Approach

Acute lymphoblastic leukaemia (ALL) commonly presents rapidly and aggressively in adults. It may mimic many other conditions, which often creates diagnostic confusion.

A definitive diagnosis can be made from a bone marrow aspiration and trephine biopsy. Leukaemic lymphoblasts may circulate in the blood; if present in sufficient numbers, this may be used to defer bone marrow examination at presentation.

Clinical presentation and history

The appearance of constitutional symptoms (fever, night sweats, weight loss) or signs and symptoms of cytopenias is often the initial cause for seeking medical attention by patients with ALL. Most patients present within a few weeks of symptom onset.

Anaemia typically manifests as fatigue, dyspnoea, palpitations, and dizziness; thrombocytopenia presents with bleeding (e.g., epistaxis, heavy menstrual bleeding) and easy bruising; neutropenia presents as recurrent infections, which may cause fever.

Lymph node involvement is common in ALL. Enlarged lymph nodes can be an initial presenting sign.

Abdominal and bone pain may be present due to infiltration of leukaemic lymphoblasts in the spleen and bone marrow, respectively.[51]

Clinical features that are less common at presentation include eosinophilia, isolated renal failure, pulmonary nodules, bone marrow necrosis, pleural/pericardial effusion, superior vena cava obstruction, hypoglycaemia, joint pain, and skin nodules.[1][6]

Genetic factors associated with the development of ALL

Historical factors suggestive of ALL include history of malignancy, family history of ALL, genetic disorder (e.g., trisomy 21, Li-Fraumeni syndrome, neurofibromatosis, Klinefelter syndrome, Fanconi's anaemia, Shwachman-Diamond syndrome, Bloom syndrome, ataxia-telangiectasia), treatment with chemotherapy, radiation exposure, smoking, and viral infections (e.g., Epstein-Barr virus).[1]​​[2][12][13][14]​​​​​[15][16][21][22][23][52]

Physical examination

Findings may include pallor, ecchymoses, petechiae, lymphadenopathy, hepatosplenomegaly, mediastinal masses, abdominal masses, testicular enlargement (unilateral and painless), renal enlargement, and skin infiltrations (skin nodules).

Lymphadenopathy is classically generalised, and the enlarged nodes are painless and freely movable.[1][6]​ T-ALL more commonly causes mediastinal masses, whereas B-ALL more commonly causes abdominal masses. The findings of stridor, wheezing, pericardial effusion, and superior vena cava syndrome may be associated with mediastinal masses. Mature B-ALL (Burkitt's lymphoma/leukaemia) may initially present as a palpable large abdominal mass from a rapidly proliferating tumour.[34][53]

Testicular involvement occurs most commonly in children and adolescents with T-ALL.[54] Testicular examination should be carried out at diagnosis in all male patients. The testes can represent a sanctuary site that is relatively protected from the effects of systemic therapy via the blood-testis barrier.[54]

Neurological assessment

Required to exclude central nervous system (CNS) involvement, which is a major complication of ALL. CNS involvement occurs in approximately 5% to 7% of patients at diagnosis; incidence is highest in patients with T-ALL (8%) and mature B-ALL (Burkitt's lymphoma/leukaemia, 13%).[9][55][56]​​[57][58]

The meninges are the primary site of CNS disease.[59] Presenting features of CNS disease include mental status changes, focal neurological signs/deficits (e.g., diplopia, chin numbness), headache, papilloedema, nuchal rigidity, and meningismus.[3][7]​​[8]

Initial laboratory tests

Should include full blood count with differential, peripheral blood smear, comprehensive metabolic panel (serum electrolytes; serum uric acid; serum lactate dehydrogenase [LDH]; renal function tests; liver function tests), coagulation profile (prothrombin time, partial thromboplastin time, fibrinogen, and D-dimers), blood group and antibody screening (for transfusion support), and viral antibody testing (including hepatitis B and C, and HIV serologies).[60][61]

Laboratory findings

Over 90% of patients have clinically evident haematological abnormalities at the time of initial diagnosis.

