Retinoic acid syndrome

Background

  • Differentiation syndrome (DS) is most current term
  • Occurs in Acute promyelocytic leukemia patients undergoing ATRA treatment (Tretinoin, Vesanoid)
    • And/or with arsenic trioxide therapy (Trisenox, ATO)
    • Chemo treatment differentiates APML blasts into mature granulocytes
    • Differentiation of blasts may cause sepsis-like "cytokine storm" leading to tissue damage
  • Incidence of DS[1]
    • Up to 25% of patients undergoing ATRA
    • Up to 31% of patients undergoing ATO
  • Up to 40% mortality in patients requiring mechanical ventilation
  • Diagnosis made clinically with symptomology
    • Requires immediate treatment with steroids
    • Steroids highly recommended even if other diagnoses possible

Clinical Features

  • Unexplained fever
  • Unexplained hypotension
  • Weight gain > 5 kg
  • Dyspnea with pulmonary infiltrates
  • Pericardial effusion
  • Pleural effusion
  • Renal failure
  • Vascular capillary leak syndrome
  • DIC
  • Never observed beyond induction therapy, when patient has achieved complete response

Differential Diagnosis

Oncologic Emergencies

Evaluation

  • Ultimately, a clinical diagnosis
  • Troponins for pericarditis
  • Severe leukocytosis on CBC
  • Sepsis workup
  • CHF workup, echo
  • Pulmonary embolism workup
  • DIC workup
  • Coagulation factor levels
  • Diagnostic bronchoscopy, BAL, biopsy usually not required
  • Imaging
    • CXR - pleural effusions, ground-glass opacities, increased cardiac silhouette
    • CT chest - pleural effusions, peripheral nodules

Management[2]

  • Dexamethasone 10mg IV q12hrs
    • Most important therapy, with possible dramatic and rapid resolution of symptoms
    • Continue treatment until complete disappearance of signs and symptoms
  • Temporary discharge ATRA or ATO only in severe cases of DS (renal failure or ICU admit)
  • Supportive
    • Mechanical ventilation for respiratory failure
    • Careful IVF admin, prioritizing blood products for coagulopathies (DIC)
    • Furosemide for fluid overload
    • CRRT/HD for refractory renal failure
    • Vasopressors
    • Empiric antibiotics
    • Avoid invasive pleural/pericardial effusion diagnostics

Disposition

  • Admit

References

  1. Montesinos P and Sanz MA. The Differentiation Syndrome in Patients with Acute Promyelocytic Leukemia: Experience of the Pethema Group and Review of the Literature. Mediterr J Hematol Infect Dis. 2011; 3(1): e2011059.
  2. Sanz MA and Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. May 1, 2014; Blood: 123 (18).
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