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Childhood Leukaemias

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

Leukaemia is the most common type of childhood malignancy, accounting for about 30% of its total incidence.1 Approximately 1 in 2,000 children will develop it before the age of 15 years.2

Of the different types of childhood leukaemia:

Aetiology and pathogenesis2

  • 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 genetic 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 in children who eventually develop leukaemia.
  • A 'second hit' causing 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
    • The 'delayed infection' hypothesis suggests that there are key times of developmental vulnerability.8 There seems to be a protective effect of early exposure to common infections, such as occurs in nursery daycare, and susceptible children who meet these normal childhood infections later, may have an abnormal immune response to them, triggering leukaemia.

Epidemiology

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

  • Childhood leukaemia is more common in Caucasian children compared with 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 Haemophilus influenzae type b (Hib) vaccination confers protection.12
  • A range of cytogenetic abnormalities has been found to be associated with an increased risk of the disease.3
  • Other genetic abnormalities such as Down's syndrome (increases risk by 10 to 20-fold).13 Fanconi's anaemia (FA), ataxia telangiectasia (AT) and Bloom's syndrome (BS) are associated with an increased risk.14 Congenital anomaly, even excluding children with Down's syndrome, increases the risk of AML and ALL.15
  • 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.16
  • 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.17

Neonatal intramuscular Vitamin K injections were, for a time, suspected of increasing the risk of childhood leukaemia although further investigations have shown no evidence supporting this association.18

Presentation

Presentation is highly variable depending on the child's age and the extent of leukaemic infiltration of the bone marrow and other sites, as well as cytokine systemic effects:

  • The classical signs of anaemia, thrombocytopenia, hepatosplenomegaly or lymphadenopathy are highly suspicious of leukaemia but initial symptoms are often nonspecific and vague, and very similar to common, self-limiting viral illness. Thus, reasonable suspicion of the condition and its prompt diagnosis are frequently a challenge.1
  • On average, a GP will see a new case of childhood cancer once every 20 years.19
  • The symptoms and signs listed below are common manifestations of the condition. There is no good evidence-base to allow rational decision-making in primary care between phlebotomy and 'wait-and-see' approaches when symptoms are more vague.20 Where symptoms are prolonged, particularly troublesome, or present atypically compared with more common illnesses in children, it may be wise to conduct initial investigations.
  • More rarely, acute leukaemia can present with life-threatening complications (see Complications below) - do not delay admission for preliminary investigation of these children - refer directly to A&E or paediatric on-call teams.20

Symptoms

  • General malaise, fatigue and lethargy
  • Prolonged or recurrent episodes of fever
  • Irritability and/or protracted crying
  • Growth retardation and/or failure to thrive
  • Shortness of breath and/or reduced exercise tolerance
  • Dizziness and palpitations
  • 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 central nervous system (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
  • Expiratory wheeze (due to mediastinal mass)
  • Cranial nerve lesions or other focal CNS pathology
  • Testicular enlargement

Differential diagnosis

The overall differential diagnosis is very wide, depending on the mode of presentation and age of the child. Some of the more common conditions that may present similarly in clinical terms, or in their ability to cause abnormalities of the FBC that are akin to leukaemia, are listed below:

Investigations

  • The most useful initial investigations in primary care are FBC and blood film. Typically, this shows pancytopenia due to bone marrow infiltration. Blasts may elevate the white cell count (despite neutropenia) and their presence on a peripheral smear is highly indicative of leukaemia.
  • However, the FBC will not always be abnormal in all cases of leukaemia, as some patients may not have marrow suppression. Similarly, peripheral blood films may be normal if blast cells are confined to the bone marrow.

    Any abnormal blood count or film in combination with suspicious clinical features should be referred urgently to a specialist centre.20

  • Further investigations conducted in secondary care are likely to include:
    • Bone marrow aspiration and biopsy - for definitive diagnosis
    • Imaging to determine the extent of the disease
    • Immunophenotyping and cytogenetic analysis to enable risk stratification
    • Lumbar puncture where there is suspected CNS infiltration

Associated diseases

Increased incidence of leukaemia in children with:

  • Down's syndrome (15 X background incidence)
  • FA
  • AT
  • BS

Staging

  • The French-American-British (FAB) classification 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 treated for leukaemia previously.
  • 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.

