Best practice and Fifteen-m inute consultations
Fifteen-minute consultation: Initial
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management of suspected acute
leukaemia by non-specialists
Sam Behjati,1,2 Amy Ruffle,2,3 Anne Kelly,2 Emmy Dickens2
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1
Department of Paediatrics, Abstract It is useful to send a stained blood
University of Cambridge,
Leukaemia is the most common cancer of film and an additional EDTA sample to
Cambridge, UK
2
Department of Paediatric childhood. Most children with a new diagnosis the PTC either before transfer or along
Oncology and Haematology, of leukaemia are clinically stable at initial with the child. Early availability of these
Addenbrooke’s Hospital, presentation. However, there are a number samples at the PCT will greatly facilitate
Cambridge, UK
3
Department of Haematology
of life-threatening complications that have the diagnostic work- up, allowing blood
and Oncology, Great Ormond to be considered and monitored for. These film microscopy and flow cytometric
Street Hospital for Children NHS complications include sepsis, tumour lysis analysis of peripheral blood. In the past, it
Foundation Trust, London, UK syndrome, mediastinal masses, bleeding and was important to send a thiopurine meth-
pain. The aim of this article is to equip the yltransferase (TPMT) level before red cell
Correspondence to
Dr Sam Behjati, University of general paediatrician with a framework for transfusion to predict the child’s ability to
Cambridge, Cambridge CB2 managing children with suspected leukaemia, metabolise thiopurine drugs in order to
1TN, UK; sam.behjati@gmail. prior to transfer to the primary treatment centre. determine dosing of 6- mercaptopurine.
com
The presentation, diagnosis and definitive However, TPMT enzyme levels have now
SB and AR contributed equally.
treatment of acute leukaemia is not in the remit been superseded by testing for the TPMT
of this article. genotype, which is not affected by trans-
SB and AR were joint first fusion and will be arranged by the PTC.
authors. Some PTCs may also request testing
for glucose-6- phosphate dehydrogenase
Received 11 November 2018 Introduction deficiency given the risk of precipitating
Revised 7 April 2019
Accepted 14 April 2019
All paediatricians will at some point care a crisis in undiagnosed children if rasburi-
Published Online First for a child who presents with suspected case is administered.
5 July 2019 leukaemia. A typical-sized district general
hospital (DGH) can expect approximately
three children to be diagnosed with Complications and management
Infection
leukaemia each year, with around 420
new cases diagnosed annually in England.1 As fewer children die from their
disease, infection has become one of the
leading causes of death in children with
Investigations leukaemia. Sepsis was responsible for over
While most children presenting with a 30% of all deaths in children in the most
new diagnosis of acute leukaemia remain recently completed UK childhood ALL
clinically stable, occasionally children can trial, UKALL 2003, and resulted in almost
become critically unwell. Early death in as many deaths as acute lymphoblastic
leukaemia is rare, although young age, leukaemia itself.2 3
particularly those under 2 years, high white At diagnosis, children with acute
cell count (more than 100×109 cells/L) leukaemia are immunosuppressed despite
and acute myeloid leukaemia (AML) are not having started chemotherapy, due to
established risk factors. a combination of bone marrow infiltra-
It is important to discuss suspected cases tion and other factors that interfere with
© Author(s) (or their of new leukaemia with the primary treat- immune cellular function. Thus, chil-
employer(s)) 2020. Re-use
permitted under CC BY.
ment centre (PTC) early while arranging dren with suspected leukaemia should
Published by BMJ. investigations (table 1) and starting appro- be managed as per neutropaenic sepsis
priate treatment (table 2). The overall aim guidelines, irrespective of their neutrophil
To cite: Behjati S, Ruffle A,
Kelly A, et al. Arch Dis of the initial management is to anticipate count. If there is any history of fever or
Child Educ Pract Ed and, where required, manage complica- other indicators of infection, take blood
2020;105:66–70. tions prior to transfer. cultures and start intravenous antibiotics
66 Behjati S, et al. Arch Dis Child Educ Pract Ed 2020;105:66–70. doi:10.1136/archdischild-2017-314043
Best practice and Fifteen-m inute consultations
Table 1 Initial mandatory investigations
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Test Indication
Chest X-ray To identify a mediastinal mass, consolidation due to infection or alveolar infiltrates suggestive of leucostasis.
