Childhood Leukaemias

Leukaemia is the commonest type of childhood malignancy, accounting for about 30% of its total incidence.¹ Approximately 1 in 2000 children will develop it before the age of 15 years.²

Of the different types of childhood leukaemia:

• Acute lymphoblastic leukaemia (ALL) is the most frequent, making up 70–80% of the total incidence of leukaemia in children.
• Acute myeloid leukaemia (AML) is the next commonest at around 20% of the total.
• Chronic myeloid leukaemia (CML) accounts for up to 5%.
• The remainder is due to a variety of unusual and rare leukaemias.

• Childhood leukaemia is a biologically diverse disease, arrived at by many different pathways.
• Children with leukaemia (particularly ALL) have a range of different chromosomal and gene abnormalities that define subsets of the disease with prognostic relevance.^3,4
• Prenatal chromosomal translocations generate chimeric fusion genes (such as TEL-AML1) that are thought to be important but insufficient disease initiators since they are found in many more neonatal cord blood samples than children who eventually develop leukaemia.
• Subsequent postnatal genetic alterations must be required to allow leukaemia to develop. In the case of ALL, it is strongly suspected that this process is linked to an abnormal response to an infection.⁵
• Extreme population mixing (as occurs with large influxes into rural areas e.g. new towns, commuter belts, military camps, evacuation⁶) may cause epidemics of common infections and ALL clusters. Leukaemia is hypothesised as a rare response to these infections in vulnerable children.⁷
• Similarly, there seems to be a protective effect of early exposure to common infections such as occurs in nursery daycare, suggesting that there are key times of developmental vulnerability.⁸

There were 470 new cases of childhood leukaemia recorded in the UK in 2003. Recorded incidence of childhood leukaemia has risen in Europe since the 1970s due in most part to a small increase in ALL in the under 5s.⁹

Age distribution

Leukaemia may affect children of any age, but each type commonly affects a particular age group, as outlined below. This age clustering is thought by some to reflect the expression of particular cytogenetic aberrations at crucial stages of development:³

• ALL's peak incidence is in 2–3 year olds.
• AML's peak incidence is in children aged <2 years.
• CML has two peaks of incidence in children aged <1 year and in early teenage years. The two peaks may reflect discrete disease entities.

Risk factors

• Commoner in caucasian children compared to those of afro-caribbean origin.¹⁰
• Boys are at slightly higher risk than girls.
• Exposure to various childhood infections, particularly influenza, is purported to increase the risk of developing leukaemia in childhood.¹¹ Hib vaccination confers protection.¹²
• A range of cytogenetic abnormalities have been found to be associated with an increased risk of the disease.³
• Other genetic abnormalities such as Down's syndrome (increases risk by about 15 times). Fanconi's anaemia, ataxia telangiectasia and Bloom's syndrome are associated with an increased risk.¹³ Congenital anomaly, even excluding children with Down's syndrome, increases the risk of AML and ALL.¹⁴
• Larger birthweight babies appear to have greater risk. This may be related to accelerated periods of fetal growth and exposure to increased levels of growth factors, rather than birthweight per se.¹⁵
• Significant exposure to ionising radiation and some chemicals is known to increase the risk of childhood leukaemia. Maternal abdominal x-ray during pregnancy increases the risk of childhood leukaemia by about 50%.
• A variety of common environmental exposures to electromagnetic radiation (e.g. high-voltage power lines, mobile phone masts), low-level radionuclides from the nuclear power industry, and others, have been claimed as causative factors, but never proven on epidemiological grounds.¹⁶

Neonatal intramuscular Vitamin K injections were, for a time, suspected of increasing the risk of childhood leukaemia although further investigation have shown no evidence supporting this association.¹⁷

Symptoms

• Prolonged or recurrent episodes of fever
• Tiredness or fatiguability
• Irritability and/or protracted crying
• Growth retardation and/or failure to thrive
• Bleeding diathesis, particularly causing epistaxis, bleeding gums and/or easy bruising
• Muscular or bony pain, particularly in the legs
• Troublesome constipation
• Prolonged cough
• Headache
• Nausea and vomiting, particularly if CNS infiltration is present
• Repeated or severe common childhood infections

Signs

• Pallor due to anaemia
• Signs of bleeding tendency such as petechiae, purpura, bruising etc.
• Signs related to severe infection
• Lymphadenopathy
• Hepatosplenomegaly
• Cranial nerve lesions or other focal CNS pathology

