Acute leukaemia in children: diagnosis and management

What causes acute leukaemia?

Acute leukaemia arises from genetic mutations in blood progenitor cells. These mutations generate both an uncontrollable capacity for self-renewal and the developmental arrest of the progenitor cells at a particular point in their differentiation.6 The body is therefore overwhelmed by immature cells or blasts that infiltrate the bone marrow, reticulo-endothelial system, and other extra-medullary sites. Eighty per cent of children with acute leukaemia have acute lymphoblastic leukaemia; most of the remainder have acute myeloid leukaemia.7 Chronic leukaemia in children is extremely rare.8

Usually, newly diagnosed children have been previously well, with no identifiable environmental risk factors for leukaemia such as exposure to ionising radiation. In our experience, many parents therefore crave an explanation for their child’s illness, asking whether it is their fault or “something in the family,” particularly if an adult family member has died of leukaemia. However, the predominant leukaemia of early childhood, acute lymphoblastic leukaemia, is not inherited and is distinct from the leukaemias more commonly seen in adults (acute myeloid leukaemia, chronic myeloid leukaemia, and chronic lymphocytic leukaemia).9 Fewer than 5% of all cases are associated with inherited predisposing genetic syndromes such as Down’s syndrome, in which there is a 20-fold increase in the risk of developing leukaemia.10

Acute lymphoblastic leukaemia probably arises from the interaction of environmental risk factors with a pre-existing genetic susceptibility. It is now known that a pre-natal mutation leads to the production of a pre-leukaemic clone which expands postnatally. A second mutation is required for overt disease to develop, most commonly between the ages of 2 and 5 years. What causes this second mutation is contentious. One hypothesis, that of “population mixing,” suggests that when genetically susceptible children move into new, rapidly expanding towns, their immune response to unfamiliar local infections is abnormal, causing leukaemia to develop.11 Alternatively, the “delayed infection hypothesis” suggests that susceptible children from excessively hygienic environments are protected from normal childhood infections, causing an aberrant immune response to later infections which triggers leukaemia.12

How does acute leukaemia present in children?

Presentations of acute leukaemia relate to three main pathological processes: bone marrow failure due to extensive infiltration by blast cells, infiltration of other tissues by blasts, and systemic effects of cytokines released by tumour cells.

Leukaemia may be strongly suspected when a child presents with classical signs of anaemia, thrombocytopenia, and pronounced hepatosplenomegaly or lymphadenopathy. However, as one high quality systematic review recently highlighted, the presenting symptoms are often vague and non-specific, mimicking those of common, self-limiting childhood illnesses.13 In our experience, parents frequently decide to consult their GP simply because their child, in some intangible way, “is just not right,” perhaps with pallor, lethargy, or malaise.

At present, there is no definitive evidence base enabling doctors, particularly GPs, to discriminate with confidence between those children for whom wait and see is appropriate practice, those for whom phlebotomy is advisable, and those who should be referred urgently to the emergency department. We failed to find any studies conducted in primary care that evaluated the positive and negative predictive value of signs and symptoms for the diagnosis of acute leukaemia, although such research is currently ongoing. Table 1⇓, based on a wide number of case reports, review articles and our own departmental experience, outlines the range of potential presentations.13 14 15 We encourage inclusion of acute leukaemia in the differential diagnosis for all children presenting with such signs and symptoms, particularly when the parent insists there is something amiss with their child.

Occasionally, acute leukaemia presents with a life threatening complication requiring immediate hospital management.16 Our experience suggests that delay in such instances may be fatal, although there is no clear evidence on this issue. We recommend that if GPs are concerned about any of these complications (table 2⇓), they should not wait for phlebotomy and subsequent results, but rather refer immediately to the emergency department or call the on-duty haematology registrar.

How is acute leukaemia diagnosed?

When leukaemia is first suspected, the most important initial investigations are a full blood count and blood film. These quick and inexpensive tests are highly sensitive, permitting accurate diagnosis of leukaemia in most patients. Furthermore, if both are within normal ranges, acute leukaemia can be ruled out with a fair degree of confidence.

Typically, the full blood count will demonstrate pancytopenia secondary to bone marrow infiltration by blasts. Although the patient is likely to be neutropenic, millions of circulating blasts tend dramatically to elevate the overall white cell count, with blasts clearly evident on the film.