Management

General

  • Children with leukaemia and their families will require long-term help and support from various agencies including the primary healthcare 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.
  • Much of the treatment of leukaemia takes place in tertiary centres: there must be guidance to families and protocols at local secondary care hospitals as to how to recognise and manage complications that may arise following discharge after treatment, in particular febrile neutropenia.
  • Many families find it helpful to be put in contact with others who have been in the same situation, whose support and practical advice is often highly valued.
  • No routine immunisations during therapy and for six months afterwards.20

Chemotherapy

  • ALL is always treated with high-intensity chemotherapy, usually via a central venous catheter (e.g. Hickman lines). There are varying schedules depending on morphoimmunocytogenetic classification and extent of disease. Phases of treatment given are:20
    • Remission-induction - usually 3-drug IV chemotherapy over 4-6 weeks, aiming rapidly to eradicate ≥99% of the leukaemic cells, enabling normal haemopoiesis to resume.
    • Consolidation and therapy directed at the CNS - this is stratified according to risk of relapse with augmented therapy for slow early responders (>25% leukaemic cells in marrow). Intrathecal methotrexate is started in this phase and continues during continuation therapy - this is directed at leukaemic cells within the CNS. Cranial radiotherapy is used much less often since the 1990s. This phase last 4-12 weeks.
    • Intensification - reinduction and reconsolidation over the next 8-12 weeks, again aiming to limit relapse. Hair grows back after this phase of treatment.
    • Continuation therapy - oral chemotherapy (methotrexate) with monthly vincristine and dexamethasone pulses. This continues over the next 2-3 years. Girls with ALL typically receive two years of treatment compared with boys' three years, as their risk of relapse is lower.
    • Allogenic bone marrow transplant is used to eliminate residual leukaemic cells in high-risk subtypes refractory to chemotherapy. Myeloablation (via total body irradiation and cyclophosphamide) is followed by the transplantation of allogenic haemopoietic stem cells. This treatment has significant morbidity and mortality associated with it due to infection and graft-versus-host disease.
  • AML is treated with intensive chemotherapy (usually four courses at monthly intervals) 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. There is no maintenance therapy; most patients' treatment will be complete at six months. 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 allogenic 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

Complications

Early

These may cause a life-threatening presentation of leukaemia:

During treatment

Late24

  • Growth hormone deficiency and short stature (where cranial irradiation applied)
  • Neurological problems including headache, motor, coordination and cognitive impairment, seizures (again following cranial irradiation)25
  • Peripheral neuropathy (due to vincristine)
  • Obesity
  • Congestive cardiac failure (due to toxicity of some chemotherapeutic agents, e.g. doxorubicin)
  • Cognitive impairment
  • Infertility (due to cyclophosphamide)
  • Psychosocial impairment
  • Second malignancy

Prognosis

  • Prognosis has improved dramatically over the last few decades. Five-year survival rates for all types of childhood leukaemia have risen from 33 to 79% between 1971 to 2000, as have cure rates (survival to point where no excess mortality) from 25 to 68% between 1971 and 1995.26
  • Outlook in ALL is now good with overall cure rate of 80%. Individual prognosis is highly dependent upon staging by the various classifications. Prognosis is best for children aged 1–10. Cure rates for the under 1s are poor at around 30%.27 Average time to cure has actually increased to 19 years for ALL, reflecting late relapse, secondary malignancies and treatment-related toxicity.26
  • Prognosis has improved recently in AML with a five-year overall survival rate of 66% and an event-free survival rate of 56%. However, patients with adverse cytogenetic features or poor treatment response do badly even with allogenic bone marrow transplants and have a less than 20% cure rate.20
  • For childhood CML patients receiving myeloablative haematopoietic stem cell transplantation from fully-matched related and unrelated donors, survival rates of 60–75% have been reported. There is significant associated morbidity.28

It is hoped that the future will bring new therapies, targeting specific molecular defects and continued improvements individualising therapy, to maximising outcomes whilst minimising complications due to treatment.

