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Home > Professional Reference > Acute Lymphoblastic Leukaemia

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Acute Lymphoblastic Leukaemia

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.

See also separate article on Childhood Leukaemias.

Acute lymphoblastic leukaemia (ALL) is a malignant transformation of a clone of cells from lymphoid progenitor cells. The majority of cases are of B-cell origin, but it can also arise from T-cell precursors. Lymphoid precursors proliferate and replace the normal cells of the bone marrow and blasts spill into the peripheral circulation. It can be distinguished from other malignancies of lymphoid tissue by the immunophenotype of the cells. Cytochemistry and cytogenetic markers are also used to classify the malignant lymphoid clone.

Epidemiology

  • There are 550 new diagnoses of ALL per year in England, Scotland and Wales, with a standardised incidence rate of 1 per 100,000 general population per annum (based on data from 1983-1993).1
  • ALL represents 12% of all leukaemia (but 80% in children).2
  • It is the most common cancer in children.
  • Peak age of incidence occurs between 2-4 years old, decreasing to become a much rarer disease of adulthood. A smaller peak occurs in people aged over 50 years.

Aetiology

Many different theories exist but few causal links have been firmly established. Interactions (e.g. environment-genetic, environment-infection) are likely to be important and a sequence of 'hits' may be required for malignant transformation.

  • Genetic factors:3
    • ALL is concordant in 25% of monozygotic twins within a year of the diagnosis of the first twin.
    • Among dizygotic twins, there is a 4-fold increase in risk of leukaemia compared with the general population.
    • Patients with trisomy 21 have 10 to 20-fold risk of developing ALL compared with the general population, and other disorders with excessive chromosomal fragility are also associated with higher risks (e.g. Fanconi's anaemia, ataxia telangiectasia).
    • 60-70% of adults and about 80% of children have identifiable cytogenetic abnormalities at diagnosis.
    • Prenatal chromosomal translocations generate chimeric fusion genes (such as TEL-AML1) that appear to be important but insufficient disease initiators since they are found in many more neonatal cord blood samples (TEL-AML1 is found in 1% of newborn babies) than in children who eventually develop leukaemia.
  • Environmental factors:
    • Leukaemia in adults does appear to be related to high doses of radiation (based on studies following survivors of atomic bomb explosions, other exposures such as the Chernobyl accident and therapeutic radiotherapy) but the position with regard to low doses seems less clear. Naturally occurring, background low-level ionizing radiation may contribute to a proportion of UK childhood ALL cases. 4
    • There is no evidence that non-ionizing radiation is a risk factor for ALL in children and concern about proximity to power lines or mobile telephone masts is without supporting evidence.1
    • Other suggested environmental risk factors (e.g. hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use) have been found to be weakly and inconsistently associated with ALL.5
    • Establishing environmental risk factors is difficult due to problems confirming and quantifying exposure, lack of a prospective cohort, confounding variables, etc.
  • Infection:6
    • Insulation from common infections in early life may predispose children to abnormal immune responses when they encounter them later, placing them at higher risk of developing ALL. Babies who attend day care appear to have a decreased risk of developing ALL.7
    • Viral aetiologies have been shown for other cancers, e.g. Epstein-Barr virus (EBV) and Burkitt's lymphoma.
    • Some studies suggest a seasonal variation in birthdate of patients or diagnosis.
    • Excess of ALL in rural, potentially immunologically naive communities with 'outbreaks' triggered by influx of new population (Kinlen's population mixing theory).5

Presentation8

Usual presentation is with symptoms due to direct infiltration of organs, from the decreased production of normal marrow cells or systemic cytokine effects.

Symptoms

  • Fatigue, dizziness and palpitations
  • Severe and unusual bone and joint pain
  • Recurrent and severe infections (oral, throat, skin, perianal infections commonly)
  • Fever without obvious infection (but infection should be assumed)
  • Left upper quadrant fullness and early satiety due to splenomegaly (10-20%)
  • Dyspnoea (due to anaemia or large mediastinal mass in those with T-cell tumours)
  • Headache, irritability or altered mental status and neck stiffness (with central nervous system (CNS) involvement)
  • Haemorrhagic or thrombotic complications due to thrombocytopenia or disseminated intravascular coagulopathy (DIC) - for example, menorrhagia, frequent nosebleeds, spontaneous bruising

