Hamish, 5, has been tired and miserable for the last week of the school holidays. On the second day back at school, his Mum is asked to collect him after a bleeding nose that lasts about fifteen minutes. The teacher comments to Mum that Hamish is looking a bit “thin & pale”, and they’ve noticed a lot of bruising on his shins.
The GP agrees and orders a full blood count, which shows:Â Hb 50 g/L (100 – 150);Â Plt 2Â x109/L (150 – 450);Â WCC 45.8 x109/L (80% lymphocytes, 30% blasts);Â “Blasts seen on film”.
Bottom Line
Acute lymphoblastic leukaemia (ALL) is the most common childhood haematological malignancy
The first presentation to the tertiary oncology centre is extremely stressful and a medically intense time
The aim of treatment is to achieve remission in induction
Acute lymphoblastic anaemia may present in a broad variety of signs and symptoms
The GP phones you, the Paeds Oncology registrar, with these results, and Hamish soon arrives into Emergency. You phone the consultant, who attends to meet family, take the history and examine Hamish.
He looks pale but bright-eyed. Vitals are 36.9oC, HR 130, RR 25, SaO2 97%, BP is normotensive with brisk capillary refill.
Further History
Has been grizzly and “not himself” for the last ten days: picking at food; complaining of sore legs for 2/7.  Not recently unwell/coryzal symptoms/diarrhoea. No wheeze. No steroid exposure. No blurry vision. Developmentally meeting milestones. No FHx of childhood malignancy.
When taking the history, specifically ask about B symptoms: fever, night sweats, and weight loss
Further examination
He is a pale boy with signs of weight loss. Bruising of the elbows, knees and legs. HS 2+ flow murmur. Lungs – no wheeze, good equal air entry. Abdomen soft, bowel sounds, liver 5cm below the costal margin, spleen 8cm below the costal margin, not tender. Enlarged inguinal nodes bilaterally. Testicular examination – normal size for age. Aside from the bruising, you identify no areas of broken skin, boils, erythema or rashes. ENT examination is unremarkable. Fundoscopy unremarkable.
Also, note any dysmorphism, Tanner stage, Lansky performance score)
What is ALL?
Acute lymphoblastic leukaemia is the most common childhood cancer. It is bimodal in incidence in childhood with peaks at around 2 years, and then at around 16 years of age.
ALL accounts for around 80% of childhood leukaemias, the remainder being acute myeloid leukaemia and rarer types. Approximately 85% of children with acute lymphoblastic leukaemia have B-cell ALL, with ~15% having T-Cell ALL. 2-3% will have Burkitt lymphoma, a mature B-cell leukaemia, treated differently from most leukaemias.
How does ALL usually present?
The most common presentations are with bone pain. Many children experience bone aches due to ‘growing pains’, so it’s important to know how to differentiate bone pain related to oncology issues and growing pains.
- Bone pain tends to wake you up in the middle of the night, whereas growing pains are usually felt more when the child is falling asleep
- Children with growing pains should not have difficulty walking
- Growing pains tend to present as a pattern i.e. same type of pain at the same of day
- Children with growing pains will have completely normal blood counts
- There should be no fever or weight loss associated with growing pains
As with this case, ALL can also present with bleeding. Other presentations include splenomegaly (10-20%), mediastinal mass, renal failure (due to hyperuricaemia), or leukostatic symptoms (respiratory distress, altered mental status) in patients with a high WCC .
Rarely do patients who initially are thought to have ITPÂ actually turn out to have ALL.