Document references

  1. Young G et al; Recognition of Common Childhood Malignancies. Am Fam Phys 2000 Apr 1; 61(7):2144-54 ; Good overview of clinical approach to possible childhood malignancy in primary care.
  2. Dickinson HO; The causes of childhood leukaemia. BMJ. 2005 Jun 4;330(7503):1279-80.
  3. Forestier E, Schmiegelow K; The Incidence Peaks of the Childhood Acute Leukemias Reflect Specific Cytogenetic Aberrations. J Pediatr Hematol Oncol. 2006 Aug;28(8):486-495. [abstract]
  4. Greaves M; Childhood leukaemia. BMJ. 2002 Feb 2;324(7332):283-7.
  5. Roman E, Simpson J, Ansell P, et al; Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol. 2007 Mar 1;165(5):496-504. Epub 2006 Dec 20. [abstract]
  6. Kinlen LJ, Balkwill A; Infective cause of childhood leukaemia and wartime population mixing in Orkney and Shetland, UK. Lancet. 2001 Mar 17;357(9259):858. [abstract]
  7. Stiller CA, Kroll ME, Boyle PJ, et al; Population mixing, socioeconomic status and incidence of childhood acute lymphoblastic leukaemia in England and Wales: analysis by census ward. Br J Cancer. 2008 Mar 11;98(5):1006-11. Epub 2008 Feb 5. [abstract]
  8. Gilham C, Peto J, Simpson J, et al; Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case BMJ. 2005 Jun 4;330(7503):1294. Epub 2005 Apr 22. [abstract]
  9. Steliarova-Foucher E, Stiller C, Kaatsch P, et al; Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCISproject): an epidemiological study. Lancet. 2004 Dec 11-17;364(9451):2097-105. [abstract]
  10. US National Cancer Institute; SEER pediatric monograph on childhood leukemia; Detailed epidemiological evidence from USA on childhood leukaemias.
  11. Kroll ME, Draper GJ, Stiller CA, et al; Childhood leukemia incidence in Britain, 1974-2000: time trends and possible relation to influenza epidemics. J Natl Cancer Inst. 2006 Mar 15;98(6):417-20. [abstract]
  12. Ma X, Does MB, Metayer C, et al; Vaccination history and risk of childhood leukaemia. Int J Epidemiol. 2005 Oct;34(5):1100-9. Epub 2005 Jun 10. [abstract]
  13. Rabin KR, Whitlock JA; Malignancy in children with trisomy 21. Oncologist. 2009 Feb;14(2):164-73. Epub 2009 Jan 28. [abstract]
  14. Colby-Graham MF, Chordas C; The childhood leukemias. J Pediatr Nurs. 2003 Apr;18(2):87-95. [abstract]
  15. Rankin J, Silf KA, Pearce MS, et al; Congenital anomaly and childhood cancer: A population-based, record linkage study. Pediatr Blood Cancer. 2008 Jul 11;. [abstract]
  16. Milne E, Laurvick CL, Blair E, et al; Fetal growth and acute childhood leukemia: looking beyond birth weight. Am J Epidemiol. 2007 Jul 15;166(2):151-9. Epub 2007 Apr 18. [abstract]
  17. Lightfoot T; Aetiology of childhood leukemia. Bioelectromagnetics. 2005;Suppl 7:S5-S11. [abstract]
  18. Fear NT, Roman E, Ansell P, et al; Vitamin K and childhood cancer: a report from the United Kingdom Childhood Cancer Study. Br J Cancer. 2003 Oct 6;89(7):1228-31. [abstract]
  19. Feltbower RG, Lewis IJ, Picton S, et al; Diagnosing childhood cancer in primary care--a realistic expectation? Br J Cancer. 2004 May 17;90(10):1882-4. [abstract]
  20. Mitchell C, Hall G, Clarke RT Acute leukaemia in children: diagnosis and management, BMJ 2009;338:b2285; Clinical review article.
  21. Weinblatt M; Acute Myelocytic Leukaemia. eMedicine, July 2009
  22. D'Antonio J; Chronic myelogenous leukemia. Clin J Oncol Nurs. 2005 Oct;9(5):535-8. [abstract]
  23. Sasse EC, Sasse AD, Brandalise S, et al; Colony stimulating factors for prevention of myelosupressive therapy induced febrile neutropenia in children with acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004139. [abstract]
  24. SIGN; Guideline 76. Long-term follow up of survivors of childhood cancer.
  25. Goldsby RE, Liu Q, Nathan PC, et al; Late-Occurring Neurologic Sequelae in Adult Survivors of Childhood Acute J Clin Oncol. 2009 Nov 16. [abstract]
  26. Shah A, Stiller CA, Kenward MG, et al; Childhood leukaemia: long-term excess mortality and the proportion 'cured'. Br J Cancer. 2008 Jul 8;99(1):219-23. [abstract]
  27. Satake N, Sakamaoto A; Acute Lymphoblastic Leukaemia. eMedicine, August 2009.
  28. Pulsipher MA; Treatment of CML in pediatric patients: should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy? Pediatr Blood Cancer. 2004 Oct;43(5):523-33. [abstract]

Internet and further reading

Acknowledgements

EMIS is grateful to Dr Chloe Borton for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2009.
Document ID: 1277
Document Version: 22
Document Reference: bgp348
Last Updated: 9 Dec 2009
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