Signs

  • Pallor
  • Tachycardia and a flow murmur
  • Nonspecific signs of infection
  • Petechiae (due to thrombocytopenia), may progress into purpura or ecchymoses
  • Abdominal distention due to hepatomegaly and splenomegaly
  • Lymphadenopathy
  • Testicular enlargement
  • Gum hypertrophy
  • Leukaemia cutis9
  • Cranial nerve palsy (especially III, IV, VI and VIII) in mature-B cell ALL

Primary healthcare professionals need to be aware that haematological cancer can present with a variety of symptoms with a wide differential; they should be prepared to investigate accordingly and urgency of referral should reflect the severity of the symptoms and signs, and findings of investigations.10

Differential diagnosis

Investigations8

Blood tests

  • Full blood count (FBC):
    • Anaemia is usual and Hb may be below 5 g/L.
    • Thrombocytopenia is also usual, to varying degrees.
    • White blood cell (WBC) count may be high, normal or low but there is usually neutropenia.
    The FBC will not always be abnormal in all cases of ALL, as some patients may not yet have marrow suppression.11
  • Blood film is likely to show blast cells but can be normal if blast cells are confined to the bone marrow.
  • Clotting: DIC may occur and this produces an elevated prothrombin time, reduced fibrinogen level and the presence of fibrin degradation products.
  • Lactic dehydrogenase levels are usually raised and rapid cell turnover may raise uric acid.
  • Liver and renal function must be checked before initiating chemotherapy.
  • If fever is present, appropriate steps should be taken to identify and treat infection, e.g. blood cultures.

Radiology

  • CXR may show pneumonia, a mediastinal mass or lytic bone lesions.
  • Testicular ultrasound if testes enlarged on examination.
  • ECG, ECHO and/or multiple-gated acquisition (MUGA) scan prior to use of anthracyclines (due to cardiotoxicity).

Haematology, immunology and genetic tests

  • Bone marrow aspiration and biopsy - World Health Organization (WHO) classification requires 20% or greater amount of blasts in bone marrow and/or peripheral blood for the diagnosis of ALL.
  • Immunophenotyping helps to reveal the subtype. Positive confirmation of lymphoid rather than myeloid origin should be sought by flow cytometric demonstration of lymphoid antigens. Therapeutically, it is important to differentiate between T-cell, mature B-cell and B-cell precursor phenotypes.
  • Bone marrow samples should undergo cytogenetics. Hyperdiploidy is common. A number of balanced translocations have been identified in ALL including:
    • t(12;21) - this is the most common translocation in childhood ALL (30% of cases). It results in the TEL-AML fusion gene and is primarily associated with the common phenotype.
    • t(9;22): also known as the Philadelphia chromosome - this occurs in about 15-30% of patients (mostly adults) and is associated with a very poor prognosis.
    • t(4;11) - this translocation results in the MLL-AF4 fusion gene. It is associated with a poor prognosis.
    • t(1;19) - associated with pre-B ALL and results in the formation of the E2A-PBX fusion gene.
  • A negative myeloperoxidase stain helps to diagnose ALL although acute monocytic leukaemia also gives negative stain with myeloperoxidase.
  • Testing for bcr-abl (oncoprotein) by polymerase chain reaction (PCR) or cytogenetics may help identify those patients in whom ALL arose as the lymphoblastic phase of chronic myeloid leukaemia (CML).

Classification

The French-American-British (FAB) classification is:

  • L1 - small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm. This subtype represents 25 to 30% of adult cases and 85% of paediatric cases.
  • L2 - large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large. This is the most common subtype at 70% of adult cases but 14% of paediatric cases.
  • L3 - large and homogeneous cells with cytoplasmic vacuolisation that often overlies the nucleus as the most prominent feature. This is just 1 to 2% of adult cases.

The WHO has proposed that this classification be abandoned because the L1 and L2 morphologies do not predict immunophenotype, genetic abnormalities, clinical behaviour or prognosis. Instead, classification should be as either precursor B lymphoblastic leukaemia or as precursor T lymphoblastic leukaemia. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt's lymphoma/leukaemia.12

Management13,14

Except for those with mature-B ALL who receive short-term intensive chemotherapy, treatment for ALL typically consists of remission-induction, consolidation (or intensification) and maintenance (or continuation) therapies, CNS prophylaxis as well as management of relapse. Much work has gone into risk assessment and stratification, attempting to limit the most intensive treatment to those at the highest risk of relapse, to spare those at lower risk unnecessary harm from treatment side-effects.

