Acute Leukaemia

Question 1

Define acute leukaemia

Answer 1

Blood cancer
Characterised by clonal proliferation of haematopoietic cells
Impaired lineal differentiation
Excess of immature cells at the expense of mature cells
Results in functional bone marrow failure

Question 2

Incidence of Acute Lymphoblastic Leukaemia (ALL)

Answer 2

Bimodal peak

• Children 4 - 14 years of age
• Adults > 50 years old

Question 3

Incidence of Acute Myeloid Leukaemia (AML)

Answer 3

Median age of presentation 70-yr
3 / 100 000 children and adults < 50-yr
20 / 100 000 8th decade of life

Question 4

Incidence of Acute Promyelocytic Leukaemia (APML)

Answer 4

10% of AML diagnoses

Question 5

Define Acute Promyelocytic Leukaemia (APML)

Answer 5

Rare subtype of AML (10%)

Immature abnormal neutrophils (promyelocytes)

Question 6

Common presenting symptoms of Acute Leukaemia

Answer 6

Anaemia, sec. to marrow failure: fatigue, dyspnoea, angina

Neutropaenic sepsis, sec. to marrow failure

Thrombocytopaenia, sec. to marrow failure, or DIC in APML: bruising, epistaxis, mucosal bleeding

Question 7

Common infectious presentation of all Acute Leukaemias

Answer 7

Secondary to neutropenia: 
Chest, Mouth, Perianal, Skin
Bacterial septicaemia
Herpes zoster
CMV
Maesles
Fungi (Candida, Aspergillus)
Pneumocystis pneumonia

Question 8

Symptoms of Laukaemic Infiltration of CNS

Answer 8

Uncommon, <10% ALL, rarely in AML

Symptoms of raised ICP (headache, N/V, HTN, confusion, visual changes)
Cranial Nerve Palsies
Meningism

Question 9

Common presentation of Acute Promyelocytic Leukaemia (APML)

Answer 9

Coagulopathy (haematological emergency)

Bleeding: intracranial, mucosal, epistaxis, bruising
Thrombosis: venous, arterial

Question 10

Genetic Abnormalities of Acute Promyelocytic Leukaemia (APML)

Answer 10

t(15;17)

Result in fusion gene ‘PML/RARA’:

Promyelocytic laekamia/retinoic acid receptor-α

Question 11

Treatment of Acute Promyelocytic Leukaemia (APML)

Answer 11

ATRA: all-trans retinoic acid
‘Differentiation Therapy’: forces promyelocytes to differentiate into final form

Arsenic trioxide
Idarubicin

Question 12

Common side effect of ATRA therapy

Answer 12

Differentiation Syndrome (Retinoic Acid Syndrome)

Question 13

Common presentation of Acute Monocytic Leukaemia (AMoL)

Answer 13

Gum hypertrophy, due to infiltration of monocytes blasts

Question 14

Classification systems for Acute Lymphoblastic Leukaemia

Answer 14

1 Morphological:
The FAB system (French, British, American) divides ALL into 3 types (L1, L2, L3) by microscopic appearance. Provides limited information

2 Immunological:
Surface markers are used to classify ALL into: ‘Precursor B Cell’, ‘T-Cell ALL’, ‘B-Cell ALL’.

3 Cytogenic:
Chromosomal analysis. Abnormalities are detected in up to 85%, which are often translocations. Poor prognosis with Philadelphia chromosome t (9; 22)

Question 15

Blood Film findings in Acute Leukaemia

Answer 15

Circulating Blasts: cells with scanty basophilic cytoplasm, open chromatin, prominent nucleoli

i. Myeloid Blasts: cytoplasmic granules, Auer rods
ii. Lymphoid Blasts: granular
iii. AMPL Blasts: densely granulated, multiple Auer rods “faggot cells”

Rarely: pancytopenia with no circulating blasts (aleukaemic leukaemia)

Question 16

Symptoms of hyperleukocytosis (leukostasis)

Answer 16

Dyspnoea and Confusion (lung and brain infiltration)

