Internal Medicine

Differentiation syndrome


Differentiation syndrome, previously retinoic acid syndrome (RAS) or ATRA syndrome, is a potentially life-threatening complication in patients with acute promyelocytic leukemia (aPML) and associated with all-trans retinoic acid (ATRA) ‘tretinoin’ and arsenic trioxide use.

Clinical features

Common symptoms:

  • Respiratory distress & fever (> 80% cases)
  • Pulmonary infiltrates & pulmonary oedema (> 50% cases)
  • Weight gain (50% cases)
Correlation between white blood cell count and chest X-ray. Note that the worsening of chest X-ray is directly linked with the fall of white blood cell due to the massive differentiation during the onset of differentiation syndrome. | Institute of Radiology, Department of Clinical and Biological Sciences of University of Turin, AOU S. Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano, Torino, Italy. WBC: White blood cells


  • Pleural effusion → respiratory distress → hypoxia
  • Volume overload: Pericardial effusionhypotensionrenal failure


Best approach for management of RAS is early recognition and prompt administration of steroids at the first sign of unexplained dyspnea, fever, weight gain or pulmonary infiltrates.

  • Corticosteroids (Dexamethasone) (10 mg IV BD for ≥ 3 days)
  • Cessation of ATRA (depending on severity of RAS)
  • Addition of another antineoplastic agent (cytarabine) to ATRA (in patients with high WBC count)
    • Major disadvantage: Bone marrow suppression

Once RAS is resolved, ATRA can be reintroduced.

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