General supportive treatment

  • Replacement therapy of blood cells may be required - pre-existing deficiency due to ALL can be profoundly aggravated by chemotherapy.
  • Growth factors may be used to alleviate profound myelosuppression, e.g. granulocyte-colony stimulating factor (GCSF) during induction was associated with faster recovery of neutrophils and platelets, and a shorter hospital stay.15
  • Antibiotics and antifungal agents may be required to treat opportunistic infection.
  • Allopurinol is often required during induction therapy to control uric acid levels.
  • A central venous catheter is usual, given the frequent requirements for venous access.

Remission induction

The goals of induction therapy are:

  1. To eliminate more than 99% of the initial burden of leukaemic cells.
  2. To restore rapidly normal haematopoiesis.
  3. To restore previous performance status.

Since the 1950s, improvements in chemotherapy and supportive care have resulted in complete remission rates of about 98% for children and 85% for adults. This is in contrast to mature B-cell ALL (an unusual variant, occurring in 5% of adult ALL) - with current conventional regimes, only 30-40% of these patients gain complete remission and few survive long-term. Minimal residual disease assessment using PCR-based strategies appear to be able to predict relapse, although they are not yet in routine clinical use.
Current induction treatment for children with high-risk ALL and virtually all adults consists of quadruple therapy, given over the course of four to six weeks:

  • Vincristine
  • Glucocorticoid (prednisone, prednisolone or dexamethasone)
  • Anthracycline
  • L-asparaginase

In children with standard-risk ALL, such intensive induction therapy may actually increase morbidity and mortality and they standardly receive triple therapy with either anthracycline or asparaginase.

Imatinib (a tyrosine kinase inhibitor) has also been used as a single agent or part of combination therapy to induce or consolidate remission. It has been useful in extending disease-free survival and improving quality of life, particularly in elderly patients with ALL, but its impact on cure rates remains unclear.16,17

Consolidation

Once normal haematopoiesis is achieved, patients undergo maintenance therapy. There is little consensus as to the best regimens and duration of treatment. Common regimens in childhood ALL include:

  • High-dose methotrexate with mercaptopurine
  • High-dose asparaginase over an extended period
  • Reinduction treatment (a repetition of the initial induction therapy in the first few months of remission).

Those with high-risk or very high-risk ALL may receive all of these treatments. Research is ongoing as to whether these approaches are effective and tolerable in adults.

Maintenance

Attempts to shorten duration of chemotherapy to 12 to 18 months have produced poor results in children and adults so, in most current trial work, patients are treated for two years or more. Maintenance usually consists of weekly methotrexate and daily mercaptopurine. Oral mercaptopurine should be given in the evening and not taken with milk or milk products.

CNS prophylaxis18,19

Patients with ALL frequently have meningeal leukaemia at the time of relapse (50-75% at one year in the absence of CNS prophylaxis) and a few have meningeal disease at diagnosis (<10%). Cranial irradiation causes acute and late complications (secondary cancers, neurocognitive deficits, endocrinopathy) so has largely been superseded by intrathecal (methotrexate, cytarabine, steroids) and high-dose systemic chemotherapy (methotrexate, cytarabine, L-asparaginase) except in patients at very high risk of relapse. It is possible to stratify risk and tailor treatment accordingly. CNS relapse risk factors include:

  • High-risk genetic factors
  • T-cell immunophenotype
  • Hyperleucocytosis
  • Presence of leukaemia cells in the cerebrospinal fluid

Stem cell transplantation (SCT)

SCT allows intensification of chemotherapies and radiotherapies as it replaces destroyed stem cells. It is difficult to compare it with intensive chemotherapy alone, as there are highly selective criteria to determine suitability for transplant and study numbers are typically small; however, SCT appears to benefit subgroups such as those with a Philadelphia chromosome or poor initial response to treatment.13 Haemopoietic stem cells are found in:

  • Bone marrow
  • Peripheral blood stream
  • Umbilical cord blood

Bone marrow transplants can be allogenic (sibling donor, HLA-matched) or autologous (own peripheral stem cells harvested and 'purged' of cancerous cells). However, in most studies, autologous transplants have been found to be inferior to allogenic ones. Sadly, HLA-matched relatives are only available to about 25% of patients, and the chance of HLA matching an unrelated donor is smaller and dependent on the size of volunteer donor registries. SCT may be offered as therapy following relapse or at first remission in younger patients with high-risk ALL.