Examine:
Fundi: papilloedema, blurred disc margins, retinal haemorrhage
CXR: pulmonary infiltrates

Question 17

Management of hyperleukocytosis (leukostasis)

Answer 17

Hydroxycarbamide
Leucapheresis (contraindicated in APML; worsens coagulapathy)

If occurring in context of AMPL: treat with ATRA

Question 18

Diagnostic Criteria for hyperleukocytosis (leukostasis)

Answer 18

AML WCC > 50 x 10^9 (if symptomatic)
AML WCC > 100 x 10^9 (if asymptomatic)
ALL WCC > 150 x 10^9 (if symptomatic)
AML WCC > 300 x 10^9 (if asymptomatic)

Question 19

Common Presentation of Acute T-Cell precursor Lymphoblastic Leukaemia (T-ALL)

Answer 19

15% of ALL

Lymphadenopathy
Hepatomaegally
Splenomaegally

Adolescent males with thymic involvement; respiratory distress due to anterior mediastinal mass +/- pleural effusion +/- supraclavicular lymph node involvement.

Question 20

Common Presentation of Acute B-Cell Precursor Lymphoblastic Leukaemia (B-ALL)

Answer 20

85% of ALL

Peak at 4 years of age

Bone marrow involvement; 
Anaemia
Bleeding
Fever 
Generalised bone pain (children won't walk), Generalised lymphadenopathy
CNS manifestations

Question 21

Genetic Abnormalities of Acute Myeloid Leukaemia (AML)

Answer 21

‘Core-binding factor’ (CBF) translocations: t(8; 21) and inv(16). Respond to high-dose cytarabine, and benefit from additional therapy with gemtuzumab ozogamicin (Mylotarg)

AML with gene mutations (prognostic significance):
Mutated NPM1 (nucleophosmin)
CEBPA

Question 22

Define ‘Complete Morphological Remission’ in Leukaemia

Answer 22

i. <5% blasts in the bone marrow
ii. Neutrophils >1 x 10^9/litre
iii. Platelets >100 x 10^9/litre

Question 23

Significance of Philadelphia chromosome t(9; 22) in Acute Leukaemia

Answer 23

This cytogenetic abnormality predicts:

i. In AML or ALL a high rate of relapse; justifies ASCT as soon as this is feasible
ii. Additional therapy with a tyrosine kinase inhibitor (TKI) such as imatinib (Glivec) to target the fusion transcription BCR-ABL

Question 24

10-year Disease Free Survival (DFS) for Acute Myeloid Leukaemia (AML) based on cytogenetic abnormalities

Answer 24

Figures are 10-yr Disease Free Survival

i. In patients with t(8; 21) 61%
ii. In patient with inv16; t(16; 16) 55%
iii. For all other patients with AML (apart from APL) <40%
iv. ‘AML complex’ (>3 chromosomal abnormalities in a cell) 18%.

Question 25

Treatment of Acute Myeloid Leukaemia (AML)

Answer 25

Backbone of AML chemotherapy is a combination of cytarabine with an anthracycline such as daunorubicin.

Most patients are given 1-2 cycles of induction chemotherapy, followed by consolidation chemotherapy with high-dose cytarabine for 1-2 cycles.

Question 26

Predisposing factors to Acute Leukaemia

Answer 26

Most cases are sporadic, predisposing factors are:

i. Chemicals (benzene)
ii. Radiation
iii. Tobacco smoke
iv. Previous chemotherapy
○ Topoisomerase inhibitors, e.g. etoposide ( 11q23 abnormalities)
○ Alkylating agents, e.g. melphalan and cyclophosphamide (deletion of chromosomes 5 and 7)
v. Inherited conditions such as Down’s syndrome.

Question 27

Family history that can increase risk of Acute Leukaemia

Answer 27

i. Chromosome breakage disorders, such as Fanconi’s Anaemia
ii. Isolated inherited gene defects in myeloid differentiation factors:
○ CCAAT / Enhancer Binding Protein Epsilon (CEBPA) mutations
○ Runt Related Transcription Factor 1 (RUNX1) mutations