Childhood Leukaemias

Leukaemia is the commonest type of childhood malignancy, accounting for about 30% of its total incidence.¹ Acute lymphoblastic leukaemia (ALL) is the most frequent, making up 70–80% of the total incidence of leukaemia in children. The next commonest is acute myeloid leukaemia (AML) which constitutes around 20% of the total. Chronic myeloid leukaemia (CML) accounts for up to 5% of the childhood leukaemias, with the remainder due to a variety of rare and unusual leukaemias.

It appears that children that suffer leukaemia (particularly ALL) have a range of different chromosomal and gene abnormalities that define subsets of the disease with prognostic relevance.^{2 3} Pre-natal chromosomal translocations generate chimeric fusion genes that are thought to initiate the disease process, and are unique to each patient's leukaemic clone. It is thought that one or more post-natal genetic alterations are also 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. Further research should help to elucidate the precise mechanisms by which these processes occur.³

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:²

• ALL peak incidence in 2–3 year olds
• AML peak incidence 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.

Leukaemia affects around 25–45 children per million.⁴ The incidence of leukaemia in children has increased slightly over the last 20 years, with most of the increase being due to ALL.

Risk factors

• Commoner in caucasian children compared to those of African-Caribbean origin ⁴
• Exposure to various childhood infections, particularly influenza, is purported to increase the risk of developing leukaemia in childhood ⁵
• A range of cytogenetic abnormalities have been found to be associated with an increased risk of the disease ²
• 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 ⁶.
• Significant exposure to ionising radiation and some chemicals is known to increase the risk of childhood leukaemia
• A variety of common environmental exposures to electromagnetic radiation (eg 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 ⁷.

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.
• Susceptibility to recurrent or 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 reticulocytopenia, 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 marrow aspiration and biopsy, imaging to detect the extent of the disease, morphoimmunocytogenetic analyses of marrow cells and possibly LP if 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 ⁸
• 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. It is vital that during all stages of treatment there is good communication between primary and secondary care teams, such that all involved in the child's care are aware of what the treatment and situation is at any given time. It is helpful if families with affected children can be put in contact with others who have been in the same situation to allow them to discuss any queries or fears that they may have.

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 are given as induction, consolidation, interim maintenance, delayed intensification, and 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 ⁹.
• 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 ¹⁰.
• CML is treated very successfully with imitinab 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.¹¹

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.¹²

Of leukaemia and its treatment include:

• Tumour lysis syndrome
• Renal impairment
• Profound immunosuppression leading to sepsis
• Haemorrhage
• Thromboembolism
• Neuropathy and encephalopathy
• Seizures
• Second malignancy
• Short stature if cranial irradiation is used
• Growth hormone deficiency
• Cognitive impairment
• Alopecia
• Mucositis causing severe mouth pain
• Hyperemesis
• GI erosion/bleeding
• Myocardial failure and arrythmia due to toxicity of chemotherapeutic agents