Treatment of relapse20

Relapse has a very poor prognosis. Most patients are referred for trial 'salvage' therapies .
Factors predicting a good outcome after salvage therapy were:

  • Young age
  • Short duration of first remission

Prevention of recurrence is the best strategy for long-term survival in ALL.

New treatment strategies in development include the use of monoclonal antibodies against antigens found on leukaemic cells, cellular immunotherapy, and molecular therapeutics.21

Complications

Most complications that arise are iatrogenic, due to the toxicity of the therapies. Acutely:

  • Key risks are haemorrhage and infection, even with blood replacement therapy. Any fever in a neutropenic patient must be treated as a medical emergency.
  • Tumour lysis syndrome is a risk, especially in children. Uric acid, phosphate and potassium are raised and calcium is low. Treat with alkaline intravenous fluids to aid renal excretion of these products. Electrolyte status should be closely monitored.
  • Stroke from sinus venous thrombosis occurs in about 1 child in 200 but prognosis seems good.22
  • Failure of the leukaemia to respond to chemotherapy usually means that they do not respond to other chemotherapy.
  • Graft-versus-host disease with allograft STC (can also occur as a chronic condition).

Longer-term complications include:

  • Cardiomyopathy, arrhythmias
  • Lung fibrosis
  • Growth delay,23 hypothyroidism, infertility
  • Secondary malignancies24,25
  • Psychosocial effects, impacts on education and occupation26,27

Increasingly, clinical protocols are being developed to reduce side-effects without sacrificing survival benefits. Drugs with carcinogenic or major organ-damaging effects are being reduced in dose or avoided and pre-conditioning therapies investigated; for example, the use of iron-chelating agents to avoid anthracycline-induced cardiotoxicity. Pharmacogenetics is also being used to predict how patients will respond to treatment.28

Prognosis

Prognosis is very much better in children than in adults, the exception being infant ALL, which carries a much poorer prognosis.29 Patients can be divided into three groups on the basis of risk:

  1. Good prognosis involves:
    • No adverse cytogenetics
    • Under 30 years old
    • Total WBC count of less than 30 x 109/L
    • Complete remission obtained within four weeks
  2. Bad prognosis occurs with:
    • Adverse cytogenetics [(t9;22), (4;11)]
    • Over 60 years old
    • Precursor B-cells with WBC count over 100 x 109/L
    • Failure to achieve complete remission within four weeks
  3. Those who do not fit into either of those categories have intermediate prognosis.

A ten-year follow-up of adults found that nearly 80% achieved complete remission but the median duration of remission was 20 months with median survival of 21 months. Six years seemed to be the critical point to indicate cure and, at ten years, 25% appeared to be long-term survivors.30 Early response to chemotherapy seems to be an important positive prognostic indicator in both adults and children.31 An extensive review found that although children could obtain remission rates of up to 100%, disease-free survival at ten years was 63% for children and 25-35% for adults.2 Adolescents have a prognosis between that of children and adults but children under the age of one have a cure rate of only about 30%.

Prevention

There are no widely accepted preventative strategies for ALL. Some studies have suggested that breast-feeding confers protection for childhood ALL but this remains controversial.32,33