ALL can also include extramedullary sites e.g. CNS, testes, liver/spleen, kidneys, and skin (rare). With this in mind, the list of presenting features includes…
- Typically weight loss (or failure to thrive), anaemia, fatigue will be present
- Bone or joint pain
- Bruising
- Epistaxis or bleeding gums
- Recurrent fever (low grade)
- Persistent cough
- Dizziness
- Lymphadenopathy (including tonsillar hypertrophy)
- Priapism
- Wheeze (from a mediastinal mass) or
- Blurry vision/diplopia
- Testicular enlargement
- Headaches (with papilloedema and retinal haemorrhages)
- Respiratory distress (hyperviscosity)
- Cranial nerve palsies
Practical points at diagnosis
For some oncology departments, there is a policy that the most senior ED doctor should place the cannula for a patient’s first presentation. In a stressful time for the child and family, this is a drip that needs to go in the first time with as little fuss as possible. It is important for the medical staff to build trust with the child and family early.
Although most specialities would have the registrar or senior resident “do the admission”, oncologists will often meet the family as soon as they are referred. The family will be seeing a lot of their oncologist, and establishing trust and rapport very early in the piece is important.
In this kind of presentation – from the community in a stable child during daylight hours – the oncologist will often have spoken to the haematologist about the film prior to meeting the patient. This enables them to give the most likely diagnosis (based on the film and history/examination) and answer a few questions.
What are the initial investigations in acute lymphoblastic leukaemia?
- Repeat FBC & send group and hold; coagulation profile; blood cultures if febrile; electrolytes, including PO4-, Mg+, Ca++ as high WCC at risk of tumour lysis syndrome; liver function tests;Â Hep B, C, HIV, EBV, CMV, herpes simplex, HHV6, syphilis and toxoplasma serology
- Blood film must be reviewed & reported by a consultant haematologist
- ECG – sinus tachycardia, normal axis
- Chest radiograph – to check for mediastinal mass
- Urinalysis
- Official height and weight – for chemotherapy and body surface area calculations (standard scales/measure, sighted by two staff)
- Pregnancy test in females of childbearing age
Once clinically stabilised (including meeting minimum platelet counts), they will have a GA lumbar puncture (usually with intrathecal chemotherapy), a bone marrow aspirate, and if there are no contraindications, insertion of a tunnelled central line.
What are the risk factors for ALL?
- Family history
- Immunosuppression
- Alkylating agents (more commonly linked to AML rather than ALL)
- Trisomy 21
- Neurofibromatosis
- Ataxia telangiectasia
- Bloom syndrome
What are good prognostic factors for ALL?
- Age  >1yo and <10yo at diagnosis
- White cell count <50×109/L at presentation
- No testicular involvement at presentation
- Not a child with Trisomy 21
- No prior steroid exposure – this is important, as steroids are themselves chemotherapeutic and can put a child into remission as a single agent. If there has been a history of URTI or wheeze, they may have been prescribed (or given a sibling’s) steroids. There are reports of spontaneous tumour lysis syndrome in undiagnosed patients as a result of steroids. Steroid exposure will move the child to a high-risk protocol.
- No CNS disease – established with first CSF examination
In recent years, cytogenetics and minimal residual disease (MRD) have added a further layer to prognosis and treatment. This analysis requires CSF and bone marrow samples.
What do remission, relapse, and cure mean?
For diagnosis – a patient has to have over 25% blasts in the peripheral blood film
For remission – a patient has to have <5% blasts in the peripheral blood film
For cure – a patient has to have no evidence of leukaemia over 5 years from diagnosis
Bone marrow is the most common site for relapses and 10% of relapses are central nervous system only. In boys, testes are a known site of relapse and present as a hard testicular lump – so make sure you examine the testes during follow-up appointments.
Using the most up-to-date study outcomes, the 5-year survival is 85%
Once the child gets further through the initial treatment and is given a standard risk, then the 5-year survival is 97%
Treatment of acute lymphoblastic leukaemia
Hamish will undergo treatment for his leukaemia, and this can be a hugely overwhelming prospect for the family. The best approach, to begin with, maybe to just give an overview of the principles of ALL treatment
When the blood film is reported, and CSF and BMA are obtained, the oncologist will confirm the diagnosis and advise a treatment protocol. There will be a number of consultations with the oncologist and parents within a relatively short period of time, during which a treatment course is plotted and a child may be enrolled in a study.
