Leukaemia in the Emergency Department

Author: John Wilson, David Quinn / Editor: Frances Balmer / Codes: HAP21, HAP7, PAP4, HC5, SLO1 / Published: 14/02/2022

Context

Leukaemia is a rare disorder with 7,933 new diagnoses in England in 20181. Despite this, leukaemia often presents acutely and often via the emergency department. The Routes to Diagnosis Project, showed that of 2,197 new presentations of acute myeloid leukaemia in 2006, 54% presented via the emergency department2.

Learning bite: The majority of patients with acute leukaemia will first present to the emergency department.

Definition

The World Health Organisation (WHO) classification system organises haematological malignancies by the cell lineage and the maturity of the diseased cell3:

  • Myeloid lineage – neutrophils, eosinophils, basophils, monocytes and platelets
  • Lymphoid lineage – B-lymphocytes, T-lymphocytes and NK-cells

Leukaemia is further split into acute and chronic subtypes:

  • Acute leukaemias are characterised by problems with cell maturation, causing death within weeks or months if untreated4. This is felt to reflect a defect originating close to the haematopoietic stem cell5.
  • Chronic leukaemias are characterised by problems with proliferation, but cells retain the ability to mature, causing death within months to years if untreated4.

Leukaemia refers to the presence of malignant cells in the peripheral blood. Lymphoma refers to the malignant proliferation of lymphocytes; which can present with lymphadenopathy or with diseased cells within the blood (i.e. a leukaemia)6. There is therefore considerable overlap between leukaemia and lymphoma, with some specific diseases clinically overlapping between the two. 

This learning session will focus primarily on Acute Myeloid Leukaemia (AML) and Acute Lymphoblastic Leukaemia (ALL). These diseases, or complications related to their treatment, are the most likely to present to an emergency department. Within the context of emergency department management, they are virtually indistinguishable, and will be referred to jointly as acute leukaemia.

Learning bite: Acute leukaemia can cause death within weeks if not recognised and treated.

Normal haematopoiesis occurs within bone marrow; in adults almost exclusively within the pelvis7. All cells derive from the pluripotent haematopoietic stem cell and the first step is to transform into either a lymphoid or myeloid stem cell. From this point, there is stepwise maturation until the development of mature cells such as neutrophils or monocytes7.

This diagram shows the stepwise maturation of normal blood cells. In acute leukaemias, there are errors at an early stage in this process which proliferate. In chronic leukaemias, there is large-scale proliferation of more mature cells.

A. Rad and M. Häggström. CC-BY-SA 3.0 license

Acute leukaemia is caused by the uncontrolled proliferation of immature leukocytes, leading to high numbers of circulating blast cells (immature white cells).

Cells proliferate by mitosis. Mitosis is regulated by multiple proteins which arrest proliferation in the presence of defective DNA8. Dysfunction of these regulatory proteins, due to a genetic mutation, leads to uncontrolled proliferation and malignancy. Mutations are ordinarily acquired, but can also be inherited causing specific familial syndromes8.

Mutations occur via large-scale changes to the underlying DNA (such as chromosomal translocations or chromosomal deletions) or small-scale changes such as point mutations8. A well-known mutation is the Philadelphia Chromosome; a translocation between chromosomes 9 and 22 leads to an abnormal tyrosine kinase (BCR-ABL1) which leads to uncontrolled cellular proliferation8. Identifying specific mutations can have both diagnostic and prognostic significance in acute leukaemia.

The reason mutations occur is poorly understood, however known risk factors include:8

  1. Previous haematological disorder – such as myelodysplastic syndrome, myelofibrosis, chronic myeloid leukaemia
  2. Inherited conditions involving defects in normal DNA function – such as Fanconi anaemia, dyskeratosis congenita, ataxia telangiectasia
  3. Inherited conditions involving defects in haematopoiesis – Down’s Syndrome
  4. Acquired damage to DNA – older age, prior history of chemotherapy or radiotherapy

Learning bite: The clinical presentation of leukaemia is primarily due to the replacement of normal functioning bone marrow tissue with diseased leukaemic cells, and the subsequent failure in the production of normal blood cells4.

Acute leukaemia has a variable presentation. Usually, patients present acutely unwell to the emergency department due to symptoms or complications of the disease4. Occasionally, leukaemia is identified after investigations into isolated cytopaenias found incidentally in an asymptomatic patient.

Symptoms are caused by problems in the development of blood cells:

  1. Symptoms of anaemia – fatigue, malaise, shortness of breath, dizziness, syncope
  2. Symptoms of thrombocytopaenia – easy bruising, petechiae, mucosal bleeding
  3. Symptoms of dysfunctional or absent white blood cells – fever, infections and sepsis. Many patients have had recurrent or unusually severe infections in the build up to the diagnosis.
  4. Symptoms related to a very high white blood cell count9

    Leukostasis is a hyperviscosity syndrome caused by high numbers of circulating blasts. This can result in headache, stroke, visual disturbances and respiratory failure9.

