The first-line investigation is usually a full blood count with differential to identify haematological abnormalities. Diagnosis relies on the identification of abnormal morphology and confirming these abnormal cells are of lymphoid lineage while excluding the possibility of myeloid lineage. Management involves pre-phase stabilisation, followed by a risk-based chemotherapy regime.
The most widely accepted classification system of ALL is the WHO classification, that was revised in 2016. ALL is broadly categorised into
- B cell lineage (85% of cases)
- T cell lineage (10-15% cases)
- Rare cases of NK cell lineage (<1% of cases)
The WHO classification system uses recurrent, non-random cytogenetic and molecular abnormalities that contribute to a predictable pattern of disease progression to sub-categorise B-ALL. Although these cytogenetic and molecular features have no influence on diagnosis, placing each case of B-ALL into its different sub-category is required to predict prognosis and allow for risk-stratification which will influence therapy options. Any cases that do not fit into one of these categories is termed ALL not otherwise specified (NOS). Examples of the B-ALL WHO classification categories include but are not limited to B-ALL with
- Philadelphia chromosome (Ph+)
- Hyperdiploid B-ALL/LBL
- Hypodiploid B-ALL/LBL
- T(v;11q23.3); KMT2A-rearranged
The cytogenetic and molecular patterns among T-ALL and ALL of NK cell lineage are not as well defined, therefore WHO classification does not have any sub-categories for them.
- The basis of this association is founded on an increased risk of developing ALL among monozygotic twins and those with chromosomal abnormalities, including trisomy 21, Klinefelter's syndrome and other inherited conditions with genetic instability, including Fanconi anaemia.
- Viral exposure
- Environment: including smoking or radiation exposure.
- This bone marrow failure contributes to the clinical manifestations of this disease.
- For example, the inability to produce mature, functional lymphocytes or any other WBC's leaves individuals at increased risk of infection.
- Lymphoblast infiltration of other organs leads to clinical features of organomegaly.
- Organomegaly - hepatomegaly (64%) or splenomegaly (61%) can present with symptoms of anorexia, weight loss, abdominal pain or distension.
- Fever (50%) can be either;
- A persistent, recurrent or refractory fever that is most likely a constitutional symptom and may present alongside a history of night sweats, weight loss.
- A response to an infection that is complicating a dysfunctional immune system.
- Lymphadenopathy (50%) - most likely presents with a persistent or progressive, painless, firm, rubbery lymph node.
- Haematological discrepancies
- Musculoskeletal pain (43%)
- Bone pain, which may present with a limp or refusal to weight bear).
- Unusual joint pains are also reported.
Less common clinical presentations include;
- Headache (<5%) - is indicative of central nervous system (CNS) involvement. The presence of other clinical features of raised intracranial pressure, including nausea, vomiting, irritability, meningism or any focal neurological deficits, would help support this diagnosis.
- Testicular enlargement (<1%) - an uncommon presentation among those being first diagnosed, but more likely among males with relapsing ALL (10%)
- Mediastinal mass (associated with the less common ALL of T-cell lineage)
- Mediastinal enlargement can present with superior vena cava compression, which can present with dysphagia, breathlessness, pain, swelling of face and upper limbs.
- Platelets: thrombocytopaenia (75% at diagnosis)
- Hb: anaemia (50% at presentation)
- WBC: can be either low (50%), high (20%) or sometimes normal if the bone marrow is not yet suppressed. A differential count usually reveals neutropaenia.
- Low WBC count indicates that although there are lymphoblasts present they have not achieved sufficient differentiation to be recognised as WBC.
- High WBC count indicates they have properties similar enough to a mature WBC to be counted.
The following investigations are required in any case presenting with suspected ALL to identify any potential complications that need immediate attention;
- Infection screen - screening for any active infections in the presence of a fever, alongside empirical antibiotic administration.
- Coagulation profile - to assess for any clotting derangements.
- Urea, electrolytes, lactate dehydrogenase, uric acid - to identify any metabolic abnormalities or tumour lysis syndrome.
The diagnosis of ALL requires examination of cell morphology and immunophenotyping. Cytogenetics is not required for a diagnosis but it is instrumental in predicting disease progression, prognosis, and determining treatment options. These investigations should be carried out on a;
- Peripheral blood smear, to examine circulating lymphoblasts (always required in the presence of an abnormal FBC result)
- Bone marrow aspiration (a biopsy is only needed if there are insufficient cells to examine from the aspiration)
- Any other samples that could have lymphoblasts present;
- Lymph node biopsy - ultrasound-guided biopsy is an early investigation in cases where lymphadenopathy is a presenting feature but may not be required in other cases. An excisional or needle biopsy is preferred to a fine needle aspiration, as it allows for a more accurate examination of morphology, making it easier to identify any abnormal cells.
- Cerebrospinal fluid - regardless of symptoms or signs of CNS involvement all children diagnosed with ALL have a lumbar puncture performed to evaluate for CNS involvement, given its association with negative prognosis, and receive prophylactic intrathecal chemotherapy.
- Examination of samples may identify WBC's with characteristic features of lymphoblasts. However, these may be morphologically indistinguishable from cells of another differential diagnosis, so further analysis of these abnormal cells is required.
- Findings on a peripheral smear may be normal if leukaemia is still confined to the bone marrow at the time of presentation.
- The most commonly accepted threshold for diagnosis is when lymphoblasts occupy >20% of bone marrow.
Immunophenotyping (using cytochemistry and flow cytometry with immunohistochemistry);
- By looking for the presence of common lymphoid antigens and features, and the absence of any myeloid properties, confirming the immunophenotype of any cells with abnormal morphology helps confirm the diagnosis.
- Through analysis of the surface antigens, this also determines whether the lymphoblasts are of B or T cell lineage.