This is a particularly tough time for both children and their parents, and more details are provided regarding prognosis and disease course.
What is the treatment likely to be?
A full treatise on the management of ALL is well beyond our scope, but I’ll provide a brief overview of the principles. The aim of the first stage, induction therapy, is complete remission, that is, no leukaemic cells on BMA or in CSF at Day 29. Induction involves intensive chemotherapy and is aiming to achieve immunosuppression. The patient is at the greatest risk of DIC or tumour lysis syndrome during induction.
On arrival, the patient will be admitted to the oncology ward, ideally in a single room.
Chemo treatment will depend on which Study protocol is being used. The aim of chemotherapy is to kill cancer cells. Consequently, this will result in the death of some healthy cells too, for example, hair cells – which is why most patients will lose their hair (it will grow back post-chemo). It also causes immunosuppression and a reduction in their three cell lines: Hb, WCC, and platelets. Patients will usually need packed red cells or platelet transfusions at some stage of their treatment. GCSF is used in some patients to help with WCC recovery.
While the patient is neutropenic, they are at increased risk of infection and should return to hospital with any temperatures, and be managed as febrile neutropenia.
Education is a key component of induction. A new diagnosis of childhood cancer is highly stressful for the child, their family (nuclear and extended) and community. It is important for the carers to ensure they have their own general practitioner.
What is the overall treatment course?
Although B-ALL and T-ALL have differing lengths of treatment with a number of cycles, the overall treatment pattern is similar.
Cycles progress in the order Induction, Consolidation, Interim Maintenance I, Delayed Intensification, Interim Maintenance II, Maintenance, with a full course of treatment lasting around three years. CNS sanctuary therapy is usually included at each stage (intrathecal methotrexate).
Each cycle involves a different regimen of chemotherapy and varying intensity. A key point is that the aim is to achieve remission in induction, with the remainder of cycles reducing the risk of relapse.
If there is CNS involvement or testicular involvement then there may also be a period of radiotherapy.
After a few months, most families will be experts in their own treatment protocol. If you are the general paediatrician seeing a child with ALL in hospital, it will be helpful to find out some information from the family prior to calling their Oncologist:
- Which study protocol are they on?
- What part of the protocol are they in?
- When was their last chemo (and what was it)?
Tumour lysis syndrome
Treating leukaemia produces its own complications. The most common time to have complications is during induction. For any new presentations of tumours, or for patients at the start of treatment, be aware of tumour lysis and how it can present.
Tumour lysis syndrome is most commonly seen at the start of treatment as this is when there is the highest tumour load.
Tumour lysis syndrome results from cell death and the subsequent release of chemicals from these cells.
It can be triggered by steroids, chemotherapy, fever, or dehydration.
What are the chemical abnormalities in TLS?
When cells die, they release their intracellular potassium and phosphate. Calcium then binds to the phosphate in the tissues. Urate is also deposited in the kidneys. The usual order of detected abnormalities is:
- High potassium
- High phosphate
- Low calcium – this can also be associated with kidney calcification
- High urea and creatinine  – this is due to renal failure and if this happens then the renal team need to be involved and the patient will likely require dialysis
How do we treat it?
Treatment is through three main ways:
- Hydration
- Allopurinol – aiming to reduce the urate
- Rasburicase – a medication that converts uric acid to allantoin which is water soluble and excreted in the urine.
Also, beware that if the patient has high potassium, they are at risk of cardiac arrest so may also need standard hyperkalaemia management.
What are the other potential complications of ALL?
Anaemia – often the presenting complaint and result of treatment. Most patients require platelet and red cell transfusions.
Febrile neutropenia – most patients will have an episode of febrile neutropenia during induction. This can be due to life-threatening sepsis. Find your hospital guideline and if you suspect febrile neutropenia, talk to your consultant early.