Serial full blood counts Assessment of white cell count and rate of change, anaemia and thrombocytopaenia.
Serial urea, electrolytes, creatinine, Tumour lysis syndrome is characterised by hyperuricaemia hyperphosphataemia, hyperkalaemia and
bone profile and uric acid hypocalcaemia leading to renal injury.
Blood cultures (if indicated) Prior to staring intravenous antibiotics, blood cultures should be taken.
Group and save In anticipation of potential need for blood products
Clotting (prothrombin time, activated Disseminated intravascular coagulation is occasionally seen in association with acute leukaemia.
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partial thromboplastin time and
fibrinogen)
Blood film Can usually be examined by the on-call haematologist at the referring hospital, with a second film made and
sent with the child to the PTC.
Additional EDTA sample Peripheral blood can be sent to the PTC for immunophenotyping, which may be sufficient to confirm or
refute the diagnosis of leukaemia.
Viral serology Pretransfusion viral serological tests (especially VZV) are required for every child with a new diagnosis of
cancer. Typically a virology screen includes VZV, HSV1, HSV2, EBV, measles, hepatitis B and hepatitis C.
PTC, primary treatment centre.
according to local policies. If there is clinical evidence 50×109 cells/L) or ‘bulky’ disease such as significant
of sepsis, manage this as you would in any child, hepatosplenomegaly, lymphadenopathy or a medi-
aggressively within ‘the golden hour’.4 astinal mass. In addition, pre-existing impaired renal
function puts children at higher risk of TLS. Although
Tumour lysis syndrome (TLS) TLS is most frequently seen following administration
TLS is a metabolic disturbance resulting from the of steroids and chemotherapy agents, it can occur
breakdown of tumour cells. Cellular lysis causes the spontaneously.
release and degradation of intracellular contents
Management of TLS is largely anticipatory to prevent
including nucleic acids, which have the potential to
its development. In acute leukaemia, some children
overwhelm the body’s normal homeostatic mech-
with low count disease and without bulky disease can
anisms.5 The resulting biochemical abnormalities
be managed with maintenance fluids, which can be oral
include hyperuricaemia, hyperkalaemia and hyper-
phosphataemia with secondary hypocalcaemia. Uric or intravenous. Others at higher risk will require hype-
acid precipitates within renal tubules; phosphate rhydration even prior to starting chemotherapy, with
crystallises with calcium within soft tissues, including intravenous fluids of at least 2.5 L/m2/day.6 With the
the kidney. Together these can result in acute kidney guidance of the PTC, the fluid rate may be increased if
injury, reducing the body’s ability to excrete electro- there is any evidence or significant risk of TLS. Potas-
lytes, which sets up a spiral of worsening metabolic sium should not be added to fluids due to the risk of
derangement and kidney failure. hyperkalaemia, even if potassium levels are very low.
It therefore follows that children at greater risk of Children should be monitored for fluid overload,
TLS are those with a large volume of disease. These particularly children with severe anaemia and infants.
are children with a high white cell count (more than In addition to records of fluid input and output, daily
Table 2 Management points to consider
Intervention Indications
Oxygen Hypoxia and/or respiratory distress that might indicate severe anaemia, infection, leucostasis within the lung vasculature
or a mediastinal mass.
Antibiotics Broad-spectrum antibiotics following local guidelines for neutropaenic sepsis should be started if there are any concerns
regarding infection irrespective of neutrophil count.
Analgesia Paracetamol±oral morphine. Non-steroidal anti-inflammatory drugs are best avoided in thrombocytopaenia.
Hyperhydration For prevention of tumour lysis syndrome following discussion with the PTC. However, transfer to the PTC should not be
Allopurinol or delayed if there is difficulty in obtaining these drugs.
rasburicase
Blood products Platelets, fresh frozen plasma and/or cryoprecipitate transfusion may be required to treat bleeding. Red cell transfusion
should be considered carefully particularly in the context of a high or rising white cell count because the further increase
in viscosity from packed red cell transfusion can precipitate complications of hyperleucostasis.
PTC, primary treatment centre.