Normocytic normochromic anaemia with low reticulocyte count is present in 80% of patients. Thrombocytopenia is very common, affecting 75% of patients.[1][6]​​ Leukocytosis is found in 50% of patients; in 25% of these patients, white blood cell (WBC) count is >50 × 10⁹/L (>50,000/microlitre). High WBC at presentation is associated with a poorer prognosis. Despite the elevation in WBC, many patients have severe neutropenia (absolute neutrophil count <0.5 × 10⁹/L [<500 cells/microlitre]), thus placing them at high risk for serious infections.[62] See Febrile neutropenia.

Leukaemic lymphoblasts may be detected on peripheral blood smear. The presence of leukaemic lymphoblasts ≥1 × 10⁹/L (≥1000/microlitre) in the peripheral blood is sufficient to defer bone marrow examination at presentation.[60]

Hypercalcaemia may occur due to bony infiltration or ectopic release of a parathyroid hormone-like substance.

Hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and elevated serum LDH may occur due to tumour lysis syndrome (TLS), particularly during treatment and if WBC count (tumour burden) is high. This can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. TLS is an oncological emergency. See Tumour lysis syndrome.

Evaluation of bone marrow

The diagnostic work-up for ALL requires haematopathology evaluation of bone marrow aspirate and trephine biopsy specimens (or peripheral blood if sufficient numbers of circulating lymphoblasts are present), which should include:[60][63]​​

  • Cytomorphology assessment

  • Immunophenotyping

  • Cytogenetic and molecular evaluation

These investigations can determine the subtype of ALL; inform risk stratification and treatment planning; and establish a baseline for measurable residual disease (MRD) assessment during treatment (see below).[60]

Cytomorphology assessment

A biopsy demonstrating bone marrow hypercellularity and infiltration by lymphoblasts is characteristic for ALL.

There is a lack of consensus regarding the proportion of lymphoblasts in the bone marrow that is required to make a diagnosis of ALL; however, a threshold of ≥20% is generally advised.[60] Note that defined lymphoblast threshold in the bone marrow (or peripheral blood) is not always required for the diagnosis of ALL (e.g., T-ALL can be diagnosed based on immunophenotyping). See Classification.

The proportion of lymphoblasts in the bone marrow can help distinguish between ALL and lymphoblastic lymphoma. See Differential diagnosis. 

Myeloperoxidase (MPO) cytochemical staining of biopsy specimens should be performed to help differentiate ALL from acute myeloid leukaemia (AML). MPO will be negative in ALL and positive in AML.[64] See Differential diagnosis.

Immunophenotypic findings

Immunophenotyping (on bone marrow specimens, or peripheral blood if sufficient numbers of circulating lymphoblasts are present) is required to assess cell markers to:[60]

  • determine lymphoid lineage (B-cell or T-cell);

  • define an aberrant phenotype for MRD assessment; and

  • detect cell surface antigens of clinical and therapeutic importance (e.g., CD20).

Leukaemic cells typically exhibit markers of one cell type. Rarely, simultaneous expression of lymphoid and myeloid markers occurs in ALL, either as ALL with aberrant expression of myeloid antigens (My+ ALL) or true biphenotypic acute leukaemia.

Cytogenetic and molecular evaluation

Cytogenetic analysis (e.g., karyotyping; fluorescence in situ hybridisation [FISH]) and molecular testing (e.g., reverse transcriptase polymerase chain reaction [RT-PCR]) of leukaemic lymphoblasts (on bone marrow or peripheral blood specimens) are required to detect recurrent genetic abnormalities (e.g., BCR::ABL1 [Philadelphia chromosome]; KMT2A rearrangements).[60][63]

Next-generation sequencing (NGS) assays can be used alongside cytogenetic analysis and RT-PCR testing to detect additional gene fusions/rearrangements (e.g., DUX4, MEF2D, ZNF384) and pathogenic mutations (e.g., SH2B3, IL7R, and JAK1/2/3 in Philadelphia chromosome-like B-ALL [Ph-like B-ALL]).[60][63]

Comprehensive cytogenetic and molecular characterisation of leukaemic lymphoblasts (alongside haematopathology evaluation of bone marrow) determines the subtype of ALL; informs risk stratification and treatment planning; and facilitates MRD assessment.[60][63]

[Figure caption and citation for the preceding image starts]: Lymphoblasts in bone marrow smear from 3-year-old male with ALL (Wright-Giemsa stain)Image and description are from the AFIP Atlas of Tumor Pathology [Citation ends].com.bmj.content.model.Caption@535ef180

Baseline measurable residual disease (MRD) testing

It is important to establish a baseline for MRD testing based on immunophenotypic and molecular features of the leukaemic lymphoblast.

