Acute leukaemia

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11.6 Acute leukaemia

1 At its most severe, acute leukaemia leads to diffuse bone marrow infiltration and failure. Pancytopenia including neutropenia, anaemia and thrombocytopenia as well as extramedullary hematopoiesis give rise to classical symptoms of infection susceptibility, easy fatigability, bleeding diathesis and hepatosplenomegaly.

2 ED supportive treatment in conjunction with a paediatric haematologist includes broad spectrum antimicrobial administration or sepsis resuscitation, packed red blood cell transfusion for symptomatic or critical anaemia and platelet replacement if the child has high potential or actual risk of thrombocytopenia-related bleeding.

Introduction

The leukaemias are a group of diseases characterised by the clonal proliferation of malignant immature white blood cell precursors. They differ in the lineage and degree of differentiation of cells involved, being broadly divided into two groups: lymphoid and myeloid. These two categories are further subdivided into an acute form that progresses more rapidly than the chronic disease, which is relatively indolent. Preconceptional germ cell and postnatal environmental exposure to electromagnetic radiation and carcinogens may play a role,¹^–³ with higher risk in children with congenital neutropenia, Down’s syndrome and Fanconi anaemia.⁴ Previous chemotherapy and radiotherapy are associated with increased risk of a secondary malignancy. Acute lymphoblastic leukaemia (ALL) comprises four-fifths of childhood leukaemia,⁴ with acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML) accounting for 15% and 2%.⁵ Together they account for one-third of all malignancies in children under 15 years old. Although children of all ages are affected, the peak incidence is between 2 and 6 years.

Classification

Leukaemogenesis represents clonal proliferation of white blood cells arrested at various stages of differentiation, lending itself to diagnostic and prognostic classification based on the cell line affected, degree of differentiation, immunophenotyping, cell receptor, cell antigen and chromosomal studies. Classification of leukaemia is complex, with the French–American–British (FAB) categories being useful for AML and immunotyping better suiting ALL.^4,⁵

Clinical presentation

Signs and symptoms in ALL and AML are similar and depend on the degree of marrow infiltration and extent of extramedullary involvement. The first symptoms are non-specific including lethargy, bone pain and loss of appetite. Classic findings in acute leukaemia include fever/infection, pallor/lethargy/easy fatigability and bruising/mucosal bleeding due to febrile neutropenia, anaemia and thrombocytopenia, respectively. Marrow infiltration leads to bone pain and extramedullary spread leads to painless adenopathy (including mediastinal), hepatomegaly, splenomegaly, skin or periorbital infiltrates and rash. Difficulty with diagnosis arises in differentiating early acute from chronic disease, when symptoms (night sweats, arthralgia, bone pain, constitutional symptoms) and signs (enlarged liver and spleen, lymphadenopathy) are variable and non-specific. Central nervous system (CNS) involvement occurs in 4% of children (cranial nerve palsy, cord compression) and testicular leukaemia in 10% of boys (painless enlarged testes). Hyperviscosity results in tissue infarction (CNS, pulmonary) and rarely priapism results from leucocyte sludging and cavernosal obstruction.

Differential diagnosis

Pancytopenia may result from acute leukaemia, aplastic anaemia, marrow infiltration by non-haematological malignancy and collagen-vascular disease. However, hepatosplenomegaly and adenopathy is unusual with the alternative diagnoses. Viral infections may lead to lymphadenopathy and hepatosplenomegaly accompanied by atypical lymphocytes rather than blast cells. Leukaemoid reactions with leucocyte counts >50 × 10⁹ L^–1 may rarely occur with acute infections and inflammatory disease such as rheumatoid arthritis. Marked lymphocytosis without leukaemic cells occurs in pertussis. Isolated thrombocytopenia in childhood may follow a viral infection or be associated with idiopathic or thrombotic thrombocytopenic purpura rather than leukaemia.

Investigations

Full blood count reveals anaemia and thrombocytopenia in 80% of cases. The majority of children have leucocyte counts below 20 × 10⁹ L^–1. Those with leucocyte counts up to 900 × 10⁹ L^–1 usually have extramedullary involvement with hepatosplenomegaly and lymphadenopathy. The neutrophil count is often depressed to below 1.0 × 10⁹ L^–1. Circulating blast cells are frequently present on blood film examination. Blood typing is necessary if red-cell transfusion is anticipated. A screen for atypical antibodies is warranted if there have previously been multiple occasions of blood product use. Cultures of blood and other potential infection sites are obtained prior to antimicrobial administration. Blood cultures may be positive in up to 25% of cases of newly diagnosed leukaemia. Tumour lysis syndrome due to massive cell death during treatment causes raised lactate dehydrogenase (LDH), liver enzymes, hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia and acute renal failure. Anterior mediastinal masses are visible on chest X-ray in 5–10% of cases and pneumonia may require exclusion. Bone-marrow aspiration and trephine (BMAT) is essential for specific diagnosis and prognostication, including complex tests such as immunophenotyping, cytogenetics, molecular studies and cell-cycle kinetics. AML is, rarely, complicated by a coagulopathy that progresses to disseminated intravascular coagulation, so that a coagulation profile and fibrinogen level may be helpful.