Document references

  1. Advisory Group on Non-Ionising Radiation (AGNIR) via HPA website.
  2. Redaelli A, Laskin BL, Stephens JM, et al; A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL). Eur J Cancer Care (Engl). 2005 Mar;14(1):53 [abstract]
  3. Faderl S, Jeha S, Kantarjian HM; The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003 Oct 1;98(7):1337 [abstract]
  4. Wakeford R, Kendall GM, Little MP; The proportion of childhood leukaemia incidence in Great Britain that may be Leukemia. 2009 Apr;23(4):770-6. Epub 2009 Jan 8. [abstract]
  5. Belson M, Kingsley B, Holmes A; Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007 Jan;115(1):138 [abstract]
  6. McNally RJ, Eden TO; An infectious aetiology for childhood acute leukaemia: a review of the evidence. Br J Haematol. 2004 Nov;127(3):243 [abstract]
  7. 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]
  8. Satake N, Sakamaoto A; Acute Lymphoblastic Leukaemia. eMedicine, August 2009.
  9. DermIS; Dermatology Information System - Leukaemia, specific skin lesions; Pictures of leukaemia cutis.
  10. Referral for suspected cancer, NICE Clinical Guideline (2005)
  11. Mitchell C, Hall G, Clarke RT Acute leukaemia in children: diagnosis and management, BMJ 2009;338:b2285; Clinical review article.
  12. WHO; Summary of classification of tumours of haematopoietic and lymphoid tissues
  13. Pui CH, Evans WE; Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166
  14. Pui CH, Robison LL, Look AT; Acute lymphoblastic leukaemia. Lancet. 2008 Mar 22;371(9617):1030-43. [abstract]
  15. 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]
  16. Brandwein JM, Gupta V, Wells RA, et al; Treatment of elderly patients with acute lymphoblastic leukemia Leuk Res. 2005 Dec;29(12):1381 [abstract]
  17. Ottmann OG, Wassmann B, Pfeifer H, et al; Imatinib compared with chemotherapy as front Cancer. 2007 May 15;109(10):2068 [abstract]
  18. Surapaneni UR, Cortes JE, Thomas D, et al; Central nervous system relapse in adults with acute lymphoblastic leukemia. Cancer. 2002 Feb 1;94(3):773 [abstract]
  19. Cortes J, O'Brien SM, Pierce S, et al; The value of high Blood. 1995 Sep 15;86(6):2091 [abstract]
  20. Fielding AK, Richards SM, Chopra R, et al; Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007 Feb 1;109(3):944-50. Epub 2006 Oct 10. [abstract]
  21. Jeha S; New therapeutic strategies in acute lymphoblastic leukemia. Semin Hematol. 2009 Jan;46(1):76-88. [abstract]
  22. Santoro N, Giordano P, Del Vecchio GC, et al; Ischemic stroke in children treated for acute lymphoblastic leukemia: a retrospective study. J Pediatr Hematol Oncol. 2005 Mar;27(3):153-7. [abstract]
  23. Chow EJ, Friedman DL, Yasui Y, et al; Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr. 2007 Apr;150(4):370 [abstract]
  24. Hijiya N, Hudson MM, Lensing S, et al; Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007 Mar 21;297(11):1207 [abstract]
  25. Neglia JP, Robison LL, Stovall M, et al; New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37. [abstract]
  26. Pui CH, Cheng C, Leung W, et al; Extended follow N Engl J Med. 2003 Aug 14;349(7):640 [abstract]
  27. Buizer AI, de Sonneville LM, van den Heuvel-Eibrink MM, et al; Behavioral and educational limitations after chemotherapy for childhood acute lymphoblastic leukemia or Wilms tumor. Cancer. 2006 May 1;106(9):2067-75. [abstract]
  28. Rocha JC, Cheng C, Liu W, et al; Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005 Jun 15;105(12):4752-8. Epub 2005 Feb 15. [abstract]
  29. Luciani M, Rana I, Pansini V, et al; Infant leukaemia: clinical, biological and therapeutic advances. Acta Paediatr Suppl. 2006 Jul;95(452):47 [abstract]
  30. Mandelli F, Annino L, Rotoli B; The GIMEMA ALL 0183 trial: analysis of 10-year follow-up. GIMEMA Cooperative Group, Italy. Br J Haematol. 1996 Mar;92(3):665-72. [abstract]
  31. Laughton SJ, Ashton LJ, Kwan E, et al; Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia. J Clin Oncol. 2005 Apr 1;23(10):2264-71. [abstract]
  32. Kwan ML, Buffler PA, Abrams B, et al; Breastfeeding and the risk of childhood leukemia: a meta-analysis. Public Health Rep. 2004 Nov-Dec;119(6):521-35. [abstract]
  33. Bener A, Hoffmann GF, Afify Z, et al; Does prolonged breastfeeding reduce the risk for childhood leukemia and Minerva Pediatr. 2008 Apr;60(2):155-61. [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: 1758
Document Version: 22
Document Reference: bgp1043
Last Updated: 9 Dec 2009
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