Behjati S, et al. Arch Dis Child Educ Pract Ed 2020;105:66–70. doi:10.1136/archdischild-2017-314043 67
Best practice and Fifteen-m inute consultations
orthopnoea (specifically ask about this) and signs of
Box 1 The first cannula
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superior vena cava obstruction (facial swelling and
prominent veins). Should a child have any symp-
Children undergoing cancer treatment often become
toms or signs of a mediastinal mass, it is important to
needle phobic. For the first few days, and in many cases,
the first month, treatment will be given through peripheral consider an early anaesthetic assessment and organise
intravenous access. Therefore, it is important to aim to urgent transfer to the PTC. Children should be nursed
minimise trauma from the very first episode of cannulation. sitting upright. Lying flat, even for the short duration
If your patient is stable enough, take your time, use a local of a CT chest, may precipitate airway obstruction.
anaesthetic cream and distraction techniques. Get all the General anaesthetic and sedation with drugs such
blood bottles ready and calculate the total volume of blood as chloral hydrate or midazolam should be avoided if
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required. If possible, insert a 22G or 20G cannula with the there is any suspicion of a mediastinal mass, due to the
aim of using it to bleed back for regular tumour lysis blood risk of precipitating airway compromise and cardio-
tests. Try to avoid dorsal hand and foot veins, which may vascular instability, even in a previously asymptomatic
later be needed for vincristine administration. It is also child. This is because these drugs cause a reduction in
preferable for the practitioner doing the cannulation to be
tone in both airway and vascular structures.7
the person most likely to be successful on the first attempt.
Hyperleucocytosis and leucostasis
or twice daily weight measurements are very useful in Hyperleucocytosis is defined as a white cell count
assessing fluid balance, especially in infants. Frusemide greater than 50×109 cells/L. However, this threshold
can be used to maintain diuresis although it should be is arbitrary and complications from hyperleucocy-
used with caution if there is risk of leucostasis. tosis can be seen at lower counts, especially in AML.8
Allopurinol should be started in children where Hyperleucocytosis significantly increases the risk of
the clinical suspicion of acute leukaemia is high.6 It morbidity and mortality. For instance, a recent case
is a xanthine oxidase inhibitor, which prevents the series reported a 30% mortality within 2 weeks of
formation of uric acid. In children either at high diagnosis in children with AML who had a white cell
risk of developing TLS or with biochemical signs of count of greater than 200×109 cells/L.9 Seeking the
the syndrome, rasburicase may be used as an alterna- opinion of your local consultant haematologist on the
tive to allopurinol. This recombinant urate oxidase blood film appearance may help you to identify AML
actively degrades uric acid and is a more potent early and thus identify the increased risk of complica-
therapy against TLS. However, it should be avoided tions from hyperleucocytosis.
in children with glucose-6-phosphate dehydrogenase Leucostasis is the process of increased blood viscosity,
deficiency as this can precipitate a haemolytic crisis. poorly deformable blasts and cytokine-induced activa-
Recommended doses for allopurinol and rasburicase tion of the endothelium resulting in vascular obstruc-
may differ between leukaemia treatment protocols tion and tissue hypoxia. If this process occurs in the
(eg, UKALL 20116) and pharmacopoeias such as the lungs, shortness of breath, coughing and hypoxia may
British National Formulary (BNF). Therefore, seek ensue. A plain chest radiograph may show diffuse inter-
advice from your PCT on current drug doses and treat- stitial or alveolar infiltrates. Leucostasis can also affect
ment schedules for both drugs. cerebral vessels and cause haemorrhagic or ischaemic
Initially, TLS is an asymptomatic biochemical abnor- events leading to symptoms of confusion, dizziness,
mality and your PTC will guide how frequently moni- tinnitus and headaches, as well as focal neurological
toring bloods should be taken, but this may be as often deficits. Other manifestations of leucostasis include
as every 4 hours in high-risk cases. Note that in very priapism, limb ischaemia, renal vein thrombosis and
high count leukaemia, cells may haemolyse in the retinal haemorrhage.8
specimen bottle en route to the laboratory, leading to Management includes oxygen, hyperhydration and
false electrolyte readings. It is therefore advisable to urgent discussion and transfer to the PTC. Definitive
perform paired gas machine and laboratory electro- treatment is that of the underlying leukaemia, and it is
lyte measurement when the white cell count is high. important this is not delayed by other interventions.
