Leukaemias: A Review: Aetiology and Pathogenesis

SYMPOSIUM: HAEMATOLOGY
Leukaemias: a review annum. The age-specific incidence is highest in infancy and fairly
uniform in all other age groups.
Neha Bhatnagar Aetiology and pathogenesis

Amrana Qureshi Acute leukaemia is characterised by a malignant clonal trans-
Georgina Hall formation of haematopoietic stem cells resulting in replacement
of normal bone marrow elements with blast cells leading to bone
marrow failure. The aetiology of childhood leukaemia remains to
Abstract be better understood but it is likely to involve an interaction
Leukaemia is the principal cancer of childhood. In the last few de- between inherited susceptibility, haematopoietic development,
cades, cure rates in childhood leukaemia have improved due to better environment and chance.
risk stratification of patients by phenotype/genotype and treatment-
related response, incorporation of more effective chemotherapy proto- Genetic factors
cols and better supportive care. Current research in acute lympho- Certain genetic syndromes are associated with an increased
blastic leukaemia (ALL) and acute myeloid leukaemia (AML) aims to susceptibility to leukaemia (see Table 1). A UK study showed
reduce treatment related toxicity by studying innovative ways to that 2.6% of children with leukaemia were reported to have a
deliver therapy without compromising treatment efficacy and thereby recognised genetic condition and this was almost entirely
improving outcomes for children. This review discusses how acute accounted for by Down syndrome (DS). Children with DS have a
leukaemia occurs and presents and describes current treatment stra- 33-fold increased risk of developing ALL and 150-fold increased
tegies in ALL and AML. risk of developing AML.
Keywords acute lymphoblastic leukaemia (ALL); acute myeloid
Prenatal origins of leukaemia
leukaemia (AML); childhood leukaemia; minimal residual disease
Molecular studies on several pairs of identical twins provide strong
(MRD); risk directed therapy
evidence that concordant ALL arises in monozygotic twins after
mutation and clonal expansion of one cell in one fetus in utero
indicating a prenatal origin of leukaemia. In addition, retrospective
Introduction
analysis of neonatal blood spots identified leukaemia-specific
Leukaemia is the most common childhood cancer accounting for fusion genes concluding that childhood leukaemia is often initi-
nearly one third of all malignancies in children <16 years of age. ated by a chromosome translocation in utero. However this is not
Acute lymphoblastic leukaemia (ALL) is the most common type the case for all childhood leukaemia and unknown postnatal
of childhood leukaemia representing 80% of cases while acute events are required for secondary transformation.
myeloid leukaemia (AML) accounts for 15% of childhood
leukaemia. Other type of leukaemia are rarely seen in children Susceptibility to childhood leukaemia: co-operative
accounting for <5% of cases. This review will therefore focus on mutations
ALL and AML in children. Acquired genetic mutations are considered to be central to the
development of leukaemia. These changes cause transformation
Epidemiology of haematopoietic stem cells leading to damage of key
biochemical steps: (i) increased rate of proliferation, (ii) block in
There are significant geographic differences in the incidence of
differentiation and (iii) resistance to apoptosis. The current
ALL with higher rates among European and North American
multi-step model of leukaemogenesis predicts that oncogenic
populations and lower rates among Asians, Africans and South
events triggered by chromosomal rearrangements are not suffi-
Americans. The incidence of childhood ALL in the UK is at four
cient by themselves to induce overt leukaemia. The spectrum of
per 100,000/annum with a higher incidence in boys than girls.
secondary mutations involved in the development of leukaemia
The peak age of presentation for childhood ALL is between 2 and
need better characterisation.
5 years. The UK incidence of AML in children is one per 100,000/
Environmental factors
Although environmental factors such as viruses or chemical
Neha Bhatnagar MBChB MRCPCH FRCPath MD(Res) is a Consultant mutagens have been implicated in the aetiology of leukaemia,
Paediatric Haematologist at John Radcliffe Hospital, Oxford direct evidence is lacking for a causal relationship in most studies
University Hospitals NHS Foundation Trust, Oxford, UK. Conflict of with the exception for ionising radiation. It is also well estab-
interest: none declared.
lished that previous exposure to chemotherapy agents such as
Amrana Qureshi MBChB MRCPCH FRCPath is a Consultant Paediatric topoisomerase II inhibitors and alkylators can predispose to
Haematologist at John Radcliffe Hospital, Oxford University Hospitals therapy related AML especially if combined with radiotherapy.
NHS Foundation Trust, Oxford, UK. Conflict of interest: none
declared.
Diagnosis
Georgina Hall PhD FRCP FRCPath is a Consultant Paediatric
Haematologist at John Radcliffe Hospital, Oxford University Hospitals Clinical presentation and examination
NHS Foundation Trust, Oxford, UK. Conflict of interest: none The presenting signs and symptoms of leukaemia are quite var-
declared. iable. Whilst most patients have an acute onset some have an
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Please cite this article in press as: Bhatnagar N, et al., Leukaemias: a review, Paediatrics and Child Health (2017), http://dx.doi.org/10.1016/
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Genetic syndromes associated with an increased susceptibility to leukaemia

