Acute Lymphoblastic Leukaemia

Epidemiology

Incidence of ALL peaks between 2 and 5 years of age. As with many childhood cancers, males are more commonly affected than females.

Pathophysiology

As with many malignancies, the precise aetiology of childhood leukaemia remains unknown. It is clearly a multi-factorial condition, with infection, genetic predisposition and numerous environmental exposures all playing a potential role in its development.

Disruptions in the regulation and proliferation of lymphoid precursor cells in the bone marrow leads to excessive production of immature “blast” cells and a subsequent drop in numbers of functional red blood cells, white blood cells and platelets.

Children with certain genetic diagnoses, such as trisomy 21, are known to be at increased risk of leukaemia.

Clinical Features

History

The specific symptoms of leukaemia are due to deficiency of the three main cell lines, so history compatible with anaemia (lethargy, looking pale), thrombocytopaenia (easy bruising/bleeding) and leukopaenia (fevers/infections) are common. Children may also complain of bone pain as a result of increased pressure from hyperplastic marrow.

More non-specific symptoms of malignancy, such as weight loss and malaise are also common. Occasionally, children may present with signs of central nervous system (CNS) involvement, such as headache or seizures.

Examination

Examination findings again suggest low red blood cells (looking pale) or platelets (unexplained or excessive bruising or bleeding) and potentially high white blood cells (lymphadenopathy). It is also important to look for hepatosplenomegaly.

Differential Diagnosis

Important differentials with salient features to help to differentiate

Differential diagnosis is linked to the presenting symptoms and signs:

• Bruising – may also be due to immune thrombocytopenia (low platelets but normal RBC/WBC), trauma (history of injury) or non-accidental injury (normal bloods with no history of injury).
• Recurrent infections – may be due to immune deficiency (long standing history of unusual/severe infections, failure to thrive, chronic diarrhoea).
• Lymphadenopathy – may be a reactive lymphadenopathy (history of recent infection).
• CNS symptoms – may be due to infection or raised intra-cranial pressure.
• Pancytopaenia – may be seen with infiltration of other malignant processes into the marrow (eg neuroblastoma – abdominal mass may be present) or aplastic anaemia (lack of blasts on blood film).

Investigations

Laboratory tests

Full blood count – likely to show either pancytopaenia or anaemia and thrombocytopaenia with a significant lymphocytosis

Blood film – likely to show the presence of blast cells

Imaging or invasive tests

All children suspected to have a new diagnosis of leukaemia should also undergo chest X ray to exclude mediastinal mass

Bone marrow aspirate/trephine is required to confirm the diagnosis

Lumbar puncture is required to check for CNS involvement

Risk scoring

There are a number of factors associated with better or worse prognosis, particularly in regard to ALL. These factors have traditionally been based on clinical and laboratory factors (see below) however, cytogenetic testing is increasingly recognised as being important in determining prognosis.

• Age – children aged 1-10 years at presentation have a better prognosis than younger or older children
• White cell count – WCC > 50 at presentation is associated with poorer prognosis
• Gender – females are thought to have a better prognosis than males
• CNS involvement – the presence of blasts within the CSF is associated with poorer prognosis.
• Leukaemia characteristics – morphology and cyotology influences prognosis.

Management

Immediate

Initially, focus is on resuscitating and stabilising an unwell child. Any child presenting with a very high white cell count will require hyperhydration, to prevent hyperviscosity.

If a mediastinal mass is present, the child’s airway is at risk of becoming compromised and steroids should be given immediately. If concurrent infection/sepsis is present, this must be treated appropriately with broad spectrum antibiotics.

Definitive and Long-term

The majority of children with ALL in the UK are managed on the UKALL 2011 protocol, the majority of these within a trial arm. Treatment is with chemotherapy given intravascularly, orally, and intra-thecally (into the CSF).  Children need supportive care with blood products (red cells, platelets) and prophylactic anti-fungal therapy throughout treatment.  There is no role for radiotherapy in the management of ALL.

Maintenance treatment is 2 years for girls and 3 years for boys.

Prognosis and Complications

Over 90% of children are now expected to survive ALL. However, many will suffer complications as a result of their treatment or initial diagnosis. Infertility, avascular necrosis, peripheral neuropathy and anxiety are all relatively common.

All children who are treated for ALL should have regular follow-up and assessment for 5 years after treatment is completed to assess for any signs of relapse, and then yearly review thereafter to evaluate for late effects of chemotherapy.

References

Authors:

1st Author: Dr Amanda Friend

Senior Reviewer: Dr Carmen Soto (Senior academic paediatric registrar)