16;16)
FISH studies
treatment of AML
supportive care - red cells, platelets, FFP/cryoprecipitate, antibiotics, allopurinol
chemo - combination (6 months)
transplantation if poor prognosis
describe features of ALL
peak in childhood
85% children cured
most common childhood malignancy
prognosis worse with increasing age
clinical features of ALL
BM infiltration local infiltration: - lymphadenopathy +/- thymic enlargement - splenomegaly - hepatomegaly - testes, CNS, kidneys, other sites - bone
ALL on blood film
anaemia
neutropenia
thrombocytopenia
usually lymphoblasts
what genetic features give a good prognosis for ALL
hyperdiploidy
T(12;21)
T(1,9)
what genetic factors give a poor prognosis in ALL
T(4;11)
hypodiploidy
what gives a good prognosis with tyrosine kinase inhibitors in ALL
T(9;22) - philodelphia chromosome
usually in CML but rarely in ALL
describe leukaemogenic mechanisms in ALL
proto-oncogene dysreg - chromosomal translocations - fusion genes - wrong gene promoter hyperdiploidy
how is ALL diagnosed
clinical suspicion blood count and film BM aspirate immunophenotyping cytogenetic/molecular genetic analysis
how is ALL treated
systemic chemotherapy - 2-3 years, boys need longer
CNS-directed therapy - eg intrathecal
supportive:
blood products
antibiotics - prophylaxis against PCP
