Haematology 2: Acute Leukaemias

Question 1

Which acute leukaemia is an emergency ?

Answer 1

APML

Question 2

What translocation causes Acute promyelocytic leukaemia (APML) ?

Answer 2

T(15;17) (PML-RARA)

Question 3

Which leukaemia is more common in patients with Down’s syndrome ?

Answer 3

AML

Question 4

What signs is characteristic in APML ?

Answer 4

Sudden onset Haemorrhage (bruising and bleeding)

DIC + Hyperfibrinolysis

Question 5

Which feature is characteristic of APML on microscopy ?

Answer 5

Multiple auer rods

Question 6

What does the variant of APML without auer rods look like on microscopy ?

Answer 6

Promyelocytes with Bilobed nuclei

Question 7

Which 2 stains are possitive in AML but not In ALL ?

Answer 7

Myeloperoxidase stain

Sudan black B stain

Question 8

Which anaemia causes Gum infiltration ?

Answer 8

Monocytic AML

Question 9

List 5 signs of AML ?

Answer 9

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

Question 10

What is the most important diagnostic test for Leukaemias ?

Answer 10

Immunophenotyping

Question 11

What is the most common leukaemia in childhood ?

Answer 11

ALL

Question 12

List 5 signs of ALL ?

Answer 12

Anaemia- SOB, pallor  
Neutropenia- infections
Thrombocytopenia- Easy bruising, bleeding
Lymphadenopathy 
Hepatosplenomegaly

Question 13

Which drug is used to treat CML or ALL with the Philadelphia chromosome abnormality ?

Answer 13

Tyrosine kinase inhibitor- Imatinib

Question 14

list features of acute laeukaemia

Answer 14

rapid onset
early death if untreated
immature cells (blasts)
bone marrow failure - anaemia, thrombocytopenia, neutropaenia

Question 15

features of AML

Answer 15

incidence increases with age
many AMLs have aberrations in chromosome count or structure
abberations are recurrent

Question 16

what types of chromosomal abnormalities are seen in AML

Answer 16

duplication 
loss
translocation - t(15;17) in APML (acute promyelocytic leukaemia
inversion 
deletion
altered DNA sequence

Question 17

what chromosomes are commonly duplicated in AML

Answer 17

+8 and +21 (predisposition as seen in Down’s syndrome)

Question 18

what chromosomal losses are common in AML

Answer 18

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

Question 19

what molecular abnormalities may be present in someone with apparently normal chromosomes in AML

Answer 19

point mutations - NPM1, CEBPA
loss of function of TS genes
partial duplication
cryptic deletion

Question 20

risk factors for AML

Answer 20

familial or constitutional predisposition ( Down syndrome)
irradiation
anticancer drugs
cigarettes

Question 21

describe leukaemogenesis in AML

Answer 21

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

Question 22

describe how a translocation in core binding factor can lead to AML

Answer 22

CBF = dimeric TF
translocation 8;21 fuses RUNX + RUNX1T1
fusion transcription factor formed
drives leukaemia by causing a differentiation block

Question 23

describe how an inversion of chromosome 16 can cause AML

Answer 23

inv (16,) t(16;16)

the inversion fuses CBF-beta to MYH11 to form a fusion product that cannon bind DNA sequence - arrests differentiation

Question 24

what is APML

Answer 24

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

Question 25

``` summarise leukaemogenesis in AML... --- --- dysregulation is important but not -- to cause leukaemia further genetic hits required -- and -- encouraged -- is blocked ```

Answer 25

``` transcription factor dysregulation is important but not sufficient to cause leukaemia further genetic hits required proliferation and survival encouraged differentiation is blocked ```

Question 26

cytological features of AML

Answer 26

fine speckled granules | auer rods

Question 27

cytochemistry for AML

Answer 27

stain for myeloperoxidase

Question 28

immunophenotyping for AML

Answer 28

``` looking at antigens on the cell surface/within the cytoplasm done by: - flow cytometry - immunocytochemistry - immunohistochemistry ```

Question 29

how is AML diagnoses

Answer 29

blood film - auer rods, immunophenotyping, bone marow aspirate cytogenetic studies t(15;17), t(8;21), inv (16)/t(16;16) FISH studies

Question 30

treatment of AML

Answer 30

supportive care - red cells, platelets, FFP/cryoprecipitate, antibiotics, allopurinol chemo - combination (6 months) transplantation if poor prognosis

Question 31

describe features of ALL

Answer 31

peak in childhood 85% children cured most common childhood malignancy prognosis worse with increasing age

Question 32

clinical features of ALL

Answer 32

``` BM infiltration local infiltration: - lymphadenopathy +/- thymic enlargement - splenomegaly - hepatomegaly - testes, CNS, kidneys, other sites - bone ```

Question 33

ALL on blood film

Answer 33

anaemia neutropenia thrombocytopenia usually lymphoblasts

Question 34

what genetic features give a good prognosis for ALL

Answer 34

hyperdiploidy T(12;21) T(1,9)

Question 35

what genetic factors give a poor prognosis in ALL

Answer 35

T(4;11) | hypodiploidy

Question 36

what gives a good prognosis with tyrosine kinase inhibitors in ALL

Answer 36

T(9;22) - philodelphia chromosome | usually in CML but rarely in ALL

Question 37

describe leukaemogenic mechanisms in ALL

Answer 37

``` proto-oncogene dysreg - chromosomal translocations - fusion genes - wrong gene promoter hyperdiploidy ```

Question 38

how is ALL diagnosed

Answer 38

``` clinical suspicion blood count and film BM aspirate immunophenotyping cytogenetic/molecular genetic analysis ```

Question 39

how is ALL treated

Answer 39

systemic chemotherapy - 2-3 years, boys need longer CNS-directed therapy - eg intrathecal supportive: blood products antibiotics - prophylaxis against PCP