See also separate Childhood Leukaemias article.
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.
- ALL is the most common cancer in children. Global incidence is about 3 per 100,000 population, with about 3 out of 4 cases occurring in children aged under 6 years.
- ALL represents 12% of all leukaemia (but 80% in children).
- Peak age of incidence occurs between the ages of 2-4 years, decreasing to become a much rarer disease of adulthood. A smaller peak occurs in people aged over 50 years.
Many different theories exist but few causal links have been firmly established. Interactions (eg, environment-genetic, environment-infection) are likely to be important and a sequence of 'hits' may be required for malignant transformation.
- ALL is concordant in 25% of monozygotic twins within a year of the diagnosis of the first twin.
- Among dizygotic twins, there is a four-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 (eg, Fanconi's anaemia, ataxia with 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.
- 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 ionising radiation may contribute to a proportion of UK childhood ALL cases.
- There is no evidence that non-ionising radiation such as proximity to power lines or mobile telephone masts is a risk factor for ALL in children.
- Other suggested environmental risk factors (eg, hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use) have been found to be weakly and inconsistently associated with ALL.
- Establishing environmental risk factors is difficult due to problems confirming and quantifying exposure, lack of a prospective cohort, confounding variables, etc.
- 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 daycare appear to have a decreased risk of developing ALL.
- Viral aetiologies have been shown for other cancers - eg, 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).
Patients with acute leukaemia typically deteriorate rapidly. Initial presentation is usually generalised fatigue and malaise but usually quickly progresses to bone marrow failure.
- 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.
- 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.
- Testicular enlargement.
- Gum hypertrophy.
- Leukaemia cutis.
- 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 the findings of investigations.
- Infections - eg, EBV, parvovirus B19.
- Myeloproliferative or lymphoproliferative disorders.
- Aplastic anaemia.
- Idiopathic thrombocytopenia.
- Metastatic cancer.
- Other cancers of childhood - eg, neuroblastoma, rhabdomyosarcoma.
- Juvenile idiopathic arthritis.
- 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.
- Leukaemia is unlikely in the presence of a normal FBC but the FBC will not always be abnormal in all cases of ALL, as some patients may not yet have marrow suppression.
- If the blood count is abnormal, a blood film is essential to help decide whether leukocytosis is likely to be caused by malignancy or inflammation.
- 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 - eg, blood cultures.
- CXR may show pneumonia, a mediastinal mass or lytic bone lesions.
- Testicular ultrasound if the testes are enlarged on examination.
- ECG, echocardiogram (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. Aspiration is the standard procedure with core biopsy only necessary if aspiration does not yield sufficient cells.
- 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. Several 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).
The French-American-British (FAB) classification has been modified by the WHO as follows:
- B-cell ALL:
- Early pre-B ALL (also called pro-B ALL) - about 10% of cases.
- Common ALL - about 50% of cases.
- Pre-B ALL - about 10% of cases.
- Mature B-cell ALL (Burkitt's leukemia) - about 4% of cases.
- T-cell ALL:
- Pre-T ALL - about 5-10% of cases.
- Mature T-cell ALL - about 15-20% of cases.
Except for those with mature B-cell 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.
Age-adapted protocols have been developed for adults with ALL. Although there is no uniform consensus, the following age groups are separated:
- Adolescents and young adults, defined as from 15/18 years to 35/40 years.
- Adult ALL, with age range from 35/40 up to 55/60 years,
- Elderly ALL protocols for patients above the age of >55/60 years.
- Frail patients not suitable for any intensive therapy, usually considered above the age of 70/75 years.
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 - eg, granulocyte-colony stimulating factor (GCSF) during induction has been associated with faster recovery of neutrophils and platelets and a shorter hospital stay.
- 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.
The goals of induction therapy are:
- To eliminate more than 99% of the initial burden of leukaemic cells.
- To restore rapidly normal haematopoiesis.
- To restore previous performance status.
When the diagnosis is established, treatment should start immediately. Pre-phase therapy with corticosteroids (usually prednisone or dexamethasone) alone, or in combination with another drug (eg, vincristine, cyclophosphamide), is often given together with allopurinol and hydration for 5-7 days.
Supportive therapy should be initiated whenever necessary - eg, to treat infections or to substitute platelets or erythrocytes. Severe neutropenia is often seen at diagnosis and is most frequent during induction therapy.
Most induction regimens are centred on vincristine, corticosteroids, and anthracycline (daunorubicin, doxorubicin, rubidazone, idarubicin), with or without cyclophosphamide or cytarabine. L-Asparaginase has been particularly explored in paediatric trials but is now more intensively used in adults. Pegylated asparaginase has the advantage of a significantly longer period of asparagine depletion. Dexamethasone is often preferred to prednisone because it penetrates the blood-brain barrier and also acts on resting leukaemic blast cells.
Current treatment regimes achieve complete remission rates of 80-90%, higher for standard-risk patients at over 90%, and less for high-risk patients at about 75%.
Once normal haematopoiesis is achieved, patients undergo maintenance therapy.
Maintenance therapy usually consists of daily 6-mercaptopurine and weekly methotrexate. In some treatment regimens, repeated cycles of vincristine, dexamethasone or other drugs in monthly or longer intervals are given. A treatment duration of 2.5-3 years is usually recommended.
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.
