11/14/24, 10\:52 AM Paediatric Leukaemia

Paediatric Leukaemia

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Leukaemia\: cancer of immature white blood cells; most common childhood cancer (31% of cases).
Aetiology\: abnormal proliferation/di
syndromes increase risk.
Haematopoiesis\: multipotent haematopoietic stem cells di
leukaemias involve immature cells, chronic leukaemias involve more mature cells.
Acute lymphoblastic leukaemia (ALL)\: 75% of childhood leukaemia; common in children aged 1-4 years; abnormal
proliferation of B or T lymphoid progenitor cells.
Acute myeloid leukaemia (AML)\: 25% of childhood leukaemia; uncontrolled proliferation of immature myeloid blast cells.
Chronic myeloid leukaemia (CML)\: rare in children; involves more mature myeloid cells; often associated with Philadelphia
chromosome (t(9;22)).
Risk factors\: genetic syndromes (Down's syndrome, Fanconi anaemia, Li Fraumeni syndrome), exposure to ionising
radiation, pesticides, certain viruses (EBV, HIV).
Symptoms\: fatigue, bone/joint pain, dyspnoea, dizziness, recurrent infections, fevers, bleeding tendency, easy bruising.
Clinical
Investigations\: FBC (blast cells, pancytopenia), blood
X-ray (mediastinal mass), bone marrow aspiration/biopsy, lumbar puncture (CSF involvement).
Management\: chemotherapy (induction, consolidation, delayed intensi
(high-risk cases), CNS treatments, supportive measures (antibiotics, blood transfusions, G-CSF, psychosocial support).
Complications\: neutropenic sepsis, thrombocytopenia, blast cell lysis, leucostasis, CNS in
cardiotoxicity, fertility issues.
Prognosis\: signi
ALL is 85-90%.
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A comprehensive topic overview

Introduction

Leukaemia is a cancer of immature white blood cells and is the most common type of cancer in children, accounting for
31% of all childhood cancer cases.
1

Aetiology

Leukaemia involves abnormal proliferation and di
Most cases of leukaemia are caused by de novo mutations (new mutations which are not inherited). However, there are
also genetic syndromes which predispose children to leukaemia.
1
Certain chromosomal and genetic abnormalities can signi
used to guide treatment.
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Haematopoiesis and development of leukaemia

A multipotent haematopoietic stem cell can di
cells (see
populations.
Acute leukaemias result from failure of lymphoid or myeloid progenitor cells to di
proliferation of these immature blast cells.
Chronic leukaemias result from the uncontrolled proliferation of cells at a later stage of di
Figure 1. An overview of haematopoiesis.
Leukaemia is categorised based up whether cells originate from lymphoid precursors (lymphocytic) or myeloid
precursors (myelogenous), and by the degree of cell di
Acute leukaemias involve more immature cells (lymphoid or myeloid progenitor cells). Chronic leukaemias involve cells at
a later stage of di
Acute lymphoblastic leukaemia (ALL)2
Acute lymphoblastic leukaemia (ALL) is the most common type of leukaemia in children making up approximately 75% of
childhood leukaemia diagnoses. It is most common in children aged 1 - 4 years.
ALL develops as a result of abnormal proliferation and failed di
uncontrolled proliferation of these immature lymphocytes (lymphoblasts) within bone marrow prevents normal
haematopoiesis, and the abnormal blasts can spread to in
Acute myeloid leukaemia (AML)3
Acute myeloid leukaemia (AML) makes up around 25% of diagnoses of childhood leukaemia.
AML results from uncontrolled proliferation and failed di
blasts disrupt normal haematopoiesis in the bone marrow and can in
Chronic myeloid leukaemia (CML)4
Chronic myeloid leukaemia (CML) is less common in children (median age of diagnosis is 60-65 years). CML develops from
blood cells of the myeloid lineage, which are more mature than those seen in AML. Use of cytogenetics has identi
Philadelphia chromosome as the cause of CML in more than 90% of cases, which results from a translocation between
chromosomes 9 and 22, t(9;22).
Patients can progress from the chronic phase to an accelerated phase, with an increase in immature blast cells. This is
followed by further progression to a blast crisis phase, where there is ≥30% presence of blast cells in the bone marrow or
peripheral blood (or extramedullary in

Chronic lymphocytic leukaemia

In contrast to adults, chronic lymphocytic leukaemia (CLL) is extremely rare in children.
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Risk factors