Down syndrome
Neurofibromatosis 1
Chromosome breakage syndromes such as Ataxia Telangiectasia, Bloom syndrome, ShwachmaneDiamond syndrome, Fanconi anaemia
Bardet-Biedl syndrome
Table 1
insidious presentation. The clinical features are a result of i) bone Chest radiography is needed to detect a mediastinal mass or
marrow failure and ii) organ infiltration (see Table 2). pleural effusion. Examination of the cerebrospinal fluid (CSF)
examination should be performed at the same time as diagnostic
Investigations bone marrow and may reveal the presence of leukaemic cells
Haematological investigations at leukaemia presentation may even though the patient lacks neurological symptoms. Diagnostic
reveal anaemia, abnormal total and differential white cell count investigations are summarised in Tables 3e5.
and thrombocytopenia. There may be profound neutropenia
(<0.5 109/litre). Coagulopathy can be life-threatening in AML, Treatment
especially in acute promyelocytic leukaemia, but is rarely seen in
ALL. The peripheral blood film typically shows a variable num- The goal of therapy is to completely eradicate the disease and
ber of blasts (Figure 1). The bone marrow aspirate is hyper- reduce the risk of relapse while limiting treatment related
cellular with more than 20% leukaemic blasts. The blasts are toxicity. The treatment is ‘risk stratified’ and ‘response adapted’.
further characterised by morphology, immunophenotyping and Patients are treated on standard or more intensive treatment
cytogenetic analysis. A bone marrow trephine is sometimes arms depending on their presenting risk features and their
required if aspiration is difficult due to a densely infiltrated treatment thereafter adapted according to the molecular
marrow or myelofibrosis. response of their disease assessed by minimal residual disease
Serum urate, phosphate and potassium are raised in patients (MRD).
with a large leukaemic cell burden and can cause renal impair- Immediate therapy includes supportive care measures such as
ment that is complicated further by tumour lysis when treatment blood product support, controlling tumour lysis syndrome (TLS),
begins. Hepatic and renal dysfunction may occur due to leu- preventing renal failure by careful attention to fluids and elec-
kaemic infiltration. trolyte balance and treatment of infection with broad-spectrum
antibiotics.
ALL: Specific therapy and prognosis

Clinical features in a patient presenting with acute Over the past 50 years through participation in clinical trials,
leukaemia there has been a dramatic improvement in the prognosis of
children with ALL. Childhood ALL is more commonly of B-cell
Symptoms of bone Anaemia e pallor, lethargy, poor appetite
lineage (80% cases) than T-cell lineage (20% cases). With cur-
marrow failure Thrombocytopenia- bleeding, bruising,
rent risk-directed therapy more than 95% of children with ALL
petechiae
achieve complete remission (CR) and w80% have long-term
Neutropenia- infection, fever
event free survival (EFS) with overall survival (OS) at w90%.
Symptoms of organ Hepatomegaly, splenomegaly,
In the UK, children and young adults up to the age of 25 years are
infiltration lymphadenopathy, mediastinal mass, bone
treated on the same clinical trial UKALL2011. Tables 6 and 7
pain, limp, testicular enlargement
outline the current National Cancer Institute (NCI) and cytoge-
CNS infiltration- headache, seizure, cranial
netic risk classification for childhood ALL. All children with T-
nerve palsy
cell ALL (irrespective of age or white cell count) receive treat-
Table 2 ment as per the NCI high-risk induction regimen.
Figure 1 Peripheral blood blasts in acute leukaemia (a) acute lymphoblastic leukaemia, (b) acute myeloid leukaemia, (c) acute promyelocytic
leukaemia, (d) myeloid-leukaemia of Down syndrome.
j.paed.2017.08.007
Diagnostic investigations in a patient presenting with acute leukaemia