Effective prophylaxis to prevent CNS relapse is an essential part of ALL therapy. Treatment modalities are CNS irradiation, intrathecal methotrexate, intrathecal triple therapy (usually methotrexate, steroids, cytarabine) and systemic high-dose therapy with either methotrexate and/or cytarabine. With a combination of these CNS prophylactic measures, the CNS relapse rate in recent adult ALL trials could be reduced from 10% to less than 5%.
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. Allogeneic SCT from a sibling or suitable unrelated donors is the main approach for intensive post-induction therapy in patients at high risk of residual disease and relapse.
Treatment of relapse
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.
The most commonly used regimens in Europe are fludarabine- and anthracycline-containing regimens - eg FLAG-Ida (fludarabine, high-dose ara-C, GCSF and idarubicin).
New treatment strategies in development include the use of monoclonal antibodies against antigens found on leukaemic cells, cellular immunotherapy and molecular therapeutics.
Most complications that arise are iatrogenic, due to the toxicity of the therapies. Acutely:
- Key risks are haemorrhage, anaemia and infection, even with blood replacement therapy. Any fever in a neutropenic patient must be treated as a medical emergency.
- Hair loss, rashes.
- Nausea, vomiting, constipation, diarrhoea, mucositis.
- Electrolyte disturbances.
- Nephrotoxicity, hepatotoxicity.
- Peripheral neuropathy.
- Psychological disturbances.
- 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.
- Graft-versus-host disease with allograft SCT (can also occur as a chronic condition).
Longer-term complications include:
- Cardiomyopathy, arrhythmias.
- Lung fibrosis.
- Growth delay.
- Secondary malignancies.[23, 24]
- Psychosocial effects, impacts on education and occupation.[25, 26]
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.
The outcome of ALL is strictly related to the age of a patient, with cure rates from 80-90% in childhood ALL, decreasing to <10% in elderly/frail patients with ALL. Childhood ALL is one of the most curable cancers.
- ALL has a poor prognosis in adults because a higher proportion of adults have unfavourable cytogenetic abnormalities, such as the t(9;22) translocation. Many cases present in patients aged over 60 years, who are unlikely to tolerate intensive chemotherapy.
- Adverse prognostic indicators include age of presentation <12 months or ≥10 years, presenting leukocyte count ≥50 x 109/L, male sex, adverse cytogenetics and extramedullary (eg, CNS) involvement.
- Early response to chemotherapy seems to be an important positive prognostic indicator both in adults and in children.
- 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.
- Adolescents have a prognosis between that of children and adults but children under the age of 1 have a cure rate of only about 30%.
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.
Further reading and references
; Scottish Intercollegiate Guidelines Network - SIGN (Mar 2013)
; Cancer Research UK
; NICE Technology Appraisal Guidance, September 2016
; Leukaemia update. Part 1: diagnosis and management. BMJ. 2013 Mar 28346:f1660. doi: 10.1136/bmj.f1660.
; A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL). Eur J Cancer Care (Engl). 2005 Mar14(1):53
; The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003 Oct 198(7):1337
; The proportion of childhood leukaemia incidence in Great Britain that may be Leukemia. 2009 Apr23(4):770-6. Epub 2009 Jan 8.
; Public Health England
; Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007 Jan115(1):138
; An infectious aetiology for childhood acute leukaemia: a review of the evidence. Br J Haematol. 2004 Nov127(3):243
; Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case BMJ. 2005 Jun 4330(7503):1294. Epub 2005 Apr 22.
; DermIS (Dermatology Information System)
; NICE Clinical Guideline (2015 - last updated July 2017)
; Acute leukaemia in children: diagnosis and management, BMJ 2009338:b2285
; European Society for Medical Oncology (2016)
; National Cancer Institute
; Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12354(2):166
; Acute lymphoblastic leukaemia. Lancet. 2008 Mar 22371(9617):1030-43.
; Colony stimulating factors for prevention of myelosuppressive therapy induced febrile neutropenia in children with acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2005 Jul 20(3):CD004139.
; Central nervous system relapse in adults with acute lymphoblastic leukemia. Cancer. 2002 Feb 194(3):773
; Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL) an MRC UKALL12/ECOG 2993 study. Blood. 2007 Feb 1
; New therapeutic strategies in acute lymphoblastic leukemia. Semin Hematol. 2009 Jan46(1):76-88.
; Leukaemia update. Part 2: managing patients with leukaemia in the community. BMJ. 2013 Apr 9346:f1932. doi: 10.1136/bmj.f1932.
; Ischemic stroke in children treated for acute lymphoblastic leukemia: a retrospective study. J Pediatr Hematol Oncol. 2005 Mar27(3):153-7.
; Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr. 2007 Apr150(4):370
; Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007 Mar 21297(11):1207
; 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 198(21):1528-37.
; Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med. 2003 Aug 14349(7):640
; Behavioral and educational limitations after chemotherapy for childhood acute lymphoblastic leukemia or Wilms tumor. Cancer. 2006 May 1106(9):2067-75.
; Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005 Jun 15105(12):4752-8. Epub 2005 Feb 15.
; Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia. J Clin Oncol. 2005 Apr 123(10):2264-71.
; Does prolonged breastfeeding reduce the risk for childhood leukemia and lymphomas? Minerva Pediatr. 2008 Apr60(2):155-61.
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