    Tumour lysis syndrome results from the rapid turnover of malignant cells. The hallmark features are renal failure, hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia.

Patients may also report symptoms due to leukaemic cells infiltrating body tissues:

  1. CNS symptoms (more likely in ALL than AML) – headache, aseptic meningitis, cranial nerve palsy
  2. Skin disease – leukaemia cutis10
  3. Gingival hypertrophy
  4. Bone and joint pain – more common in paediatrics and includes cases without cytopaenias11-12
  5. Mediastinal invasion – superior vena cava obstruction
  6. Scrotal invasion – testicular swelling

Learning bite: Acute leukaemia can present in a myriad of ways. Have a low threshold to investigate further.

Initial investigations in the emergency department

Full blood count (FBC)

The suspicion of acute leukaemia will usually be raised by the FBC. Acute leukaemia normally causes leucocytosis, although a leucopaenic or pancytopaenic picture can be seen.

A haematological disorder is more likely if there are abnormal counts in at least two cell lines (e.g. anaemia with thrombocytopaenia), known as bicytopaenia. 

Blood film

If leukaemia is suspected, a blood film should be requested as the first-line investigation (although commonly this will already have been requested within the laboratory).

Acute leukaemia is characterised by the appearance of “blasts” (immature white blood cells) on the blood film. A diagnosis of acute leukaemia is made if blasts account for over 20% of the total white cell count in either peripheral blood or bone marrow3.

Occasionally, very few or no blasts will be seen within the peripheral blood; this does not rule out the presence of an underlying leukaemia within the bone marrow. A haematology referral can be made to consider a bone marrow test to investigate further.


Ed Uthman from Houston, TX, USA, CC BY 2.0 via Wikimedia Commons.

This image shows the typical appearance of a blast on a peripheral blood film.

Further investigations for leukaemia

If acute leukaemia is suspected, a variety of further investigations are required. Some of these may be initiated in the emergency department, although generally they will be the responsibility of the haematologist taking over the patient’s care. These include:

Tests for alternative (non-malignant) causes of cytopaenia

These include B12/folate, HIV, parvovirus B19 and immunoglobulins. The history may suggest other specific tests, for example for liver disease, autoimmune conditions or inherited haematological disorders.

Bone marrow tests

Aspirate (liquid bone marrow) and trephine (a core biopsy of bone) samples are taken from the pelvis by the haematologist under local anaesthesia.

This confirms the specific diagnosis and allows for prognostication and identification of specific targets for novel treatments.

Lumbar puncture

Patients with ALL will need a lumbar puncture to exclude central nervous system involvement, regardless of clinical symptoms. This will be performed by the haematologist.

Other investigations that may be required in the emergency department

Other investigations may be required in the ED around the time of initial diagnosis, either to exclude other diagnose(s) or to aid initial stabilisation.

Coagulation screen

DIC is frequently encountered at diagnosis so all patients should have a coagulation screen. DIC is suggested by a low fibrinogen, high D-dimer, deranged APTT/PT and low platelet count.

Blood cultures and markers of infection (CRP)

The white cell count may be high in leukaemia, but cells are not functional against infection. All patients with acute leukaemia must be assumed to be immunosuppressed. Fever and other signs of infection should be treated seriously. Blood cultures and a CRP should be sent and there should be a low threshold for starting broad-spectrum intravenous antibiotics.

U&Es, Bone profile, Uric acid

Tumour lysis syndrome may be suspected if there is a very high white cell count.  The hallmark features of tumour lysis syndrome are renal failure, hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia.

Learning bite: All patients with suspected acute leukaemia should have a full blood count, blood film and coagulation screen including fibrinogen in the emergency department. Consider initial tests for infection and tumour lysis syndrome depending on the presentation.

It is unlikely that specific management of a leukaemia will be required in the emergency department. Most patients undergoing initial treatment for acute leukaemia will be managed as inpatients, so acute complications of induction chemotherapy are unlikely to present to the emergency department.

However, emergency physicians are best placed to recognise and initiate treatment for the complications of newly presenting or known acute leukaemia, including sepsis, venous thromboembolism, DIC, leukostasis, tumour lysis syndrome and superior vena cava obstruction, whilst liaising with the haematology team.

Learning bite: Patients with acute leukaemia are immunocompromised. Have a low threshold for starting broad-spectrum intravenous antibiotics while awaiting results.

Sepsis

Sepsis may be the presenting complaint in a patient with undiagnosed leukaemia. Fever or another symptom of infection are also the commonest reason for a patient with known leukaemia to present to emergency services. Leukaemia patients are immunosuppressed, even if they have a normal neutrophil count.

Patients with an infection should be started on broad spectrum intravenous antibiotics and discussed with haematology.