Full blood count and blood film
Coagulation profile including fibrinogen
Urea & electrolytes
Liver function tests
Calcium, phosphate, urate
Bone marrow aspirate þ/ trephine
Immunophenotyping
Cytogenetics
CSF cytospin
Chest X-ray
Table 3
Immunological markers for classification of acute Cytogenetic risk classification in childhood ALL
lymphoblastic leukaemia (ALL) and acute myeloid
Good risk Hyperdiploidy or high hyperdiploidy (>50
leukaemia (AML)
chromosomes)
B-lineage ALL CD19, cCD22, cCD79a, CD10, TdT t(12;21)/ETV6-RUNX1
T-lineage ALL CD7, CD5, CD2, cCD3, TdT High risk Intrachromosomal amplification of
AML CD13, CD33, CD117, cMPO, CD14, CD15, chromosome 21 (iAMP21)
CD16, CD42, CD61 t(17;19)(q22;p13)/TCF3(E2A)-HLF
MLL rearrangement
Table 4 Near haploidy (<30 chromosomes) and Low
Hypodiploidy (30e39 chromosomes)
Classification of acute myeloid leukaemia according to Table 7

the French-American-British (FAB) group
AML Cytogenetic MRD low risk (N ¼ 980, 5-year EFS 95.6%). An intermediate
abnormality outcome was seen in the MRD indeterminate group (N ¼ 937 5-
year EFS, 86.7%).
M0 Undifferentiated leukaemia
The current UKALL 2011 trial aims to further improve sur-
M1 Acute leukaemia without maturation
vival and quality of survival by addressing:
M2 Acute leukaemia with granulocytic t(8;21)
(i) treatment related mortality (TRM) and morbidity. The
maturation
toxicity of UKALL 2003 was unacceptably high in the
M3 Acute promyelocytic leukaemia t(15;17)
context of such a high disease free survival. TRM in
M4 Acute myelomonocytic leukaemia inv(16)
remission was 3.2%.
M5 Acute monocytic leukaemia
(ii) poor prognosis for central nervous system (CNS) relapse.
M6 Acute erythroleukaemia
Children who suffer CNS relapse on UKALL 2003 had a 5-
M7 Acute megakaryoblastic leukaemia
year EFS of only 30%.
Table 5 (iii) poor prognosis of very early marrow relapse. This carries
a dismal prognosis with less than 20% survival even after
haematopoietic stem cell transplantation (HSCT) in sec-
National Cancer Institute (NCI) risk classification for ond remission in UKALL 2003. Improving the prognosis of
childhood B-cell acute lymphoblastic leukaemia this group is key to improving OS in ALL.
(iv) superior outcomes for young adults (16e24 years) treated
Standard risk Age 1e9 years at diagnosis and with a highest
on paediatric protocols as young adults with ALL can
white blood count (WBC) before starting
achieve better outcomes when treated with a paediatric
treatment of <50 109/litre
protocol as evidenced by UKALL 2003 data.
High risk Age >10 years at diagnosis and/or with a
diagnostic WCC >50 109/litre
Phases of therapy
Table 6 Induction
The goal of induction therapy is to reduce the leukaemic
UKALL 2003 (2003e2011) confirmed the predictive value of burden to a haematologically undetectable level with the aim of
minimal residual disease (MRD) based therapy. It showed a achieving morphological remission. This is defined as a normo-
three-fold increase in relapse risk in the MRD High Risk group cellular bone marrow with less than 5% blasts and normal
(N ¼ 940, 5-year EFS 80.7%) by comparison with children at haematopoiesis.
j.paed.2017.08.007
The duration of induction regimen in UKALL 2011 is typically the cerebrospinal fluid (CSF) are dexamethasone, methotrexate
4e5 weeks with: and cytarabine. Specific intrathecal treatment, most commonly
(i) dexamethasone. Several large studies have reported a methotrexate is required to prevent or treat CNS disease. Other
decreased relapse risk with the use of dexamethasone options include cytarabine and triple chemotherapy with meth-
rather than prednisolone. otrexate, cytarabine and hydrocortisone. In UKALL2011 the
(ii) vincristine. randomisation of high dose versus standard dose intravenous
(iii) asparaginase. methotrexate is being addressed with regard to reducing CNS
and additionally for NCI high-risk cases relapse.
(iv) anthracycline. Cranial irradiation is effective CNS therapy but it is now
In UKALL 2011, a randomisation between a short course (14 reserved for patients with CNS relapse due to substantial asso-
days) of higher dose versus the standard course (28 days) of ciated side-effects such as neurotoxicity, endocrinopathy and
standard dose dexamethasone is being addressed to determine secondary cancer.
treatment related burden. This randomisation stopped in 2017
and all patients are now receiving standard dose dexamethasone Treatment of specific ALL subtypes
for 28 days. Patients with a specific subtype of precursor B-cell ALL, Phila-
MRD assessment at the end of induction (EOI) using sensitive delphia chromosome positive ALL (Phþ) benefit from targeted