Genetic syndromes which predispose individuals leukaemia include\:
5,6,8,9
Down's syndrome\: patients are 30 times more likely to develop ALL, and 150 times more likely to develop AML. The
characteristic leukaemia seen in Down's syndrome is M7 acute megakaryoblastic AML.
Fanconi anaemia
Li Fraumeni syndrome
Ataxia telangiectasia
Nijmegen breakage syndrome
Other risk factors include\:
1,6
Exposure to ionising radiation
Pesticides
Viruses such as Epstein-Barr virus (EBV), human immunode

Clinical features

Symptoms of leukaemia are often vague and non-speci
Symptoms of generalised fatigue/malaise may progress to more speci

History

Typical symptoms of leukaemia include\:
2-8,11
Fatigue and malaise
Bone and joint pain\: particularly a
Dyspnoea\: caused by anaemia, mediastinal mass or infection
Dizziness and palpitations
Recurrent and/or severe infections
Fevers
Thrombocytopenia\: bleeding tendency (epistaxis, bleeding gums), easy bruising, rashes

Clinical examination

Typical clinical
2-8,11
Weight loss
Skin\: pallor, petechial rash, bruising
Cardiovascular\: tachycardia,
Abdomen\: distension, hepatomegaly and/or splenomegaly
Lymphadenopathy

Uncommon clinical presentations

Uncommon clinical presentations of leukaemia include\:
2-8,11
Central nervous system (CNS), due to in
nausea/vomiting, cranial nerve palsies.
Testicular enlargement (1-2% males with new ALL diagnosis)
11
Leukaemia cutis (rare in
Red
The following red
12,13
An urgent specialist assessment is required if any of the following red
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Unexplained petechiae
Unexplained hepatosplenomegaly
An urgent full blood count is required if any of the following red
Pallor
Persistent fatigue
Unexplained fever
Unexplained persistent infection
Generalised lymphadenopathy
Unexplained bruising or bleeding
Persistent/unexplained bone pain

Di

Table 1. The di
Infective Malignant Autoimmune Haematological
Infectious
mononucleosis
Parvovirus B19
Other viruses (
HIV,
cytomegalovirus)
Osteomyelitis
Lymphoma
Rhabdomyosarco
ma
Other solid
tumours
Systemic lupus
erythematosus
Juvenile
idiopathic arthritis
Aplastic anaemia
Fanconi anaemia
Myelodysplasia
Myelo
Megaloblastic
anaemia
Lymphoproliferati
ve disorders

Investigations

Bedside investigations

Relevant bedside investigations include\:
5,6
Observations\: fever can indicate malignancy or infection, and tachycardia can occur in infection or anaemia.
Urine dip\: infection is an important di
Electrocardiogram (ECG)\: may show tachycardia, and a baseline is useful before cardiotoxic chemotherapy.

Laboratory investigations

Relevant laboratory investigations include\:
2-6,11
Full blood count\: blast cell proliferation causes raised white blood cell count, and pancytopenia will occur with bone
marrow suppression (anaemia and thrombocytopenia are common, while white blood cell count may be variable).
Blood
cells should normally not be seen in peripheral blood, so this is highly suspicious for leukaemia if seen on microscopy.
10
Coagulation pro\: may be deranged or show disseminated intravascular coagulation.
Baseline kidney and liver function\: these are needed prior to starting chemotherapy. Liver tests may indicate liver
in
this is usually seen post-chemotherapy).
Raised lactate dehydrogenase and uric acid\: occur with increased cell turnover.
Blood cultures\: if presenting with fever/signs of infection.
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Glucose-6-phosphate dehydrogenase (G6PD)\: G6PD de
it can result in a haemolytic crisis.

Imaging

Relevant imaging investigations include\:
2-6,11
Chest X-ray\: it is extremely important to identify early if a mediastinal mass is present before the child receives any
anaesthetic. A mediastinal mass may be present in T-cell lymphoblastic lymphoma, which overlaps with T-cell ALL, and
can cause airway compromise, cardiovascular collapse, and death. An X-ray may also show infection, enlarged nodes,
and lytic bone lesions.
Echocardiogram\: prior to starting cardiotoxic chemotherapies.
Other investigations2-5,8,11
Bone marrow aspiration and trephine biopsy are used for both diagnosis and monitoring. A biopsy may be used for\:
Diagnosis (presence of ≥20% blasts)
Minimal residual disease analysis after treatment (see below)
Cytogenetics\: detects chromosomal aberrations
Immunophenotyping\: uses
The use of cytogenetics and immunophenotyping is important for disease classi
guide treatment.
Cytogenetics detects chromosomal abnormalities and is used for risk strati
groups (low, intermediate and high). These are used to indicate prognosis and guide treatment.
5,8,9
A lumbar puncture may also be performed looking for the presence of leukaemic cells in cerebrospinal
Minimal residual disease
At the end of induction chemotherapy, the blast cell count should be ≤5% for patients to be classed as being in remission.
Presence of residual disease (i.e. persistent leukaemic cells) indicates the need for more intensive chemotherapy.