• The most useful initial investigations in primary care are FBC with differential, and reticulocyte count.
• The FBC will not always be abnormal in all cases of leukaemia, as some patients may not have marrow suppression, or may have blast cells confined to the bone marrow.
• The presence of blast cells on a peripheral smear is highly indicative of leukaemia.
• Anaemia, particularly if accompanied by reticulocytopaenia, raised MCV, low platelets, leucopenia or leucocytosis should raise suspicions of leukaemia and prompt further haematological evaluation.¹
• Further investigations conducted in secondary care are likely to include:
  • Bone marrow aspiration and biopsy
  • Imaging to detect the extent of the disease
  • Morphoimmunocytogenetic analyses of marrow cells
  • Lumbar puncture where there is suspected CNS infiltration

Increased incidence of leukaemia in children with:

• Down's syndrome (15 X background incidence)
• Fanconi's anaemia
• Ataxia telangiectasia
• Bloom's syndrome

• The FAB system is widely used in ALL, but does not correlate with immunophenotypic and cytogenetic classifications. ALL is staged L1–L3 based upon morphological characteristics of blast cells.
• There is no staging system for AML because by the time of diagnosis it has already spread throughout the bloodstream, and invariably invaded other body tissues. Patients are often grouped according to whether or not they have been previously treated for leukemia.¹⁹
• CML is staged as being in the chronic, accelerated or blast phases depending upon disease activity, symptoms and the proportion of leukaemic cells that have undergone blast transformation.

General

• Children with leukaemia and their families will require long term help and support from various agencies including the primary health care team.
• A diagnosis of childhood leukaemia reverberates around the family and has implications for all, not just the child with the disease. Initial shock, anger, fear at diagnosis will transmute into potentially long stays in hospital and frequent outpatient visits. These may impact on educational continuity and social development, as well as parental absence from work and home. Siblings may feel neglected with the understandable shift of focus to the sick child.
• Good communication between all of the many professionals involved in the child's care is critical.
• Many families find it helpful to be put in contact with others who have been in the same situation whose support and practical advise is often highly valued.

Chemotherapy

• ALL is always treated with high-intensity chemotherapy, usually via a central venous catheter. There are varying schedules depending on morphoimmunocytogenetic classification and extent of disease. Phases of treatment given are:
  • Induction
  • Consolidation
  • Interim maintenance
  • Delayed intensification
  • Maintenance
  Intrathecal chemotherapy or CNS irradiation may be used to treat CNS infiltration. Patients with high-risk disease may be treated with allogeneic stem-cell transplantation during first relapse, although efficacy and long-term outcomes are uncertain for this technique. Molecular targeted monoclonal antibody therapies may play an increasing role in the future.²⁰
• AML is treated with intensive chemotherapy to destroy the leukaemic cell population as quickly as possible. The patient must then be supported through a period of intense marrow suppression until haematopoietic recovery occurs. All-trans-retinoic acid (ATRA) may be used as an adjunct in promyelocytic leukaemias to induce remission. Patients with Down's syndrome and AML respond differently to chemotherapy and often have a more benign course, so less taxing chemotherapy regimens are given. Marrow ablation with grafting of HLA-matched or allogeneic bone marrow may be used in advanced cases.²¹
• CML is treated very successfully with imatinib anti-tyrosine kinase therapy in adults and this is being evaluated in children. Myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors is the mainstay of long-term treatment.²²

Colony stimulating factors are often used to promote haematopoietic function following chemotherapy. They have been proven to be effective in reducing hospital stay and risk of infections in children with ALL.²³

Of leukaemia and its treatment include:

• Tumour lysis syndrome
• Renal impairment
• Profound immunosuppression leading to sepsis (febrile neutropenia)
• Haemorrhage
• Thromboembolism
• Neuropathy and encephalopathy
• Seizures
• Alopecia
• Mucositis causing severe mouth pain
• Hyperemesis
• GI erosion/bleeding

Longer term complications include:²⁴

• Growth hormone deficiency and short stature (where cranial irradiation applied)
• Obesity
• Congestive cardiac failure (due to toxicity of some chemotherapeutic agents)
• Cognitive impairment
• Infertility
• Psychosocial impairment
• Second malignancy