methods directs further therapy in order to reduce the risk of treatment with tyrosine kinase inhibitors (TKI). The Phþ chro-
relapse and prevent over-treatment. mosome, t(9;22) leads to the fusion of the BCR and ABL1 genes
Consolidation, interim maintenance and intensification resulting in tyrosine kinase activation.
therapy Imatinib is a selective inhibitor of the BCR-ABL tyrosine ki-
The goals of the next three blocks of therapy are to further nase and can be used with multi-agent ALL chemotherapy
reduce the disease burden and give intensive CNS directed without excessive toxicity resulting in high response rates.
therapy. A wide variety of chemotherapy agents are used during Recently a novel subgroup of patients has been described as Ph-
post-induction consolidation. chromosome like or BCR-ABL like ALL; these patients lack the
UKALL 2003 examined the value of augmented Berlin- BCR-ABL1 fusion protein yet they have a gene expression profile
Frankfurt-Mu € nster (BFM) therapy in patients with MRD Risk at similar to that of BCR-ABL1 ALL and similarly are at high risk of
EOI. The 5-year EFS were significantly better for patients in the relapse. A subset of these Ph-like patients harbour tyrosine ki-
intensification arm when compared with the standard arms due nase activating gene fusions such as EBF1-PDGFRB and achieve
to a halving the risk of relapse. The improved EFS translated into good response when treated with Imatinib in combination with
a better OS without an increased risk of TRM. conventional ALL therapy.
These results have led to a change in the UKALL 2011 protocol
where patients with MRD Risk at EOI will all receive augmented AML: Specific therapy and prognosis
BFM consolidation. MRD will again be measured upon recovery During the past 40 years, survival rates for patients with AML
from consolidation at week 14. Patients with MRD less than 0.5% have risen from less than 10% to more than 50% because of
at week 14 will form the MRD Intermediate Risk group and will intensification of chemotherapy, use of SCT and improved
continue augmented BFM therapy. Patients with MRD Low Risk supportive care. All major national groups report similar out-
at EOI continue on a standard intensity regimen. comes in childhood AML with OS 65e70% and EFS 50e60%.
All patients now receive only one delayed intensification (DI) However, the cumulative incidence of relapse (CIR) remains
block as no survival benefit was found with two DI blocks in high at 35e40% and is the major cause of death. The current
UKALL 2003. Patients with MRD 0.5% at week 14 form the international study of childhood AML, Myechild01, aims to
MRD High Risk group and are very unlikely to be cured with build on the international experience gained and reduce or
ongoing chemotherapy thus, these patients will be eligible for the intensify therapy on risk group stratification based on cytoge-
national relapse/refractory ALL trial with novel cytoreductive netic and molecular genetic characteristics as well as response
therapies and considered for HSCT. to induction therapy using MRD instead of morphological
Continuation (or maintenance) therapy response alone (Table 8). The trial aims to identify patients who
All treatment regimens for ALL include a phase of mainte- are at high risk of relapse and offers these patients a HCST in
nance therapy in which patients are treated with less-intensive first remission.
chemotherapy to complete 2 years in girls and 3 years in boys.
Phases of therapy for AML
This consists of weekly low-dose methotrexate and daily 6-
Induction
mercaptopurine. Intensification of maintenance through admin-
This is the first phase of chemotherapy and should be started
istration of vincristine and steroid “pulses” has been widely
as soon as the diagnosis of AML is confirmed with the goal of
used. UKALL 2003 did not specifically assess the toxicity of these
inducing remission. The backbone of induction treatment has
pulses however, they were found to be a significant source of
been the combination of anthracycline and cytarabine. Many
morbidity and burden of care when discussed with patients and
clinical trials have been conducted testing variations of this
parents. UKALL 2011 therefore aims to examine their role in
standard of care. Myechild01 aims to study the effect of
maintenance therapy.
intensifying anthracycline therapy in induction as this has been
CNS-directed therapy
reported to improve outcome in adult AML patients. In this
Treatment for subclinical or overt CNS leukaemia is an inte-
study, induction treatment is further intensified in with the
gral part of ALL. The main drugs given systemically which reach
j.paed.2017.08.007
related toxicity compared to a full myeloablative conditioning