Classi

The two most widely known classi
Health Organisation (WHO) classi
However, there is less emphasis on the use of classi
strati
French-American-British (FAB) classi is based on morphology (the appearance of cells under a microscope) and
cytochemical staining of leukaemic cells.
World Health Organisation (WHO) classi system uses cytogenetics (chromosomal analysis) and
immunophenotyping (use of antibodies to detect white blood cell antigens).

Management

Chemotherapy is the mainstay of treatment in leukaemia.
Acute lymphocytic leukaemia2,5,6,8,9
The stages of chemotherapy for ALL include\:
1. Induction\: intensive phase lasting 4-6 weeks that aims to destroy all leukaemic blast cells. To reduce the risk of tumour
lysis syndrome, pre-phase treatment with hydration and allopurinol/rasburicase is given prior to chemotherapy.
2. Consolidation and CNS treatment\: the aim is to maintain remission. Lumbar puncture with intrathecal methotrexate aims
to prevent spread to the CNS.
3. Delayed intensi
4. Maintenance\: treatment continues for 2 years in girls, and 3 years in boys. This can involve oral or intravenous
chemotherapy, steroids, and intrathecal treatments.
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Chemotherapy agents commonly used include corticosteroids, vincristine, anthracyclines, asparaginase,
cyclophosphamide and cytarabine.
Acute myeloid leukaemia3,6
The stages of chemotherapy for AML include\:
1. Induction\: intensive phase which aims to destroy all leukaemic cells.
2. Post-remission treatment\: usually involves two further courses of chemotherapy, aiming to destroy residual cells and
prevent a recurrence.
Bone marrow tests are repeated following induction, to assess whether remission has been achieved.
Other treatments 2-6,8,9
Other treatments for leukaemia include\:
Bone marrow transplant\: this is only used in patients with a high risk of disease recurrence, or with recurrence following
standard chemotherapy.
Testicular radiotherapy\: used for patients with testicular in
CNS treatments\: chemotherapy drugs may be injected intrathecally (via lumbar puncture), and occasionally radiotherapy
is used for in
Supportive measures 2-6,8,9
Other supportive measures for leukaemia include\:
Education for families\: it is vital that children present quickly when they are unwell, particularly when febrile.
Broad-spectrum antibiotics urgently for children presenting with suspected neutropenic sepsis.
Prophylactic antimicrobials\: particularly co-trimoxazole (to prevent p n e u m o c y s t i s j i r o v e c i i ) in ALL, and antifungals in
AML.
Blood transfusions.
Allopurinol (prevention of tumour lysis syndrome).
Insertion of a central venous catheter for chemotherapy and blood sampling.
Granulocyte-colony stimulating factor (G-CSF)\: to support cell counts (e.g. prolonged neutropenia).
Psychosocial support, educational support, advice about

Complications

Early complications of leukaemia include\:
5,6,11
Neutropenic sepsis
Thrombocytopenia\: bleeding, stroke, haemorrhage (lung or gastrointestinal)
Blast cell lysis
Leucostasis\: stroke, pulmonary oedema, heart failure
CNS in
Therapy-related complications of leukaemia include\:
5,6
Corticosteroid side e
Neutropenic sepsis
Tumour lysis syndrome
Mucositis, gastrointestinal in
Renal and hepatic toxicity
Neurotoxicity
Venous thromboembolism
Alopecia
Long-term complications of leukaemia include\:
5,6
Secondary cancers
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Avascular necrosis (a complication of high-dose steroids)
Cardiotoxicity (e.g. secondary to anthracycline treatment)
Reduced growth hormone\: short stature and obesity
Fertility issues
Tumour lysis syndrome11,14
Tumour lysis syndrome is an oncological emergency caused by lysis of tumour cells, either due to chemotherapy
treatment or sometimes spontaneously in highly proliferative tumours.
It results in electrolyte imbalances including hyperphosphataemia, hyperkalaemia, hypocalcaemia,
hyperuricaemia.
Clinical manifestations include\:
Acute kidney injury
Cardiac arrhythmias
Nausea and vomiting
Seizures.
Prophylactic hydration and allopurinol are important prior to chemotherapy. Rasburicase may be used if white cell
count is >50, as this will actively break down the uric acid, while allopurinol prevents uric acid production.
Treatment involves aggressive hydration, rasburicase or allopurinol, and haemo
G6PD de

