Acute lymphoblastic leukaemia

See also the separate Childhood leukaemias article.

What is acute lymphoblastic leukaemia?

Acute lymphoblastic leukaemia (ALL) is a malignant transformation of a clone of cells from lymphoid progenitor cells. The majority of cases of acute lymphoblastic leukaemia 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. Acute lymphoblastic leukaemia can be distinguished from other malignancies of lymphoid tissue by the immunophenotype of the leukaemia cells. Cytochemistry and cytogenetic markers are also used to classify the malignant lymphoid clone.

Epidemiology¹

• 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.²

• There are about 790 new acute lymphoblastic leukaemia cases in the UK every year.

• Acute lymphoblastic leukaemia accounted for under 1% of all new cancer cases in the UK in 2016-2018.

• The peak age is 0-4, with males being more affected than females.

Many different theories exist but few causal links to acute lymphoblastic leukaemia 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.

Genetic factors³

• 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 acute lymphoblastic 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 acute lymphoblastic leukaemia.

Environmental factors

• Acute lymphoblastic 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.⁴

• 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.⁵

• 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.⁶

• Establishing environmental risk factors is difficult due to problems confirming and quantifying exposure, lack of a prospective cohort, confounding variables, etc.

Infection⁷

• 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.⁸

• 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).

Presentation

Patients with acute lymphoblastic leukaemia typically deteriorate rapidly. Initial presentation of acute lymphoblastic leukaemia is usually generalised fatigue and malaise but usually quickly progresses to bone marrow failure.²

Acute lymphoblastic leukaemia 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 cutis.⁹

• 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.¹⁰

Differential diagnosis

• Infections - eg, EBV, parvovirus B19.

• Myeloproliferative or lymphoproliferative disorders.

• Myelodysplasia.

• Aplastic anaemia.

• Idiopathic thrombocytopenia.

• Lymphoma.

• Metastatic cancer.

• Other cancers of childhood - eg, neuroblastoma, rhabdomyosarcoma.

• Osteomyelitis.

• Juvenile idiopathic arthritis.

Investigations¹¹

Blood tests

• 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.

  • 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.¹²

  • 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.²

• 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.

Radiology

• 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.¹³

• 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 acute lymphoblastic leukaemia, 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).

Classification¹⁴

The French-American-British (FAB) classification for acute lymphoblastic leukaemia 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.

Acute lymphoblastic leukaemia treatment and management¹³

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.

Remission induction¹³

The goals of induction therapy for acute lymphoblastic leukaemia 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, acute lymphoblastic leukaemia 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 clinical 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 for acute lymphoblastic leukaemia achieve complete remission rates of 80-90%, higher for standard-risk patients at over 90%, and less for high-risk patients at about 75%.

Maintenance¹³

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.

CNS prophylaxis¹⁵

The incorporation of CNS prophylaxis, consisting of cranial radiation and intrathecal chemotherapy, has led to effective control of CNS disease and reduced the incidence of CNS leukaemia from over 65% to less than 10%.

Unfortunately, whilst CNS prophylaxis has resulted in significant success, there is an associated risk of neurotoxicity. Cranial irradiation causes neurocognitive and neuroendocrine effects and with secondary CNS tumours.

Intrathecal chemotherapy is the mainstay of prophylaxis, using methotrexate, intrathecal triple therapy (usually methotrexate, steroids, cytarabine) and systemic high-dose therapy with either methotrexate and/or cytarabine.¹⁶

Stem cell transplantation (SCT)¹¹

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 relapse¹³

Relapse has a very poor prognosis in patients with acute lymphoblastic leukaemia. 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.¹⁷

A pioneering personalised T-cell (CAR-T) cell therapy for people under the age of 25 with relapsed or refractory B-cell acute lymphoblastic leukaemia (ALL) will be made available through the Cancer Drugs Fund following a recommendation by the National Institute for Health and Care Excellence (NICE).¹⁸

The therapy - known as Kymriah® and given as a single intravenous infusion - involves using a person's own immune cells and modifying them to fight the cancer. It has the potential to be a cure for those who have not responded to current treatment or have relapsed after stem cell transplant.

Complications²⁰

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

• Key risks with acute lymphoblastic leukaemia 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.²¹

• Graft-versus-host disease with allograft SCT (can also occur as a chronic condition).

Longer-term complications include:

• Cardiomyopathy, arrhythmias.

• Lung fibrosis.

• Growth delay.²²

• Hypothyroidism.

• Infertility.

• 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.²⁷

Acute lymphoblastic leukaemia prognosis¹³

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.²

• 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 . One study reported that the combination of blast count and platelet count during and after induction chemotherapy was a significant and independent prognostic factor for treatment outcome in paediatric ALL.

• 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.²⁸

• 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%.

Prevention

There are no widely accepted preventative strategies for ALL. Some studies have suggested that breastfeeding confers protection for childhood ALL but this remains controversial.²⁹