Cytogenetic and molecular risk group assignment in regimen without increasing the relapse risk. Children identified
paediatric acute myeloid leukaemia as high risk based on poor cytogenetics at presentation or
Good risk t(8;21) those with good/intermediate risk cytogenetics who are MRD
inv(16) positive will qualify for HSCT and will be eligible for this
Mutation of NPM1 without FLT3-ITD randomisation.
Intermediate risk t(9;11) CNS-directed therapy
t(11;19) As in ALL, intrathecal chemotherapy is important to prevent
All other abnormalities which are neither poor or treat CNS disease. The most commonly used drug is cytar-
or good risk abine, however, triple chemotherapy with methotrexate, cytar-
Poor risk -5/del(5q) abine and hydrocortisone may be used for cases with clinical
-7 CNS involvement such as cranial nerve lesions. Intrathecal
inv(3) chemotherapy is given with the first two cycles of chemotherapy.
t(9;22) Cranial irradiation may be considered for CNS disease that is
t(4;11), t(6;11), t(10;11) e MLL refractory to intrathecal chemotherapy.
rearrangements
Treatment of specific AML subtypes: acute
t(6;9)
promyelocytic leukaemia (APL)
FLT3-ITD without NPM1 or Core binding factor
APL or AML M3 (FAB classification) is a subtype of AML
leukaemia
defined by a specific morphology, characteristic coagulopathy
Table 8 and in the majority of cases the presence of t(15;17), which
results in the PML-RARA fusion gene that is sensitive to treat-
ment with all-trans-retinoic acid (ATRA). The combination of
use of gemtuzumab ozogamicin (Mylotarg), an anti-CD33 ATRA with chemotherapy has made a dramatic improvement to
monoclonal antibody that directly targets the leukaemic cells. survival. ATRA is included in all phases of therapy (induction,
Induction chemotherapy is highly myelosuppressive resulting consolidation, maintenance). The current APL guidelines in
in prolonged cytopenias that may last for up to 4 weeks from children and adolescents recommends (i) risk stratification by
the initiation of therapy. During this period, patients are at a risk group (standard risk e WBC 10 109/litre, high risk WBC
high risk of life-threatening infection, thus aggressive support- > 10 109/litre), (ii) molecular MRD monitoring of PML-RARA
ive care usually in isolation cubicles is necessary. Disease sta- transcripts to guide therapy and (iii) a lower cumulative
tus has traditionally been assessed at the EOI by determining anthracycline dose compared to previous paediatric APL studies
morphological remission in the bone marrow (defined as blasts in the UK. Arsenic trioxide (ATO) is considered first line therapy
less than 5%). Patients may also achieve cytogenetic remission in refractory/relapsed disease. ATO alone offers an advantage of
defined by the absence of a previously detected leukaemia inducing molecular remission in the majority of patients
clone associated cytogenetic abnormality. In Myechild01, without significant myelosuppression and it is particularly
remission is defined by the absence of MRD assessed by attractive for children as it avoids further anthracycline expo-
multiparameter flow cytometry designed to detect less than sure. Adult studies have shown that treatment with ATRA and
0.1% leukaemic blasts in bone marrow or for those patients ATO in newly diagnosed APL patients was well tolerated and
who have a molecular marker a three log reduction in tumour led to sustained remission without additional cytotoxic chemo-
burden. therapy. Future trials will study the synergistic effect of ATRA
Consolidation and ATO in paediatric patients also. Allogeneic HSCT is
Having achieved remission the aim of consolidation chemo- reserved for patients who have persistent MRD despite ATO
therapy is to optimise the quality of that remission and thereby therapy.
reduce the subsequent rate of relapse. This usually involves
further two or three courses of intensive chemotherapy. Combi- Myeloid-Leukaemia of Down syndrome (ML-DS)
nations using cytarabine at increased dosage are often used. ML-DS is classified as a specific subtype of AML and is char-
Myechild01 aims to study the use of upfront fludarabine in acterised by the presence of megakaryoblasts. Up to 10% of
consolidation as its use has long been effective in the relapse infants with DS present with transient abnormal myelopoiesis
AML setting. Each intensive chemotherapy course results in a (TAM) at birth. The majority of these infants undergo sponta-
prolonged period of pancytopenia. neous resolution within 3 months, however w20% can prog-
Allogeneic HSCT ress to ML-DS within the first 5 years of life. Both TAM and ML-
The most effective way to prevent AML relapse is allogeneic DS are characterised by the presence of GATA1 mutation sug-
HSCT from a HLA-compatible donor, however, this has not gesting they are clonally linked conditions, however additional
always translated into a significant OS advantage due to a high mutations beyond GATA1 are necessary to produce ML-DS.
transplant related mortality. Myechild01 aims to evaluate the Children with ML-DS have better outcomes when compared
role of reduced intensity conditioning in allogeneic HSCT in with children with sporadic AML with long-term survival rates
first CR to test if this regimen is associated with less treatment of w80e90%. This has been attributed, at least in part, to
j.paed.2017.08.007
regimens resulting in improved quality of life coupled with

