Acute Leukaemia Flashcards
Define acute leukaemia
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
Incidence of Acute Lymphoblastic Leukaemia (ALL)
Bimodal peak
- Children 4 - 14 years of age
- Adults > 50 years old
Incidence of Acute Myeloid Leukaemia (AML)
Median age of presentation 70-yr
3 / 100 000 children and adults < 50-yr
20 / 100 000 8th decade of life
Incidence of Acute Promyelocytic Leukaemia (APML)
10% of AML diagnoses
Define Acute Promyelocytic Leukaemia (APML)
Rare subtype of AML (10%)
Immature abnormal neutrophils (promyelocytes)
Common presenting symptoms of Acute Leukaemia
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
Common infectious presentation of all Acute Leukaemias
Secondary to neutropenia: Chest, Mouth, Perianal, Skin Bacterial septicaemia Herpes zoster CMV Maesles Fungi (Candida, Aspergillus) Pneumocystis pneumonia
Symptoms of Laukaemic Infiltration of CNS
Uncommon, <10% ALL, rarely in AML
Symptoms of raised ICP (headache, N/V, HTN, confusion, visual changes)
Cranial Nerve Palsies
Meningism
Common presentation of Acute Promyelocytic Leukaemia (APML)
Coagulopathy (haematological emergency)
Bleeding: intracranial, mucosal, epistaxis, bruising
Thrombosis: venous, arterial
Genetic Abnormalities of Acute Promyelocytic Leukaemia (APML)
t(15;17)
Result in fusion gene ‘PML/RARA’:
Promyelocytic laekamia/retinoic acid receptor-α
Treatment of Acute Promyelocytic Leukaemia (APML)
ATRA: all-trans retinoic acid
‘Differentiation Therapy’: forces promyelocytes to differentiate into final form
Arsenic trioxide
Idarubicin
Common side effect of ATRA therapy
Differentiation Syndrome (Retinoic Acid Syndrome)
Common presentation of Acute Monocytic Leukaemia (AMoL)
Gum hypertrophy, due to infiltration of monocytes blasts
Classification systems for Acute Lymphoblastic Leukaemia
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)
Blood Film findings in Acute Leukaemia
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)
Symptoms of hyperleukocytosis (leukostasis)
Dyspnoea and Confusion (lung and brain infiltration)
Examine:
Fundi: papilloedema, blurred disc margins, retinal haemorrhage
CXR: pulmonary infiltrates
Management of hyperleukocytosis (leukostasis)
Hydroxycarbamide
Leucapheresis (contraindicated in APML; worsens coagulapathy)
If occurring in context of AMPL: treat with ATRA
Diagnostic Criteria for hyperleukocytosis (leukostasis)
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)
Common Presentation of Acute T-Cell precursor Lymphoblastic Leukaemia (T-ALL)
15% of ALL
Lymphadenopathy
Hepatomaegally
Splenomaegally
Adolescent males with thymic involvement; respiratory distress due to anterior mediastinal mass +/- pleural effusion +/- supraclavicular lymph node involvement.
Common Presentation of Acute B-Cell Precursor Lymphoblastic Leukaemia (B-ALL)
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
Genetic Abnormalities of Acute Myeloid Leukaemia (AML)
‘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
Define ‘Complete Morphological Remission’ in Leukaemia
i. <5% blasts in the bone marrow
ii. Neutrophils >1 x 10^9/litre
iii. Platelets >100 x 10^9/litre
Significance of Philadelphia chromosome t(9; 22) in Acute Leukaemia
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
10-year Disease Free Survival (DFS) for Acute Myeloid Leukaemia (AML) based on cytogenetic abnormalities
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%.
Treatment of Acute Myeloid Leukaemia (AML)
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.
Predisposing factors to Acute Leukaemia
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.
Family history that can increase risk of Acute Leukaemia
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
