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08/02/2023 1
ACUTE LYMPHOBLASTIC
LEUKAEMIA
ANGAI A.H

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Outline
Introduction
Definition
Epidemiology
Aetiology
Pathogenesis
Classification
Clinical features
Laboratory investigations
Differential diagnosis
Treatment
Prognosis
Conclusion

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INTRODUCTION
Leukaemias are a group of disorders characterized by the accumulation of
malignant white cells in the bone marrow and blood. These abnormal cells
cause symptoms because of
(i) bone marrow failure (e.g. anaemia, neutropenia, thrombocytopenia); and
(ii) infiltration of organs (e.g. liver, spleen, lymph nodes, meninges, brain, skin
or testes).

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Definition
Leukaemias are malignant neoplasms of the haemopoietic
stem cell characterized by excessive clonal proliferation and
diffuse replacement of the bone marrow by the neoplastic cells
with spilling over into the peripheral blood and organ infiltration.
They are classified broadly into;
1. Acute Leukaemias
2. Chronic Leukaemias

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Acute Leukaemias
Acute Leukaemias are malignant clonal disorders originating in
haematopoietic stem cells or its committed progenitors characterized
by the proliferation of poorly differentiated blast (immature) cells in the
bone marrow and subsequent spillage into the peripheral blood and
tissues.
Acute leukaemias are usually aggressive diseases and are normally
defined by the presence of over 20% of blast cells in the blood or bone
marrow at clinical presentation.
Acute Leukaemias are further subdivided into
i. Acute myeloblastic leukaemia (AML) and
ii. Acute lymphoblastic leukaemia (ALL).

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AML is a malignant neoplasm of haematopoietic stem cells originating in bone
marrow and characterised by proliferation of blast cells of myeloid lineage.
ALL is a malignant neoplasm of haematopoietic stem cells of lymphoid lineage
arising from the bone marrow.

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Epidemiology
ALL is the most common haematologic malignancy of childhood.
 Highest at 3- 7 years with 75% of cases occurring before the age
of 6 with a secondary rise after the age of 40.
Males are frequently more affected than females.

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Aetiology of ALL
Unknown
Various factors associated with increased risk of acute leukaemias
include:
i) Genetic factors
Inherited susceptibility
Association with congenital or hereditary syndromes-e.gDown’s
syndrome (20 times increased incidence),Bloom’s
syndrome,Fanconi’s syndrome,Klinfelter’s syndrome,Ataxia
telangiectasia,Osteogenesis imperfect,Wiskott-Aldrich
syndrome,Diamond- Blackfan syndrome,Kostmann’s syndrome
etc

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ii). Acquired conditions include;
Aplastic anaemia
Myelodysplastic syndrome (MDS)
Paroxysmal nocturnal haemoglobinuria (PNH)
Myeloproliferative neoplasms (MPN)
iii). Environmental factors include;
Chemicals – chronic exposure to benzene.
Radiation – radiation to the marrow is leukaemogenic. Also , paternal irradiation
has been identified as a risk factor. Radiation may be natural UV light, diagnostic or
therapeutic
Viral infections – HTLV causing ATLL, EBV causing Burkitt’s lymphoma/Leukemia
Drugs – Alkylating agents e.g. Chlorambucil, Melphalan, Etoposide
Infections – children with less exposure to infection particularly of a high social
class have increased risk of developing acute leukaemia

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Pathogenesis of ALL
Initial primary genetic damage from either
spontaneous mutation, familial defects, drugs
or chemicals, irradiation etc.
Subsequent proliferation with minimal to no
differentiation (or disorderly differentiation)
and maturation results in acute leukaemia
Leukaemic cells accumulate in bone marrow,
suppress normal HSC and normal
haematopoiesis and eventually replace normal
precursor cells by clonal expansion, spill over
into the peripheral blood and infiltrate organs

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Manifestation of leukaemia is
mainly due to suppression of normal
haematopoiesis and organ
infiltration
Resultant effect is paucity of normal
red cells, white cells and platelets;
Organ infiltration results in their
enlargement and malfunction

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Classificaion of ALL
1. French-American-British (FAB) Classification Based on Morphology
2. WHO Classification Based on Morphology and Cytogenetic features

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FAB Classification
FAB sub classified ALL into L1–L3 based on lymphoblast morphology
and immunological markers
L1-small monomorphic lymphoblasts with indistinct nucleoli and scanty
cytoplasm
L2-large, heterogeneous lymphoblasts with more abundant cytoplasm
and prominent nucleoli
L3-large blasts with deeply basophilic & vacuolated abundant cytoplasm
and prominent nucleoli (Burkitt’s type cells)

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WHO Classification

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Clinical Features of ALL
Signs and symptoms of acute lymphoblastic leukaemia are non –specific
most of the time however, can be related to
Progressive bone marrow infiltration and replacement of normal
haemopoietic cells by leukaemic cells leading to bone marrow failure
Organ/tissue infiltration and spillage of leukaemic cells into peripheral
circulation