Hyperviscosity syndrome – can be a presenting complaint, associated with WCC >100×109/LÂ
Bone Marrow Transplants
In cases where leukaemia has not responded to treatment, or when the patient relapses, then a bone marrow transplant is a common course of treatment.
Bone marrow transplants are used with the aim of completely resetting the patient’s immunity.
What are the other indications for a bone marrow transplant?
BMTs are usually done for:
- Malignancies – ALL, CML, neuroblastoma, non-Hodgkin’s lymphoma, Wilm’s tumour, rhabdomyosarcoma
- Bone marrow disease – aplastic anaemia, thalassaemia, sickle cell disease, Wiskott-Aldrich syndrome, chronic granulomatous disease, severe combined immunodeficiency, Diamond-Blackfan syndrome
- Metabolic disease – mucopolysaccharoidoses, adreneleukodystrophy, glycogen storage disorders
Where do the cells come from?
BMTs can be allogenic or autogenic.
Allogenic transplants can be from a sibling, an unrelated donor, or from cord blood (related or unrelated). Any full sibling has a 1 in 4 chance that they will be a match.
Matching is done via tissue typing and mainly checks the HLA match – aiming for 6 out of 6 alleles matched in a sibling donor, or 5 out of 6 in a cord transplant (as this is a more naive immune system).
Stem cells will be collected from the donor via a bone marrow aspirate, from the cord of a newborn, or via apheresis (peripheral blood stem cell collection).
Autologous transplants are more commonly used in children with brain tumours – these are often given as mini-transplants. As these patients often have intense chemotherapy, the stem cells are collected from the patient prior to starting chemo and then given back to them at the end of each cycle to help build them up before the next cycle.
What are the stages of a bone marrow transplant?
The key stages are:
- Pre-transplant evaluation – this will include the decision to proceed to transplant, donor selection and tissue typing, and also an assessment of pre-transplant organ function.
- Conditioning therapy – this usually lasts 5-10 days and consists of high-dose chemotherapy and radiation. These will be termed minus days i.e. the first day of conditioning might be D -7.
- Infusion of the stem cells – this is known as D0. Stem cells are infused over minutes to hours (depending on the volume). Isolation commences from the time of infusion. Note that patients can have toxicity from DMSO (dimethyl sulfoxide) which is used to preserve the stem cells – this can cause nausea/vomiting, haematuria, an unpleasant odour. It is mainly excreted via the lungs over 48 hours.
- Engraftment – this is when a neutrophil count of 0.5 is achieved on two consecutive days.
- Post-transplant – this is usually split into early (0-3 months) and late (3-12 months)
What are the complications?
Some patients will experience early problems that are not directly related to the stem cells, but rather are side effects of the high-dose chemotherapy.
Complications from the actual BMT include:
- Nausea/vomiting
- Mucositis
- Pancytopenia – bleeding and life-threatening infections
- Veno-occlusive disease
- Graft versus host disease
- Opportunistic infections – CMV, PCP
Treatment-related mortality in matched sibling donors is 5-10%. In unrelated donors, it is 20-25%.
There are huge psychosocial implications for families during the transplant. There will be fear that the child will die during treatment or relapse after the treatment. There will be the distress of watching their child endure complications of the treatment we are giving. Also, being stuck in a room for months can lead to loneliness and isolation. Parents can often second-guess their decision to proceed to transplant. Overall is it a highly stressful time, and it’s important to be mindful of this when dealing with these families.
Selected References
National Cancer Institute – Childhood Acute Lymphoblastic Leukaemia Treatment (PDQ) – Risk-based Treatment Assignment
Peppercorn J et al. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet 2004; 363: 263–70
QPHON Guide to the Care of Children with Cancer in Queensland Document No. 2.1 15062012 © 2012 State of Queensland Queensland Health. via Q-Health intranet.