Sometimes, however, the white cell count may be only slightly raised and, if blasts remain sequestered within the bone marrow, it can even be lower than normal. Nor are clearly identifiable blasts always present. In these cases, the only clue that there is a serious underlying problem may be a few atypical cells in the blood film or the presence of leukoerythroblastic features. In our experience, any abnormal count or film, in conjunction with a suspicious clinical picture, should prompt urgent referral to a specialist centre for further investigation or, as a minimum, telephone discussion with an on-duty haematologist.

How is a child with acute leukaemia managed?

After urgent investigations and supportive care (box), the tertiary referral centre will aspirate bone marrow, usually under general anaesthetic in children, to obtain a definitive diagnosis of acute leukaemia. The aspirate provides morphological, immunological, and genetic information which, alongside clinical factors such as the child’s age, sex, presenting white cell count, and initial response to chemotherapy, enables patients to be categorised according to their risk of subsequent relapse.

Simple light microscopy will usually allow classification of the diagnosis as acute lymphoblastic leukaemia or acute myeloid leukaemia. Immunophenotyping using flow cytometry identifies patterns of cell surface antigens associated with particular subtypes of acute lymphoblastic leukaemia or acute myeloid leukaemia. For example, the majority of children with acute lymphoblastic leukaemia have the precursor B cell type, which is positive for the CD10 and CD19 cell surface markers. Around 15% of children with acute lymphoblastic leukaemia will have the T cell (CD3 positive) phenotype.3 These children tend to be male and older, with more frequent central nervous system involvement and bulkier disease, including mediastinal masses. Cytogenetic analysis identifies specific genetic abnormalities, such as the TEL/AML1 or BCR-ABL gene fusions, which correlate with a good or poor prognosis, respectively.17

Patients are categorised into low, standard, or high risk groups, with treatment determined, as far as possible, by risk status. For example, in both acute lymphoblastic leukaemia and acute myeloid leukaemia, very intensive treatment such as allogeneic bone marrow transplant is reserved for very highrisk cases (<10% of cases), protecting standard risk patients from unnecessary toxic side effects.18 Bespoke therapy has been further refined over the last 10 years by PCR- based techniques for the assessment of “minimal residual disease.” These techniques are over a hundred times more sensitive than morphological methods at identifying residual leukaemia (they can pick out one cell in 100 000), enabling clinicians to predict future, as yet subclinical, relapse and plan treatment accordingly.19

What are the key complications of treatment for acute leukaemia?

The longer term side effects of the commonly used chemotherapeutic agents range from peripheral neuropathy (vincristine) and cardiotoxicity (doxorubicin) to decreased fertility (cyclophosphamide) and hepatotoxicity (cytarabine).13 However, most children will have few, if any, long term complications of therapy, especially now that the use of cranial radiotherapy has been minimised.

By far the most important acute complication is neutropenic sepsis which, as with meningococcal sepsis, can rapidly trigger overwhelming multi-organ failure. A delay of even an hour or two in prescribing appropriate broad spectrum antibiotics (guided by local protocols) may impair the child’s chances of survival.22 Before leaving the tertiary care centre, parents are educated in the risks of subsequent fever in their child and the urgent need to visit the emergency department if, for example, they take one temperature reading over 38.5°C or two over 38.0°C. Typically, tertiary referral centres also supply parents with written guidelines about when to contact primary and secondary physicians, and secondary physicians with written protocols for how to manage complications.

Parents frequently worry about travel abroad and routine immunisations. A comprehensive review of trial evidence and expert opinion advises that no routine immunisations should be given while the child is on therapy or for 6 months afterwards. The review outlines recommended schedules for subsequent immunisation. Unless it is particularly frequent or extensive, foreign travel is considered safe.23

Where should research be directed next?

• The aetiology of acute leukaemia, particularly gene-environment interactions

• Refined selection, on the basis of cytogenetic and molecular data, of patients at either very low or very high risk of relapse

• Novel immunotherapeutic agents that target specific molecular defects such as gene fusions.

In the future, standard combination chemotherapy protocols might be tailored to an individual’s unique genetic profile; this approach, together with novel molecular agents directed at leukaemia specific mutations, would continue with the current goals of minimising treatment toxicity for patients at low risk of relapse while improving the outlook for patients at high risk.