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Differentiation Syndrome

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Shared care information

This presentation is unlikely to occur in a shared care centre. Please discuss with the oncologist on call.

What is Differentiation Syndrome?

Acute Promyelocytic Leukaemia (APML) is characterised by chromosomal rearrangements of 17q21 involving the gene encoding the Retinoic Acid Receptor Alpha (RARĪ±) which is most commonly fused to the PML gene on chromosome 15 as a result of the t(15;17)(q22;q21). In a minority of cases RARĪ± is fused to an alternative partner. This protein inhibits differentiation of the myeloid progenitor beyond the promyelocyte stage. The differentiation agents all trans retinoic acid (ATRA) and Arsenic induce differentiation of the leukaemic promyelocytic clone by binding to the abnormal fusion protein thus releasing the differentiation block.

Differentiation syndrome is a potentially life threatening complication of ATRA or Arsenic therapy which occurs in 5% - 20% of patients. Patients with hyperleucocytosis (> 10 x 109 /L) at diagnosis are at the highest risk of this syndrome. Most treatment protocols recommend Dexamethasone prophylaxis for patients with high white counts. The pathophysiology of DS is poorly understood but it is thought to be due to an excessive inflammatory response with cytokine and chemokine overproduction. There is some evidence in adult studies that DS is associated with worse coagulopathy and therefore higher rates of haemorrhage and/or thrombosis.

Prompt recognition and early intervention is vital and pre-emptive treatment should be started as soon as DS is suspected. Ideally there should be a plan in place for stringent monitoring from the start of induction therapy.

Clinical features

These include:

  • Unexplained fever
  • Weight gain
  • Respiratory distress
  • Interstitial pulmonary infiltrates
  • Pleural or pericardial effusions
  • Hypotension
  • Acute renal failure

This may occur on a background of a critically unwell patient with DIC associated with APML. There are no pathognomonic signs or symptoms. Investigations are important for supportive care and it may be necessary to exclude infective causes of respiratory distress or sepsis like syndromes. The presence of infection does not rule out concomitant DS.

Management

Refer to the patient's treatment protocol for specific management details. A general outline is listed below:

  • Dexamethasone 0.25 mg/kg/dose IV q12h (max 10 mg/dose) for 3 days or until resolution of symptoms
  • Temporary discontinuation of ATRA or Arsenic in patients who are most severely affected.
  • Frusemide as required
  • Supportive care of respiratory or other organ systems which may require ICU.

When differentiation syndrome has resolved, restart ATRA at 75% of initial dose. If there are recurrent episodes decrease to 50% of dose.

References

  1. Ribeiro R (2014). How I treat children and adolescents with acute promyelocytic leukaemia, British Journal of Haematology, 164(1):24-38
  2. Sanz M (2014). How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood, 123 (18): 2777-2782

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Document Control

  • Date last published: 01 March 2015
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network