It is important to discuss any abnormalities, including However, within an intensive care setting, apher-
both elevated and low electrolytes, early and before esis or an exchange transfusion may occasionally be
making corrections as these may show an evolving instigated.
picture. Very occasionally, children with severe TLS
will require haemofiltration. Coagulopathy
Serious bleeding in acute leukaemia is rare with only
Mediastinal mass 3% of children showing evidence of coagulopathy at
Children with leukaemia, particularly with T ell disease, diagnosis.10 There is a greater risk of serious bleeding
may have mediastinal lymphadenopathy, which can at presentation in some children, including those with
cause airway obstruction. Signs and symptoms of an acute myeloid leukaemia (AML) and hyperleucocy-
obstructive mediastinal mass include wheezing, stridor, tosis. There is a rare subtype of myeloid leukaemia,
68 Behjati S, et al. Arch Dis Child Educ Pract Ed 2020;105:66–70. doi:10.1136/archdischild-2017-314043
Best practice and Fifteen-m inute consultations
70–80 g/L15), do not necessarily apply at presentation,
Box 2 Communicating the diagnosis of leukaemia
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and discussion with the PCT is advised before giving
red cells. When transfusion is required due to severe
►► Not all families are aware that leukaemia is a malignant
anaemia, in the context of hyperleucocytosis, smaller
disease, and it may help to describe the condition as a
‘cancer of the blood’. volumes are often used, such as 5 mL/kg over 4 hours,
►► It is unlikely that a definitive diagnosis of leukaemia in parallel with hyperhydration.
will be made prior to transfer. Therefore, terms such At diagnosis, UK national guidelines16 do not recom-
as ‘suspected leukaemia’ or ‘likely leukaemia’ may be mend any special blood product requirements as all
useful and avoid committing to any specific subtype of blood products are now hepatitis E negative and
leukaemia solely on the basis of a blood film. leucodepleted. However, your own PTC may have
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►► Parents may ask about prognosis, and it would be local guidelines regarding cytomegalovirus- screened
reasonable to tell them that it is highly likely that blood products and also suggest viral serology testing
the disease will be treatable but that more specific before transfusion. There is no specific evidence
information can only be given after the results of further to guide the optimum haemoglobin transfusion
tests.
threshold, although current practice would suggest
►► Transfer to a children’s oncology ward with an uncertain
diagnosis can be frightening, both for parents and that a threshold between 70 g/L and 80 g/L may be
children. This can be helped with sensitive preparation. reasonable.
Pain
acute promyelocytic leukaemia, which requires Pain is surprisingly common at presentation in
aggressive correction of coagulopathy to prevent leukaemia with 43% of children having limb pain
life-threatening bleeds at presentation. The Nordic at presentation14 and this may be under-recognised.
group reported eight deaths (14%) from intracranial Surrogate markers of pain can be useful, such as
haemorrhage and/or disseminated intravascular coag- not using limbs and being clingy or unsettled. Non-
ulation, out of a total of 57 patients with AML and a steroidal anti-
inflammatory drugs are best avoided
WCC more than 200×109 cells/L.9 By contrast, signif- due to their effects on platelet function in a child who
icant coagulopathy is extremely uncommon in acute is already at risk of thrombocytopaenia due to their
lymphoblastic leukaemia (ALL) with only two cases of underlying disease. In this context, oral morphine
intracranial haemorrhage seen in over 2500 children sulfate may be useful. Attempts should also be made to
in the UKALL 2003 trial.11 minimise procedural pain (box 1).
Coagulation should always be checked at diag-
nosis,12 although the correlation between serious
haemorrhage, coagulopathy or the use of prophylactic Communication
plasma is questionable.13 When considering correction It is essential to tell the family that a diagnosis of
of abnormal clotting results in the absence of bleeding, leukaemia is suspected prior to transfer to the PTC.
it is important to consider the potential risks of admin- Families need to be prepared that they will be trans-
istering plasma components. Discuss any abnormal ferred to an oncology ward, which can identified as
results with your PTC who will provide patient- such from signs, posters and patients. Similarly, chil-
specific guidance. dren should be given age appropriate information.
While a detailed discussion of how to break bad news is
Blood product support beyond the scope of this article, there are some specific
Although serious bleeding is rare, minor bleeding is points we would like to highlight about communi-
much more common, affecting 38% of children with cating a diagnosis of suspected leukaemia (box 2).