Cytogenetic and molecular analysis
- This is not required for diagnosis but is required to categorise ALL according to the WHO classification.
- Identification of cytogenetic features involves chromosomal banding techniques and fluorescence in situ hybridisation (FISH) while various molecule techniques are required for characteristic molecular features.
- Burkitt's lymphoma: this can present with a rapidly expanding mass, with significant overlap of other clinical features and morphology. It can be differentiated from ALL through histology with the characteristic 'starry sky' appearance of highly proliferative cells with basophilic cytoplasm. Confirmation of Burkitt's lymphoma involves identification of a mature germinal centre immunophenotype and cytogenetic features specific to Burkitt lymphoma cells.
- Acute myeloid leukaemia (AML): is clinically and morphologically indistinguishable from ALL, with the only slight difference being that ALL has a predisposition for testicular, and CNS involvement, whereas AML has a predisposition to involve skin and gums or other mucous membranes. Cytochemistry and immunophenotyping of blood or bone marrow samples can confirm AML through the presence of myeloid features and antigens and absence of any lymphoid antigens.
- Aplastic anaemia: can clinically resemble the manifestations of panocytopaenia from ALL. It is distinguished from ALL by hypocellular bone marrow and the absence of any blast cells.
- Immune thrombocytopaenia (ITP): can present similarly to ALL with unusual bruising/bleeding. ITP is usually always in an otherwise well, healthy child compared to ALL which is always associated with another clinical sign. Isolated low platelet count with otherwise normal full blood count, an absence of any blasts, and normal cellular architecture on bone marrow sample, is normal for ITP.
- Reactive lymphocytosis to a range of infectious diseases can present with non-specific features similar to ALL. They can all be differentiated by positive serology, viral tests, or cultures, and normal haematopoiesis on bone marrow examination. Examples include;
- Treating any infection, metabolic complication and if indicated giving a transfusion to stabilise the patient.
- Following diagnosis, initial management also known as pre-phase therapy is started for roughly 5-7 days;
- Corticosteroids with or without another drug
- CNS prophylaxis is given intrathecally
- All cases should have a baseline evaluation of renal and liver function tests and a baseline cardiac evaluation with echocardiography (prior to anthracycline administration which has a potential cardiac toxic effect).
Each patient treatment follows a risk-based therapy regimen. The types of chemotherapy agents used are tailored according to the immunophenotype and cytogenetic features of their disease. Although regimes differ in intensity and chemotherapeutic agents used, they are all based on the following phases;
- Induction: with the goal to eradicate the presence of leukaemic cells to <5% of blasts and to restore normal haematopoiesis.
- Evaluation for complete remission or good response to induction is assessed within 6-16 weeks of starting and can be a good predictor of prognosis.
- Consolidation: the goal is to prevent the growth of leukaemia from any residual cells (known as a minimal residual disease (MRD)) and to prevent the development of drug resistance, by using numerous agents with multiple mechanisms of action.
- MRD is evaluated regularly to assess the response to treatment.
- For those with complete remission, consolidation is straight forward.
- For those who don't achieve a complete remission following induction, termed high-risk cases, ESMO guidelines advise allogeneic haematopoietic cell transplantation leads to better outcomes.
- Maintenance: this involves less intense more chemotherapeutic agents and aims to prevent relapse. A commonly used regime includes daily 6-mercaptopurine and weekly methotrexate.
Long-term monitoring for relapse or any adverse effects of chemotherapy and catching up on missed vaccinations once finished chemotherapy are all important aspects of long-term management.
- Panocytopaenia - this can be due to either bone marrow suppression from the disease or the bone marrow suppressive effect of therapy.
- This can manifest clinically as thrombocytopaenia (unusual bleeding or bruising), anaemia (fatigue, pallor, syncope or dyspnoea) and/or neutropaenia (recurrent infections or fever).
- Febrile neutropaenia is treated as a medical emergency. Priorities include a thorough assessment with blood cultures and treated empirically with broad-spectrum antibiotic therapy.
- Regular assessment of FBC with a differential count will help to identify low levels of any lineage of a cell. When indicated these can be corrected with red blood cell or platelet transfusions, and it usually considered appropriate to give prophylactic antibiotics in the event of a severe neutropaenia.
- This occurs when very high numbers of lymphoblasts (>100 x 10^9/L) are circulating peripherally, which leads to impaired circulation, and perfusion of some organs. Most commonly the lungs, brain and eyes are affected.
- In severe cases, leukapheresis may be required to remove the high number of circulating cells.
- Tumour lysis syndrome - as lymphoblasts lyse and release their contents, leading to deranged metabolic abnormalities (hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcemia). This is very common following induction therapy, particularly among haematological malignancies given their high number of tumour cells and fast rate of replication. Treatment involves rapid rehydration with IV fluids, allopurinol and close monitoring.
- GI toxicity - the extent of toxicity following chemotherapy varies between individuals, leading to a spectrum of disrupted GI symptoms. These include nausea, mucositis, diarrhoea, constipation or abdominal pain.
- Corticosteroid-related avascular necrosis
- L-asparaginase-related coagulopathy - L-asparaginase is a chemotherapeutic agent which is becoming more widely used. The mechanism of coagulopathy and thrombosis is due to fibrinogen and anti-thrombin 3 depletion.
- Anthracycline-related cardiotoxicity
Risk factors associated with a worse prognosis include;
- Older age
- Higher WBC at presentation
- Adverse cytogenetic features eg. t (9;22), low hypodiploid
- Failure to achieve early complete remission
- Speed of response
- The extent of minimal residual disease (MRD)
- MRD is an evaluation looking at the number of residual cells that persist following therapy, it is evaluated regularly and helps to risk stratify each case.