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Features of bone marrow failure include;
1.Anaemia; weakness, lethargy, light headedness, palpitations.
2.Infections; candidal infections, viral infections like herpes. They typically
present with fever
3.Haemorrhage, petechial rashes, bleeding gums, menorrhagia, rectal
bleed, retina haemorrhages.
4.Neutropenia; fever, malaise, features of mouth, throat, skin, respiratory
perianal or other infections

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Features of tissue/organ infiltration include;
1.Splenomegaly, hepatomegaly, lymphadenopathy
2.CNS infiltration causing meningeal syndrom, cranial nerve palsies
3.Bone pains as a result of marrow expansion and cortical bone erosion
4. Leucostasis as a result of spillage of cells into the circulation. Features include, confusion,
retinal haemorrhages, hypoxia
5. Mediastinal involvement particularly in infiltration of the thymus in T-ALL.
Many patients have fever at presentation, which usually resolves after starting
chemotherapy.

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Laboratory Investigations
Aims to;
1. Establish the presence of acute leukaemia and distinguish it from other
neoplastic and reactive conditions.
2. Distinguish between AML and ALL
3. Classification of AML or ALL into a specific subtype
4. Therapeutic and prognostic implications/ options.

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Laboratory studies in diagnosis of acute leukaemia include;
Full blood count-
•Moderate to severe anaemia,usually normocytic normochromic
•Blood film shows excess blasts irrespective of total WBC count
•Platelets –most often reduced
Bone marrow aspiration cytolology-
• = > 20% blast in the marrow irrespective of the cellularity,
most often blasts are > 90% of all nucleated BM cells
Cytochemistry- Myeloperoxidase, Sudan black, Chloroacetate
esterase, Non-specific esterase, Periodic acid Schiff’s reaction, Acid
phosphatase for classification of AL into AML or ALL –
complements morphological classification

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Immunological cell marker analysis (Immunophenotyping).
Gives information about the lineage and stage of development of the particular
cell.
Cell surface antigens named according to the internationally accepted CD (cluster
of differentiation) system are analyzed
Since blood and marrow cells are in fluid suspension, flow cytometric analysis is
the method of choice.
Helps in diagnosis and classification, prognostication, monitoring of therapy
Cytogenetic studies
Confirmation of diagnosis, assessment of prognosis and response to therapy,
assessment of clonality, and detection of minimal residual disease.
Molecular Genetic studies: employs methods like Southern blot analysis,
polymerase chain reaction based techniques and FISH.

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Other investigations that may be necessary
include:
Renal function test –U & E, Creatinine, uric
acid
Serum uric acid levels may be elevated
LFT –may reveal extent of disease
involvement
CXR –R/o thymic involvement in T-ALL
(involvement of thymus shows as
mediasternal mass on X -ray)

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Diagnosis
Based on the findings in the bone marrow and peripheral blood
The type of leukaemic cells seen determines the type of acute
leukaemia
BM blasts ≥ 20% establishes the diagnosis

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Differential diagnosis
Infectious mononucleosis
Myelodysplastic syndrome
NHL infiltrating the marrow

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Treatment of Acute Leukaemia
The aim of treatment in AL is to induce complete remission and then to
consolidate this with intensive therapy, hopefully eliminating the disease.
Treatment may be supportive or definitive
Supportive Care
•Blood and blood product transfusion
•Treatment & prophylaxis of infections
•Control and treatment of bleeding complications
•Prevention and or treatment of tumour lysis syndrome
•Psychological support
•Nutritional support
•Antiemetic therapy
•Reproductive issues

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Definitive Treatment
•Haemopoietic stem cell transplant-This is aimed at completely
replacing patient’s HSC (BM) with donor SC to take over the process of normal
haematopoiesis. When SCT is successfully done, the patient is cured of the
leukaemia
•Chemotherapy –involves using cytotoxic drugs to induce remission,
consolidate and maintain the remission induced
Remission in AL means, being free of the clinical symptoms and sign of the
disease in question and the return of laboratory parameters to normal

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Prognosis
A number of factors affect prognosis following diagnosis.
For ALL, favourable prognostic factor include;
Age; 1- 10 years
Sex ; female
Total Leucocyte Count (TLC): < 50 X 109/L
Immunophenotype; common ALL
CNS disease; Absence of blasts in CSF
Genetic abnormality; Hyperdiploidy
Remission after first induction; early

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For ALL, unfavourable prognostic factor include;
Age; <1, >10 years
Sex ; male (testicular relapse)
TLC; > 50 X 109/L
Immunophenotype; T-ALL, Early B- ALL (Smlg+)
CNS disease; Presence of blasts in CSF
Genetic abnormality; Hypodiploidy
Remission after first induction; failure to remit

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Conclusion
Acute leukaemias are very fatal
diseases which if not treated,
patient dies in a matter of weeks
from time of diagnosis
SCT is curative in selected patients

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References
1.. Essential Haematology by A V Hoffbrand, J E Pettit and P A H Moss.