Acute lymphoblastic

leukaemia
 Introduction
• Acute lymphoblastic leukaemia (ALL) is caused by an
accumulation of lymphoblasts in the bone marrow and is the
most common malignancy of childhood.
• The incidence of ALL is highest at 3 – 7 years with 75% of cases
occurring before the age of 6.
• There is a secondary rise after the age of 40 years.
• Eighty - five percent of cases are of B – cell lineage and have an
equal sex incidence;
• there is a male predominance for the 15% of T - cell ALL (T -
ALL).
 Learning outcomes
• Describe ALL
• Discuss the pathogenesis of ALL
• Discuss the classification of ALL
• Discuss the clinical features of ALL
• Discuss the Lab investigations for ALL
 Pathogenesis
• Certain germline polymorphism in a group of genes mainly
involved in B - cell development (e.g. IKZF1) are more frequent in
patients with B - cell ALL (B - ALL).
• Interestingly, IKZF1 is also deleted in the leukaemic cells in 30% of
high risk B - ALL and 95% of ALL BCR - ABL1 positive cases.
• In most cases the first event occurs in the fetus in utero , with a
secondary event possibly precipitated by infection in childhood.
• The first event is a translocation (e.g. t(12; 21)) or point mutation.
• The second event involves genome – wide copy number
alterations, some of which encode for functions relevant to
leukaemogenesis
 Classification
• Acute lymphoblastic leukaemia, B cell or T cell, is subclassified
by WHO (2008) according to the underlying genetic defect
• Within B - ALL there are several specific genetic subtypes such
as translocations, rearrangements of the MLL gene or
alteration in chromosome number (diploidy)
• The subtype is an important guide to the optimal treatment
protocol and to prognosis.
• In T - ALL an abnormal karyotype is found in 50 – 70% of cases
and the NOTCH signalling pathway is activated in most cases
 Classification of ALL
Immunological marker

Mic Group FAB

CD2 CD7 CD10 CD19 TdT clg Karyotype

Early B- precursor ALL L1, L2 - + + + - t(4:11); t(9:22)

Common ALL L1, L2 - + + + - q- ; near-haploid;

t(1:19);t(9:22)

Pre B - ALL L1 - + + + + t(1:19); t(9:22)

B – cell ALL L3 - +/- + - - t(8:14); t (2:8) ; t(8:22)

Early T- precursor ALL L1, L2 + + - + t/del(9p)

T – cell ALL L1, L2 + + - + 6q-

FAB classification of lymphoblastic
leukaemia
L1
• Lymphoblastic leukaemia with homogeneous structure
L2
• Lymphoblastic leukaemia withvaried structure
L3
• Burkitt’s leukaemiaL
 L1 Lymphoblastic leukaemia with homogeneous structure

• Between 25% and 30% of cases in adults, and 85% of cases in

children.
• Blasts are homogeneous, nucleus is regular ,chromatin is
homogeneous ,small or no nucleoli, scanty cytoplasm, and mild to
moderate basophilia.
Immunophenotype
• B Cells CD19,CD22, CD79a,CD10, CD20 Cytoplasmic or superficial
immunoglobulin
• T cells CD3,CD7, CD5, CD2 ,CD4
L2 Lymphoblastic leukaemia withvaried
structure
• Accounts for 70% of
cases inadults, and 14%
in children.
• Nucleus is irregular,
heterogeneous
chromatin structure,
large nucleoli.
• Easy confused with AML
• Immunophenotype asme
as L1
L3 Burkitt’s leukaemia
• Rare subtype, accounting forless
than 1% to 2% of cases
• Large blasts, prominent nucleoli,
stippled homogeneous
chromatin structure, abundant
cytoplasm, abundant
cytoplasmic vacuolation(bubble
type) covering the nucleus.
• Immunophenotype is the same
as L1 and L2
 Clinical features
Bone marrow failure
• Anaemia (pallor, lethargy and dyspnoea);
• Neutropenia (fever, malaise, features of mouth, throat, skin,
respiratory, perianal or other infections);
• Thrombocytopenia (spontaneous bruises, purpura, bleeding gums
and menorrhagia).
Organ infiltration
• Tender bones, lymphadenopathy ,moderate splenomegaly,
hepatomegaly and meningeal syndrome (headache, nausea and
vomiting, blurring of vision and diplopia).
• Papilloedema and sometimes haemorrhage
Investigations
• Haematological investigations reveal a normochromic
normocytic anaemia with thrombocytopenia in most cases.
• The total white cell count may be decreased, normal or
increased to 200 × 109 /L or more.
• The blood film typically shows a variable numbers of blast
cells.
• The bone marrow is hypercellular with > 20% leukaemic
blasts.
• The blast cells can be characterized by morphology
cytochemisty immunological tests and cytogenetic analysis.
Specialized tests for (ALL).
Cytochemistry
• Myeloperoxidase −
• Sudan black −
• Non - specifi c esterase −
• Periodic acid – Schiff + (coarse block positivity in ALL)
• Acid phosphatase + in T - ALL (Golgi staining)
Immunoglobulin and TCR genes
• B - ALL: clonal rearrangement of immunoglobulin genes
• T - ALL: clonalrearrangement of TCR genes
Immunological markers (flow cytometry)
Chromosomes and genetic analysis
cytochemistry and immunophenotyping

Indirect immunofluorescence
reveals nuclear terminal
deoxynucleotidyl transferase (TdT)
(green) and membrane CD10
(orange)
 Chromosomes and genetic analysis
• Cytogenetic analysis shows differing frequencies of abnormalities in
infants, children and adults which partly explains the different
prognoses of these groups
• Hyperdiploid cells have > 50 chromosomes and generally have a good
prognosis whereas hypodiploid cases ( < 44 chromosomes) carry a
poor prognosis.
• The most common specific abnormality in childhood B - ALL is the
t(12; 21)(p13; q22) TEL - AML1 translocation
• The frequency of the Philadelphia translocation t(9; 22) increases with
age and carries a poor prognosis.
• Translocations of chromosome 11q23 involve the MLL gene and are
seen particularly in cases of infant leukaemia.
Treatment
General supportive therapy
• General supportive therapy for bone marrow failure
includes the insertion of a central venous cannula,
blood product support and prevention of tumour lysis
syndrome.
• Any episode of fever must be treated promptly.
Prognosis in acute lymphoblastic leukaemia