Makindo Medical Notes

📚 Related Subjects: | Differentiation Syndrome | Tretinoin (All-trans-retinoic acid, ATRA) | Acute Promyelocytic Leukaemia (APL) | Acute Myeloblastic Leukaemia (AML)

⚠️ Differentiation Syndrome is a life-threatening complication of therapy with differentiating agents such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in the treatment of Acute Promyelocytic Leukaemia (APL). Prompt recognition and steroid treatment are essential to reduce mortality.

📘 About

• Previously known as “Retinoic Acid Syndrome”.
• Occurs in patients receiving ATRA or ATO during induction therapy for APL.
• Represents an inflammatory capillary leak syndrome resulting from rapid differentiation of malignant promyelocytes.
• Mortality can reach 10–20% if not promptly treated, but is reversible with corticosteroids if recognised early.

🧬 Aetiology / Pathophysiology

• ATRA and ATO induce differentiation of leukaemic blasts into mature granulocytes.
• Differentiating cells secrete cytokines and vascular factors (e.g. IL-1β, IL-6, TNF-α, VEGF) causing endothelial activation, capillary leak, and tissue infiltration.
• This leads to fever, pulmonary oedema (ARDS), renal impairment, and hypotension.
• Histologically characterised by interstitial infiltration of maturing myeloid cells with oedema.

⚠️ Clinical Features

• Typically develops 7–12 days after initiation of ATRA/ATO.
• Early symptoms: fever, weight gain, bone pain, malaise.
• Progresses to:
  • Respiratory distress / ARDS
  • Oedema and serosal effusions (pleural, pericardial)
  • Hypotension and acute kidney injury
• Severe cases can lead to multiorgan failure if untreated.

🧪 Investigations

• 📉 Coagulopathy: transient abnormalities resembling DIC.
• 📈 LFTs: raised transaminases and triglycerides.
• 🩻 Chest X-ray: interstitial or alveolar infiltrates, pleural effusions.
• 🫀 Echocardiography: may reveal pericardial effusion.
• 🧫 Bloods: elevated inflammatory markers and WCC (leukocytosis).

🚨 Differential Diagnosis

• Sepsis or pneumonia (may mimic the same respiratory findings).
• Fluid overload or cardiac failure post-chemotherapy.
• Disseminated intravascular coagulation (DIC) from APL itself.

🩺 Management

• 🏥 Emergency recognition: suspected cases should be treated immediately — do not wait for confirmation.
• 💉 Corticosteroids:
  • Dexamethasone 10 mg IV every 12 hours until symptoms resolve.
  • Continue for ≥3 days or until stable; taper as appropriate.
• 💊 Supportive therapy: oxygen, diuretics, fluid balance monitoring, and treatment of renal impairment.
• 🧬 ATRA/ATO adjustment: withhold or reduce dose in severe cases, restart cautiously once stabilised.
• 🛡️ Prevention: prophylactic dexamethasone 2.5–5 mg BD during induction in high-risk patients (e.g. WCC >10×10⁹/L).

💡 Key Learning Points

• Occurs only with differentiating therapies (ATRA, ATO).
• Results from cytokine-mediated capillary leak and organ infiltration.
• Dexamethasone is life-saving — treat on suspicion.
• Do not confuse with sepsis — patients may be afebrile or non-toxic despite infiltrates.
• Monitor WCC, weight, and respiratory status closely during induction.

📚 References

• Frankel SR et al. Differentiation syndrome: pathophysiology, prevention, and treatment. Leukemia 2011;25(11):1763–1771.
• Lo-Coco F, Avvisati G et al. Management of differentiation syndrome in APL: an update. Blood Rev. 2014;28(3):117–122.
• BNF: Tretinoin (All-trans-retinoic acid)

💡 Teaching tip: Differentiation syndrome should be treated as a medical emergency in all APL patients on ATRA/ATO who develop fever, hypoxia, or oedema. Immediate dexamethasone can be life-saving — never delay treatment while awaiting confirmation.