MRD testing enables depth and speed of remission to be assessed during treatment. It is prognostically important and can guide therapeutic decisions. The method used for MRD testing depends on the patient, and the assays available to the treating centre.

The preferred sample for MRD testing is the first small volume (of up to 3 mL) pull of the bone marrow aspirate, if feasible.[60]

Lumbar puncture

A lumbar puncture is required in all patients given the frequency of CNS involvement. The procedure should only be performed once raised intracranial pressure has been ruled out.

Lumbar puncture should be carried out at a time consistent with the treatment protocol being used. Paediatric-inspired protocols typically include lumbar puncture at diagnostic work-up. However, the National Comprehensive Cancer Network ALL Panel recommends the first lumbar puncture be performed concomitantly with initial intrathecal therapy to avoid seeding the CNS with circulating leukaemic lymphoblasts, unless symptoms require a lumbar puncture to be performed earlier.[60]

Diagnostic lumbar puncture in adults: animated demonstration
Diagnostic lumbar puncture in adults: animated demonstration

How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.

Detection of lymphoblasts in the initial cerebrospinal fluid (CSF) sample by multi-parameter flow cytometry can identify patients at high risk of CNS relapse.[71][72]

CNS involvement at diagnosis can be graded based on the presence of lymphoblasts, WBCs, and red blood cells (RBCs) in the CSF, using the Children’s Oncology Group classification.[73][74]​​ Higher grade (i.e., increased lymphoblasts, WBCs, and RBCs [traumatic lumbar puncture] in the CSF) is associated with poorer outcomes. See Diagnostic criteria.

Imaging

Chest radiograph may be performed to identify a mediastinal mass, pleural effusion, or lower respiratory tract infection.[75]​ Pleural effusions should be tapped and samples sent for cytology and immunophenotyping. A mediastinal biopsy should be avoided if possible, though this may be the primary site of involvement for some patients and in such cases is unavoidable.

CNS imaging (e.g., computed tomography [CT]/magnetic resonance imaging [MRI] of head) should be performed in patients with major neurological signs and symptoms (e.g., lowered consciousness level, meningismus, or focal neurological signs/deficits) to identify meningeal involvement or CNS bleeding.[60] Spinal cord and parenchymal brain involvement may occur, but is very rare.

CT thorax should be performed in the presence of a widened mediastinum on chest radiograph. CT neck, thorax, abdomen, and pelvis should be performed if there is palpable lymphadenopathy or other evidence of extramedullary disease.[60]

In males with an abnormal testicular examination or symptoms, scrotal ultrasound should be performed to characterise the nature of the abnormality and to establish a baseline prior to treatment initiation.[60]

Echocardiogram or multigated acquisition (MUGA) scan should be considered in all patients to assess cardiac function before initiating treatment.[60] Anthracyclines are used in most treatment regimens for ALL and are potentially cardiotoxic.[Figure caption and citation for the preceding image starts]: Chest x-ray of patient presenting with dyspnoea, showing widened mediastinum and tracheal displacementFrom the personal collection of CR Kelsey [Citation ends].com.bmj.content.model.Caption@152dad83

Other investigations

The following tests may be carried out once a diagnosis of ALL is confirmed:[60][76]

  • Human leukocyte antigen (HLA)-typing

  • Thiopurine methyltransferase (TPMT) phenotyping

  • Nudix hydrolase 15 (NUDT15) phenotyping

HLA-typing is required to identify a suitable donor for stem cell transplantation and for obtaining HLA-matched platelets in the event of platelet alloimmunisation during platelet transfusion.

TPMT and NUDT15 phenotyping help to guide dosing of mercaptopurine during maintenance therapy.[76]

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