Acute Leukaemia

Question 1

What is acute leukaemia?

Answer 1

A neoplastic condition characterised by:
Rapid onset
Early death if untreated
Immature cells (blast cells)
Bone marrow failure

Question 2

What symptoms can occur due to bone marrow failure in acute leukaemia?

Answer 2

Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding

Question 3

How would you differentiate acute myeloid leukaemia on blood film under microscope?

Answer 3

Fine granules

Question 4

What is the epidemiology of AML?

Answer 4

Increases with age
Prognosis worse with increasing age
40% of adults cured

Question 5

What are the risk factors for AML?

Answer 5

Irradiation
Certain drugs
Benzene exposure
Mostly unknown

Question 6

What chromosome features may be found in AML?

Answer 6

Many AMLs have aberrations in chromosome count or structure

Such abberations are recurrent and may be directly involved in the development of the leukaemia

Question 7

List the types of chromosomal abnormalities

Answer 7

Duplication
Loss
Translocation (new chromosome is called a derivative)
Inversion
Deletion

Question 8

What do chromosomal translocations and inversions in leukaemia lead to?

Answer 8

Altered DNA sequence
creation of new fusion genes (AML and ALL)
Abnormal regulation of genes (mainly ALL)

Question 9

What is the relationship between chromosomal duplication and leukaemia?

Answer 9

Common in AML

Disease hotspts: +8, +21 gives predisposition

Question 10

What is the relationship between chromosomal loss or deletion and leukaemia?

Answer 10

Common in AML

Disease hotspots - deletion and loss of 5/5q & 7/7q

Question 11

What happens in most acute myeloid leukaemia?

Answer 11

Block in maturation, blast cells accumulate

Question 12

Why do people get AML?

Answer 12

Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking
Unknown

Question 13

How does leukaemogeneis occur in AML?

Answer 13

Multiple genetic hits - at least 2 interacting molecular defects, synergise to give leukaemic phenotype

Question 14

What are the types of abnormalities leading to leukaemogenesis in AML?

Answer 14

Type 1 abnormalities: promote proliferation and survival

Type 2 abnormalities: block differentiation (which would normally be followed by apoptosis)

Question 15

What is required for differentiation?

Answer 15

Transcription factors: bind to DNA, alter structure to favour transcription, regulate gene expression

Question 16

What is the gene abnormality in acute promyelocytic leukaemia?

Answer 16

t(15;17)

Question 17

What are features of acute promyelocytic leukaemia?

Answer 17

Molecular mechanisms understood so molecular treatment can be applied
An excess of abnormal promyelocytes
Disseminated intravascular coagulation
Auer rods

Question 18

How do we distinguish between AML and ALL?

Answer 18

Cytological features: myeloid - granules and auer rods
(Cytochemistry)
Immunophenotyping: cell surface and cytoplasmic antigens

Question 19

What are the features of AML on blood film?

Answer 19

Granules

Auer rods

Question 20

What clinical features occur due to bone marrow failure in AML?

Answer 20

Anaemia: pallor, fatigue
Neutropenia: infection, may be severe and life threatening (septic shock, renal failure, DIC)
Thrombocytopenia: bleeding

Question 21

What clinical features occur due to local infiltration failure in AML?

Answer 21

Splenomegaly
Hepatomegaly
Gum infiltration (if monocytic)
Lymphadenopathy occasionally
Skin, CNS, other sites

Question 22

What are the steps in diagnosis of AML?

Answer 22

Clinical history
Physical examination
Blood count and film
Bone marrow aspirate (morphology)
Cytogenetic studies
Immunophenotypic
Molecular studies and FISH in selected patient

Question 23

What are the important features of clinical history in AML?

Answer 23

Past drug/irradiation exposure

Question 24

What can occur as result of a high white cell count in AML?

Answer 24

Hyperviscosity: retinal haemorrhage, retinal exudates

Question 25

Why is blood count and film important in diagnosis of AML?

Answer 25

Usually diagnostic: circulating blasts | Auer rods - proves myeloid

Question 26

What are the treatments available for AML?

Answer 26

``` Supportive care Chemotherapy Combination chemotherapy Targeted molecular therapy Possibly immunotherapy Transplantation (haematopoietic stem cell transplantation) ```

Question 27

What supportive care is given in AML?

Answer 27

Correct the effects of inadequate bone marrow function: Red cells Platelets FFP/Cryoprecipitate if DIC Antibiotics Long line Allopurinol, fluid and electrolyte balance

Question 28

How does the chemotherapy affect the bone marrow?

Answer 28

Damages DNA Normal stem cells: often quiescent, checkpoints allow repair of DNA damage Leukaemia cells: continuously dividing, lack of cell cycle checkpoint control

Question 29

What is combination chemotherapy?

Answer 29

Use two or more chemotherapy drugs Different mechanisms of action Synergy Non-overlapping toxicity

Question 30

What determines the prognosis for AML?

Answer 30

``` Patient characteristics: age, fitness Morphology Immunophenotyping Cytogenetics Genetics Response to treatment ```

Question 31

What is the epidemiology of ALL?

Answer 31

Peak incidence in childhood Most common childhood malignancy 85% of children cured Prognosis worse with increasing age

Question 32

What are the clinical features of ALL?

Answer 32

Lymphadenopathy: more common in T-lineage, infiltration of thymus, CNS and testes much more common than AML Bone marrow failure: anaemia, neutropenia, thrombocytopenia Local infiltration: lymphadenopathy, splenomegaly, hepatomegaly, kidney, bone

Question 33

What are the peripheral blood pathological features of ALL?

Answer 33

Anaemia Neutrophenia Thrombocytopenia Usually lymphoblasts

Question 34

What are the bone marrow and other tissue pathological features of AML?

Answer 34

Lymphoblast infiltration Lymphoblasts may be B or T lineage B-lineage - starts in bone marrow T-lineage - starts in thymus

Question 35

What are the leukaemogenic mechanisms of ALL?

Answer 35

Proto-oncogene dysregulation: chromosomal translocation - fusion genes, wrong gene promoter, dysregulation by proximity to T cell receptor

Question 36

What is required for the diagnosis of ALL?

Answer 36

``` Clinical suspicion Blood count and film Bone marrow aspirate Immunophenotyping Cytogenetic/molecular genetic analysis Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen ```

Question 37

What are the principles of specific therapy in ALL?

Answer 37

Systemic chemotherapy CNS-directed therapy Molecularly targeted treatment Transplantation

Question 38

What symptoms in children should make you consider leukaemia as a diagnosis?

Answer 38

``` Bone pain Limping Pallor Bruising Organomegaly ```

Question 39

What symptoms in adults would make you consider leukaemia?

Answer 39

``` Pallor Bruising Bleeding Infection Organomegaly ```