Leukostasis

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Leukostasis is the clinical manifestation of neurological and/or respiratory symptoms due to poor microvascular blood flow due to a very high blast count that can occur in patients with leukaemia (most commonly acute myeloid leukaemia (AML)). A high white cell count can occur without symptoms and this is termed hyperleukocytosis; when this is symptomatic the term used is leukostasis. Leukostasis is often a life-threatening condition and if cure or life-prolongation is the aim, then emergency treatment is required. In the palliative care context, the development of leukostasis usually indicates that the patient is in the last one or two weeks of life and comfort care is almost certainly going to be the appropriate course of action. Not all patients referred to palliative care services with incurable leukaemias will develop leukostasis as some leukaemic patients never have a particular high white cell count despite the fact that their bone marrow is full of blasts; in these patients death usually occurs as a complication of a cytopaenia (profound anaemia, haemorrhage due to thrombocytopaenia or sepsis due to neutropaenia).

Epidemiology

Leukostasis is more common in leukaemias with large blast cells, in particular AML.

In AML symptoms of leukostasis generally develop when the cell count reaches levels of around 400, although in occasional patients symptoms can develop at much lower numbers. In vitro studies suggest that leukostasis is unlikely to develop until the white cell count is greater than 300.

In acute lymphoblastic leukaemia (ALL) leucostasis is rarely seen although in vitro studies suggest that leukostasis is unlikely to develop until the white cell count is greater than 600. Tumour lysis is a much more common problem in ALL.

In chronic lymphocytic leukaemia (CLL) leukostasis is rare although is occasionally occurs with white cell counts over nearing 1000.

In chronic myelocytic leukaemia (CML) leukostasis is rare in the chronic phase but not uncommon with acute transformation.

Pathophysiology

The pathophysiology is poorly understood but three processes are probably behind the symptoms that develop:

  1. The large levels of circulating blasts increases blood viscosity causing plugs to form in the capillaries and microcirculation which results in poor blood flow (microvascular plugs will be seen on a biopsy of affected tissue). Diuretics and red cells transfusion worsen this
  2. The high numbers of dividing blasts in the blood require large amounts oxygen causing local tissue hypoxaemia
  3. The blasts release cytokines and inflammatory mediators causing local tissue damage

In vitro studies show that blasts counts of > 300 in AML and > 600 in ALL are required for a significant rise in blood viscosity.

Clinical Features

Respiratory symptoms and signs

About 30% of patients have dyspnoea and low oxygen saturations. Imaging, although unlikely to be of any value in the palliative care setting, may reveal diffuse interstitial or alveolar infiltrates.

Neurological symptoms and signs

Neurological symptoms occur in about 40% of patients and include blurred vision, headache, dizziness, tinnitus, gait disturbances, sleepiness and coma. These symptoms often persist for a few days after the white cell count has dropped with treatment. Imaging, although unlikely to be of any value in the palliative care setting, may be useful if excluding an intra-cranial haemorrhage was necessary, as many patients with leukaemia will also have thrombocytopaenia and will be at high risk of bleeding.

Fever

Almost all patients with leukostasis will have a fever and it is difficult to exclude an infection therefore in patients for whom treatment is being considered, empirical antibiotics (to cover febrile neutropaenia) should be given to any febrile patient. In the palliative care context however IV antibiotics are unlikely to be appropriate.

Uncommon symptoms and signs

Occasionally patients develop other symptoms and signs including

  • Chest pain and ECG changes of myocardial ischaemia
  • Right heart failure
  • Renal failure
  • Priapism
  • Acute limb ischaemia
  • Bowel infarction

Laboratory Findings

A rising white cell count in untreated AML often follows a predictable pattern with an apparent doubling time. For example, if a patient had a white cell count of 50 two weeks ago, 100 a week ago and 200 today, then it is likely that his white cell count will be in the order of around 400 in a week and symptoms will probably have started to develop. Once symptoms have developed, a person's life expectancy is measured in weeks, with a 20-40% one week mortality rate.

In addition to a rising white cell count, various other features may be noted if bloods are being taken:

  • A manual platelet count that is much lower than the automated platelet count as fragments of blasts may be counted as platelets by a machine
  • Spurious hyperkalaemia due to it being released from blasts in the blood tube
  • Features of disseminated intravascular coagulation (DIC) with an inreased INR, decreased fibrinogen, increased fibrin-degradation products and D-dimer
  • Features of spontaneous tumour lysis syndrome with hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia and acute renal failure
  • Leukostasis is diagnosed clinically on the basis of symptoms with a massively elevated white cell count.

Management and Prognosis

Leukostasis is a medical emergency and in cases where treatment is being contemplated, urgent cytoreductive therapy is indicated. This would normally be via induction chemotherapy in a haematology unit; occasionally, if induction therapy could not be immediately instituted then a combination of hydroxurea with leukopheresis would be appropriate whilst arranging for induction chemotherapy. Patients would normally also receive IV hydration and allopurinol to reduce the incidence of tumour lysis syndrome and acute renal failure.

In the palliative care context, patients may be referred by a haematology unit where treatment has failed and a rising white cell count and leukostasis has already developed. Alternatively a patient with pancytopaenia in the context of leukaemia or myelodyplasia may already have been referred to a palliative care unit and is receiving community follow-up with an expectation of a short life expectancy when the team note that the white cell count has began to rapidly rise. In both scenarios, the patient is probably in his last few weeks of life and it is very unlikely that any medical intervention will prolong life. An open and honest conversation with the patient and family is a key part of good palliative care and it is likely that the patient will rapidly become sleepy. Analgesia and anti-emetics (e.g. via a continuous subcunaneous infusion) may be needed.

For palliative patients whom want to try to prolong their life it is reasonable to give a trial of oral hydroxyurea. An appropriate total daily dose is approximately 50mg/kg, for example, a typical dose might be 1.5 g orally twice daily. If this is effective it would typically drop the white cell count by about 50% within 24 to 48 hours. Anaemia and thrombocytopaenia are common complications and the dose may need to be adjusted downwards if these become profound. Hydroxyurea can be given at home or in an inpatient unit, but it may be worth considering giving it with IV hydration and allopurinol to minimize the risk of tumour lysis syndrome. If ineffective or poorly tolerated the hydroxyurea should be discontinued although if it is effective it may increase a person's life span by a number of weeks or even months.

Authors

Graham Llewellyn Grove