Prognosis

The prognosis in leukaemia has signi
rate from 33% in 1971 to 79% in 2000.
6
Improvements in survival, particularly in ALL, have resulted from e
extensive involvement of clinical trials in treatment.
The overall cure rate in ALL is now 85-90%.
15
In patients with disease recurrence, this usually happens within the
2
The best prognosis is in children aged between 1 and 10 years.
6

References

Children’s Cancer and Leukaemia Group. T y p e s o f c h i l d h o o d c a n c e r . Available from\: [LINK]
Children’s Cancer and Leukaemia Group. A c u t e l y m p h o b l a s t i c l e u k a e m i a ( A L L ) . Available from\: [LINK]
Children’s Cancer and Leukaemia Group. A c u t e m y e l o i d l e u k a e m i a ( A M L ) . Available from\: [LINK]
Patient UK, authored by C.Tidy. C h r o n i c m y e l o i d l e u k a e m i a ( C M L ) . Available from\: [LINK]
Patient UK, authored by C. Tidy. A c u t e l y m p h o b l a s t i c l e u k a e m i a . May 2016. Available from\: [LINK]
Patient UK, authored by C.Tidy. C h i l d h o o d l e u k a e m i a s . Sep 2016. Available from\: [LINK]
Cancer Research UK. A c u t e m y e l o i d l e u k a e m i a \: t y p e s . Aug 2019. Available from\: [LINK]
Terwilliger and M Abdul-Hay. A c u t e l y m p h o b l a s t i c l e u k a e m i a \: a c o m p r e h e n s i v e r e v i e w a n d 2 0 1 7 u p d a t e . Available from\: [LINK]
June Pui et al. C h i l d h o o d A c u t e L y m p h o b l a s t i c L e u k a e m i a \: P r o gr e s s T h r o u g h C o l l a b o r a t i o n . Sep Leukaemia Care. T h e l i n k b e t w e e n D o w n’ s s y n d r o m e a n d l e u k a e m i a . Available from\: [LINK]
2015. Available from\: 2017.
[LINK]
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Kar and N. Hijaya. D i a g n o s i s a n d I n i t i a l M a n a g e m e n t o f P a e d i a t r i c A c u t e L e u k a e m i a i n t h e E m e r ge n c y D e p a r t m e n t S e t t i n g.
June 2018. Available from\: [LINK]
National Institute of Clinical Excellence (NICE). H a e m a t o l o g i c a l c a n c e r s \: i m p r o v i n g o u t c o m e s . N I C E g u i d e l i n e N G 4 7 .
Published May 2016. Available from\: [LINK]
National Institute of Clinical Excellence (NICE). H a e m a t o l o g i c a l c a n c e r s – r e c o g n i t i o n a n d r e f e r r a l . Nov 2016. Available from\:
[LINK]
Science Direct. T u m o u r l y s i s s y n d r o m e . Available from\: [LINK]
Vora e t a l . T r e a t m e n t r e d u c t i o n f o r c h i l d r e n a n d y o u n g a d u l t s w i t h l o w-r i s k a c u t e l y m p h o b l a s t i c l e u k a e m i a d e
m i n i m a l r e s i d u a l d i s e a s e ( U K A L L 2 0 0 3 ) \: a r a n d o m i s e d c o n t r o l l e d t r i a l . Published Feb 2013. Available from\: [LINK]

Image references

Figure 1. A. Rad & M. Häggström. S i m p l i CC-BY-SA]. Available from\: [LINK]

Reviewer

Dr Simon Bomken
MRC Clinician Scientist and Honorary Consultant Paediatric Oncologist
Wolfson Childhood Cancer Research Centre

Related notes

Acute Myeloid Leukaemia
Anaemia Overview
Chronic Myeloid Leukaemia
Disseminated Intravascular Coagulation (DIC)
Haemolytic anaemia

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Contents

Introduction
Aetiology
Risk factors
Clinical features
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