Chemotherapy related side-effects long-term survival. A
Drug Potential side-effects
FURTHER READING
Steroids Steroid-induced diabetes, steroid-induced
1 Creutzig U, van den Heuvel-Eibrink MM, Gibson B, et al. Diagnosis
hypertension, myopathy, avascular necrosis,
and management of acute myeloid leukemia in children and ado-
weight gain, mood disturbance
lescents: recommendations from an international expert panel.
Vincristine Peripheral neuropathy, constipation, jaw pain
Blood 2012; 120: 3187e205.
Asparaginase Pancreatitis, thrombosis, anaphylaxis
2 Gibson B, Webb D, Howman A, De Graaf SS, Harrison CJ,
Anthracyclines Cardiomyopathy
Wheatley K. Results of a randomized trial in children with Acute
General side-effects Hair loss, nausea, vomiting, mucositis,
Myeloid Leukaemia: medical research council AML12 trial. Br J
of chemotherapy myelosuppression, sepsis, tumour lysis
Haematol 2011; 155: 366e76.
syndrome
3 Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytoge-
Table 9 netic classification in acute myeloid leukemia: determination of
prognostic significance of rare recurring chromosomal abnormal-
ities among 5876 younger adult patients treated in the United
hypersensitivity of ML-DS blasts to cytarabine. Children with Kingdom Medical Research Council trials. Blood 2010; 116:
ML-DS also have a significantly lower relapse rate than non- 354e65.
DS AML. Treatment failure in DS children was mostly 4 Myechild01 International Randomised phase III clinical trial in
due to chemotherapy-related toxicity, particularly related to Children with Acute Myeloid Leukaemia-Incorporating an
anthracyclines. embedded dose finding study of Gemtuzumab Ozogamicin in
combination with induction chemotherapy.
Complications of chemotherapy 5 United Kingdom National Trial for children and young adults with
acute lymphoblastic leukaemia and lymphoma 2011.
Life threatening infections observed during therapy are one of the 6 Vora A, Goulden N, Wade R, et al. Treatment reduction for children
most frequent complications experienced by patients with and young adults with low-risk acute lymphoblastic leukaemia
leukaemia. Infections, most often bacterial is the primary cause defined by minimal residual disease (UKALL 2003): a randomized
of TRM in children receiving leukaemia therapy. As chemo- controlled trial. Lancet Oncol 2013; 14: 199e209.
therapy regimens have become more intensive invasive fungal 7 Vora A, Goulden N, Mitchell C, et al. Augmented post-remission
infections have also been observed during leukaemia treatment therapy for a minimal residual disease defined high-risk subgroup
and prophylactic anti-fungal therapy is given to high risk pa- of children and young people with clinical standard-risk and
tients. Viral infections such as varicella can also cause significant intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a
morbidity in children with leukaemia. Pneumocystis jirovecii can randomised controlled trial. Lancet Oncol 2014; 15: 809e18.
cause severe and often fatal pneumonitis in children receiving
multi-agent chemotherapy. Other acute toxicities related to spe-
