What is differentiation syndrome?

From the Guidelines

Differentiation syndrome is a life-threatening complication of acute promyelocytic leukemia (APL) treatment with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO), characterized by fever, weight gain, respiratory distress, and organ dysfunction, requiring immediate administration of dexamethasone and supportive care. The syndrome typically presents with a range of symptoms, including fever, weight gain, respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, hypotension, and acute kidney injury 1. Management of differentiation syndrome includes immediate administration of dexamethasone 10 mg IV every 12 hours until symptoms resolve, followed by a gradual taper, as recommended by the European LeukemiaNet 1. In severe cases, ATRA or ATO therapy may need to be temporarily interrupted. Supportive care with fluid management, oxygen supplementation, and possibly mechanical ventilation may be required.

• Key features of differentiation syndrome include:
  • Fever
  • Weight gain
  • Respiratory distress
  • Pulmonary infiltrates
  • Pleural or pericardial effusions
  • Hypotension
  • Acute kidney injury Prophylactic steroids (prednisone 0.5 mg/kg/day) are often given to high-risk patients with elevated white blood cell counts to prevent differentiation syndrome, as suggested by the ESMO clinical practice guidelines 1. The syndrome occurs due to the rapid differentiation of immature leukemic cells, which release inflammatory cytokines causing capillary leak syndrome and tissue infiltration. Early recognition and prompt treatment are essential, as mortality rates can reach 30% if left untreated 1. Clinicians should maintain a high index of suspicion in any APL patient on differentiation therapy who develops unexplained fever, respiratory distress, or fluid retention.

From the FDA Drug Label

Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules. Symptoms include fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure.

Differentiation Syndrome is a potentially life-threatening or fatal condition that can occur in patients with acute promyelocytic leukemia (APL) who receive tretinoin capsules. The symptoms of differentiation syndrome include:

• Fever
• Dyspnea
• Acute respiratory distress
• Weight gain
• Radiographic pulmonary infiltrates
• Pleural and pericardial effusions
• Edema
• Hepatic, renal, and multi-organ failure It is essential to immediately administer dexamethasone and initiate hemodynamic monitoring at the first signs or symptoms of differentiation syndrome 2.

From the Research

Definition and Characteristics of Differentiation Syndrome

• Differentiation syndrome (DS) is a life-threatening complication of therapy with differentiating agents, such as all-trans retinoic acid (ATRA) or arsenic trioxide (ATO), in patients with acute promyelocytic leukemia (APL) 3, 4, 5, 6, 7.
• DS is characterized by clinical manifestations including unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, congestive heart failure, and acute renal failure 3, 4, 5, 6.

Incidence and Prognostic Factors

• The incidence of DS in patients with APL ranges from 2 to 37%, with the wide variation likely attributed to different diagnostic criteria, use of prophylactic treatment, and different treatment regimens 5.
• Roughly one quarter of patients with APL undergoing induction therapy will develop DS 3.
• The development of DS, particularly of the severe form, is still associated with a significant increase in morbidity and mortality during induction 3.

Management and Treatment

• The therapy for DS is based on early intravenous administration of high-dose dexamethasone to counteract the cytokine storm responsible for the DS 4, 6.
• Supportive measures for the management of DS include furosemide and dialysis to manage acute renal failure, peripheral, and pulmonary edema 4.
• In severe cases, discontinuation of ATRA or ATO is recommended until recovery 6.
• Treatment with corticosteroids +/- cytoreductive therapy should commence as soon as DS is suspected to reduce DS-related morbidity and mortality 5.

Clinical Presentations and Diagnostic Criteria

• DS can lead to severe inflammatory response syndrome and shock if adequate measures are not taken immediately 7.
• Radiological features of lung nodules with changes in ground-glass opacity can represent DS 7.
• The diagnosis of DS can be based on imaging results in the absence of a low total leukocyte count 7.