ALL at diagnosis.14 This is related to thrombocyto-
paenia and therefore affects predominantly the mucosa
and skin. National guidelines would advise transfusing Clinical bottom line
platelets if platelet counts are less than 10×109 plate-
lets/L. Raising this threshold to 20×109 platelets/L ►► Communicate early with your primary treatment centre.
in feverish children routinely is no longer recom- ►► Most children presenting with acute leukaemia are
mended.15 In the presence of significant bleeding clinically stable yet have the potential to deteriorate and
transfusion should be based on the clinical situation require intensive clinical care.
rather than the platelet count. ►► Monitoring for complications should include infection,
At presentation, many children will be anaemic, but tumour lysis syndrome, hyperleucocytosis and
red cell transfusions may not be required. In hyperleu- coagulopathy.
cocytosis, red cell transfusion should be avoided due to ►► Ensure appropriate analgesia; some children will require
the risk of complications of leucostasis such as TLS or oral morphine for adequate pain relief.
►► Parents should be aware that you suspect leukaemia
stroke. Therefore, the conventional transfusion thresh-
prior to transfer.
olds for children undergoing chemotherapy (below
Behjati S, et al. Arch Dis Child Educ Pract Ed 2020;105:66–70. doi:10.1136/archdischild-2017-314043 69
Best practice and Fifteen-m inute consultations
Transfer 4 Anon. Sepsis: recognition, diagnosis and early management:
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2017-314043 on 5 July 2019. Downloaded from http://ep.bmj.com/ on June 24, 2025 by guest.
It is important to consider and discuss with your PTC © NICE (2017) Sepsis: recognition, diagnosis and early
an appropriate timing for transfer, and these conver- management. BJU Int 2018;121:497–514.
sations should include senior decision makers. There 5 Jones GL, Will A, Jackson GH, et al. Guidelines for the
management of tumour lysis syndrome in adults and children
are some children who require urgent transfer, such
with haematological malignancies on behalf of the British
as those with a very high white cell count, medias-
Committee for Standards in Haematology. Br J Haematol
tinal mass or clinical instability. Many children who
2015;169:661–71.
are clinically stable and have low count disease can 6 UKALL2011 Trial: United Kingdom National Randomised
be safely managed in a DGH overnight, or even for Trial For Children and Young Adults with Acute Lymphoblastic
several days, if there is no bed immediately available in Leukaemia and Lymphoma, 2011.
Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies.
the nearest PTC. These children need to be monitored 7 Hammer GB. Anaesthetic management for the child with a
closely with regular observations, clinical assessment mediastinal mass. Paediatr Anaesth 2004;14:95–7.
and blood tests and require regular discussion with the 8 Ganzel C, Becker J, Mintz PD, et al. Hyperleukocytosis,
PTC. leukostasis and leukapheresis: practice management. Blood Rev
2012;26:117–22.
Acknowledgements We would like to thank Dr Kristina Marshall for 9 Zeller B, et al. Hyperleucocytosis in paediatric acute myeloid
reviewing the manuscript. leukaemia - the challenge of white blood cell counts above 200
Contributors SB conceived of the paper. AR and SB were both co-authors on × 10. Br J Haematol 2017;178:448–56.
this paper. AR did the literature search. ED and AK contributed expert views. All 10 Ribeiro RC, Pui CH. The clinical and biological correlates of
authors have contributed to editing successive drafts and agreed the content of
the final article. coagulopathy in children with acute leukemia. J Clin Oncol
1986;4:1212–8.
Funding This study was funded by Wellcome Trust (Grant 110104/Z/15/Z).
11 Astwood E, Vora A. Personal practice: how we manage the risk
Competing interests None declared. of bleeding and thrombosis in children and young adults with
Patient consent for publication Not required. acute lymphoblastic leukaemia. Br J Haematol 2011;152:505–
Provenance and peer review Commissioned; externally peer reviewed. 11.
Open access This is an open access article distributed in accordance with 12 Sibson KR, Biss TT, Furness CL, et al. BSH Guideline:
the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which management of thrombotic and haemostatic issues in paediatric
permits others to copy, redistribute, remix, transform and build upon this work malignancy. Br J Haematol 2018;180:511–25.
for any purpose, provided the original work is properly cited, a link to the
licence is given, and indication of whether changes were made. See: https:// 13 Sutor AH, Mall V, Thomas KB. Bleeding and thrombosis in
creativecommons.org/licenses/by/4.0 /. children with acute lymphoblastic leukaemia, treated according
to the ALL-BFM-90 protocol. Klin Padiatr 1999;211:201–4.
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