Some specific factors to bear in mind when treating infections in known leukaemia patients include:

  1. Resistant organisms. Patients have often had multiple previous antibiotics and may be colonised with resistant bacteria, influencing empirical antibiotic choice13. Check microbiological records and consider discussion with a microbiologist.
  2. Indwelling lines. The possibility of line infection should be considered in all patients with a line. The stereotypical history of fever after line use is not always present. The addition of a specific gram-positive antibiotic (such as vancomycin or teicoplanin) can be considered, in addition to broad spectrum therapy13. If the patient is unwell consider emergency line removal, after discussion with the haematologist.
  3. G-CSF. In the context of acute myeloid leukaemia, G-CSF is theorised to drive the underlying malignant clone and therefore is generally not used.

Venous Thromboembolism (VTE)

Patients with acute leukaemia are at high-risk of VTE. Thrombocytopaenia does not protect against VTE but does make treatment more challenging. The co-existence of indwelling catheters, DIC, reduced pharmacological VTE prophylaxis due to thrombocytopaenia, and occasionally chemotherapy drugs themselves, add to the risk of VTE formation.

If possible, radiological proof should be attained prior to treatment, and this may necessitate out of hours scanning. Patients with leukaemia and VTE can be anticoagulated if their platelet count is > 50 x 109/L. If platelets are  <50 x 109/L then discussion should be had with haematology about whether platelet transfusion is indicated to facilitate anticoagulation14

Tumour lysis syndrome

Initial management is with supportive care (such as medical management of hyperkalaemia and attention to hydration), and sometimes emergency renal replacement therapy will be needed. There are specific treatments for this condition which may be recommended by haematology.

Acute promyelocytic leukaemia (APML)

APML is a specific form of acute leukaemia characterised by severe coagulopathy which can rapidly lead to death through haemorrhage. The provisional diagnosis can be made based on the appearance of the blasts on the blood film. If suspected, specific APML therapy will be given immediately, even overnight. For this reason, all patients newly presenting with suspected leukaemia in the ED require a coagulation screen and discussion with haematology urgently, in order to catch the few who have this specific form of the disease.

Leukostasis

Patients with very high white counts (>75-100 x 109/L) should be assessed for symptoms of leukostasis. This is a hyperviscosity syndrome which may present with a myriad of symptoms such as respiratory symptoms (perhaps mimicking pulmonary embolism) and neurological/visual symptoms (perhaps mimicking stroke), and more rarely myocardial ischaemia, bowel ischaemia, ischaemic limb, or acute kidney injury. Emergency treatments for those with very high counts and/or clinical symptoms include chemotherapy and leukopharesis (removal of white cells from blood).

Anaemia

Symptomatic anaemia is common both at initial diagnosis and, later on, as a complication of chemotherapy (due to bone marrow suppression). Particularly where the diagnosis of leukaemia is yet to be formally made, consider whether haematinic deficiency may be the cause of the patient’s presentation, as an alternative diagnosis to leukaemia.

If severely symptomatic, then red cell transfusion should be considered. At presentation, this can be managed in the normal way. Later down the line, once patients have received treatments such as chemotherapy and bone marrow transplant, irradiated blood may be required15 – if in doubt it is safer to be cautious and use such products, but if time allows then advice could be sought from a haematologist. CMV negative blood is never required for these patients16.

  • The clinical symptoms of leukaemia overlap with a myriad of other conditions. Often the picture seen in the emergency department is of bi- or pan-cytopaenia with non-specific symptoms such as fever, malaise, bruising and lethargy. It is important to consider leukaemia in these patients, but also remember there are a number of more likely causes (such as B12 deficiency).
  • Ruling out acute leukaemia by a blood film. Leukaemia cannot be ruled out by an absence of blasts on the blood film. If in doubt, discussion with haematology is advised.
  • Attributing fever to leukaemia rather than infection. Leukaemia as a primary cause of fever is rare, and the consequences of not treating infection are disastrous. In all leukaemia patients, fever should be presumed due to infection and treated as such until proven otherwise.
  • Assuming that a patient who has had multiple rounds of chemotherapy has a poor prognosis. In acute leukaemia, chemotherapy regimens are designed to have multiple courses in order to maximise the chance of cure. Multiple previous treatments do not necessarily reflect prior treatment failure or disease progression.
  • Some chronic haematological disorders can transform into acute leukaemia. If the clinical picture fits, then consider acute leukaemia even where a patient comes with a label of an alternative haematological illness.
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3 Comments

  1. Dr Muhammad Yaseen says:

    nice session

  2. Moses Adebola Taiwo says:

    This further impresses on me that patients presenting unwell in ED require good history, a high index of suspicion and “routine” blood tests

  3. Dr. Chris Wheeler says:

    Helpful in furthering my understanding of why my patient did not require a blood film with a mild leucopenia and fever.

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