Prognosis

The cure rate for ALL is 80%,⁴ compared with only 30–50% for AML,⁵ depending on whether adverse prognostic factors are present. Poor-risk AML has a dismal outlook, with less than 20% achieving long-term remission. Adverse prognostic factors include age (ages <1, >10 years), certain chromosomal translocations (such as t(4;11) in infant ALL), a very high-presenting leucocyte count and poor response to first-course treatment. Although the cumulative risk of ALL relapse is 15–20%, the risk of developing second malignancies after successful treatment is low.^4,⁵

Management

Management requires close collaboration with a paediatric haematologist. Emergency department supportive treatment focuses on the sequelae of acute leukaemia: febrile neutropenia and sepsis (broad-spectrum antimicrobial agents), actual or potential bleeding from thrombocytopenia (platelet transfusion) and correction of acute or symptomatic anaemia, which are described elsewhere. Chemotherapy may give rise to bone-marrow suppression, similar to the sequelae of acute leukaemia. Children who relapse or do not achieve remission are candidates for bone-marrow transplantation. Barrier nursing, isolation, antimicrobial and antiviral chemoprophylaxis, vaccination and post-exposure administration of immunoglobulin (e.g. varicella zoster virus) and careful monitoring for early infective complications help prevent complications related to immunosuppression. Psychosocial support of the child and family is important.

Controversies and future directions

The future management of leukaemia will be influenced by new and improved risk stratified therapy to improve outcomes and minimise adverse effects. High-risk patients could be identified by molecular analysis, in vitro pharmacodynamic, pharmacogenetic, pharmacogenomic and drug resistance studies to receive more intensive and targeted therapy. ⁶^–⁹

The increasing use of severely myelotoxic chemotherapy and unrelated bone-marrow transplantation has improved prognosis in acute leukaemia but has given rise to complications related to marrow suppression.

Biological (e.g. monoclonal antibodies) rather than cytotoxic agents and agents with better specificity for leukaemic cells result in less ‘collateral damage’¹⁰ Gene therapy, although promising, remains experimental and clinically unproven.¹¹

1 Schutz J., Ahlbom A. Exposure to electromagnetic fields and the risk of childhood leukaemia: a review. Radiat Prot Dosimetry. 2008;132:202-211.

2 Infante-Rivard C. Chemical risk factors and childhood leukaemia: a review of recent studies. Radiat Prot Dosimetry. 2008;132:220-227.

3 Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer. 2006;6:193-230.

4 Smith O.P., Hann I.M. Clinical features and therapy of lymphoblastic leukemia. In: Arceci R.J., Hann I.M., Smith O.P., editors. Pediatric Hematology. 3rd ed. London: Blackwell Publishing Ltd; 2006:450-481.

5 Kean L.S., Arceci R.J., Woods W.G. Acute myeloid leukemia. In: Arceci R.J., Hann I.M., Smith O.P., editors. Pediatric Hematology. 3rd ed. London: Blackwell Publishing Ltd; 2006:360-383.

6 Zwaan C.M., Kaspers G.J.L. Possibilities for tailored and targeted therapy in paediatric acute myeloid leukaemia. Br J Haematol. 2004;127:264-279.

7 Aplenc R., Lange B. Pharmacogenetic determinants of outcome in acute lymphoblastic leukemia. Br J Haematol. 2004;125:421-434.

8 Harrison C.J. Cytogenetics of paediatric and adolescent acute lymphoblastic leukemia. Br J Haematol. 2009;144:147-156.

9 Pui C.H., Robison L.L., Look A.T. Acute lymphoblastic leukemia. Lancet. 2008;371:1030-1043.

10 Blair A., Goulden N.J., Libri N.A., et al. Immunotherapeutic strategies in acute lymphoblastic leukemia relapsing after stem cell transplantation. Blood Rev. 2005;19:289-300.

11 Brown P., Smith F.O. Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date. Paediatr Drugs. 2008;10:85-92.

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