cific chemotherapy agents are outlined in Table 9. Practice points
With prolonged survival of children with leukaemia, late ef-
fects related to the disease and its treatment need to be monitored
C Leukaemia is the most common childhood cancer.
in particular growth, neurocognitive deficits, cardiac dysfunc-
C Certain genetic syndromes are associated with an increased
tion, sexual development and fertility and secondary malignancy. susceptibility to leukaemia in particular Down syndrome.
C Leukaemogenesis is a multi-step process with a prenatal origin
Conclusion and postnatal secondary mutations that are necessary for acute
transformation that remains to be better understood.
Moderneday management of childhood leukaemia has evolved C The presenting signs and symptoms of leukaemia are a result of
over the last four decades through basic, translational, and bone marrow failure and organ infiltration. Blasts are seen on
clinical research resulting in improved outcomes. Since 1980s, peripheral blood film and bone marrow aspirate that can be
the UK clinical trials for childhood leukaemia have recruited further characterised by morphology, immunophenotyping and
nearly all children with ALL and AML allowing the data cytogenetic analysis.
collection necessary for these huge evidence based advances. C Leukaemia is a heterogeneous disease; response to treatment is
Risk-directed therapy with MRD monitoring has redefined the single most important prognostic factor resulting in MRD
remission in leukaemia and is applied in all treatment protocols based risk directed treatment regimens with intensive remission
as an assessment of relapse risk and to guide treatment de- induction followed by consolidation and continuation phase.
cisions. Accurate, comprehensive identification of the full range C Supportive care with blood product support and treatment of
of genetic alterations in leukaemia is important to identify infection is an integral part of leukaemia treatment.
deregulated pathways amenable to inhibition with targeted C Future research will improve our understanding of the genomic
therapies as the future goal of childhood leukaemia is to landscape of leukaemia with the aim to personalise treatment
develop personalised treatment specific to molecular defects while decreasing the intensity and toxicities of conventional
driving each individual’s disease while decreasing treatment chemotherapy regimens.
intensity and reducing toxicity of conventional chemotherapy
j.paed.2017.08.007

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SYMPOSIUM: HAEMATOLOGY

Neha Bhatnagar Aetiology and pathogenesis

Genetic syndromes associated with an increased susceptibility to leukaemia

ALL: Speciﬁc therapy and prognosis

Diagnostic investigations in a patient presenting with acute leukaemia

Classification of acute myeloid leukaemia according to Table 7

related toxicity compared to a full myeloablative conditioning

regimens resulting in improved quality of life coupled with

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