Makindo Medical Notes

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

💊 All-trans-retinoic acid (ATRA) — also known as Tretinoin — represents a landmark advance in the treatment of Acute Promyelocytic Leukaemia (APL). By inducing differentiation of malignant promyelocytes, ATRA has transformed APL from one of the most fatal subtypes of AML into one of the most curable forms of adult leukaemia.

📘 About

• Always refer to the BNF prescribing guidance for up-to-date dosing and safety information.
• ATRA is an active metabolite of vitamin A belonging to the retinoid family.
• It acts by inducing terminal differentiation of leukaemic promyelocytes, reversing the maturation arrest caused by the PML-RARA fusion gene.
• ATRA, combined with arsenic trioxide or chemotherapy, achieves cure rates above 90% in modern protocols.
• Other uses include Kaposi’s sarcoma, squamous cell carcinoma of the head and neck, ovarian carcinoma, and neuroblastoma (investigational or off-label).

⚙️ Mode of Action

• ATRA binds to retinoic acid receptors (RARs) within the nucleus, forming heterodimers with retinoid X receptors (RXRs).
• This binding modulates gene transcription involved in cell growth, apoptosis, and differentiation.
• In APL, the PML-RARA fusion protein inhibits normal transcriptional activation — ATRA overcomes this repression, allowing maturation of malignant promyelocytes into neutrophils.
• ATRA thereby transforms the biology of APL from proliferative arrest to cellular differentiation and eventual remission.

🎯 Indications

• Acute Promyelocytic Leukaemia (APL) — used in induction and consolidation phases, often in combination with arsenic trioxide or anthracycline-based regimens.

💊 Dose Range (consult BNF or datasheet)

Maximum treatment duration: 90 days (or until complete remission). Always check product literature for concomitant chemotherapy or arsenic dosing.

⚠️ Side Effects

• 🚨 Differentiation (Retinoic Acid) Syndrome: fever, respiratory distress, oedema, weight gain, pleural/pericardial effusions, hypotension, renal failure. Requires prompt treatment with corticosteroids (e.g. dexamethasone 10 mg BD).
• 🎯 Headache, skin/mucosal dryness, cheilitis, arthralgia.
• 🩸 Leucocytosis may occur early in therapy; monitor FBC.
• 🧠 Pseudotumour cerebri (raised intracranial pressure), particularly with concurrent tetracycline use.
• See BNF for full adverse effect profile.

🚫 Cautions / Contraindications

• ❌ Pregnancy: teratogenic — strict contraception required for at least one month before, during, and one month after treatment.
• Use with caution in hepatic impairment; monitor LFTs.
• Avoid vitamin A supplements (risk of toxicity).
• Monitor for signs of differentiation syndrome — early intervention improves outcomes.

📚 References

• BNF: Tretinoin (All-trans-retinoic acid)
• Lo-Coco F et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukaemia. N Engl J Med. 2013;369(2):111–121.
• Grimwade D, Mistry AR. Mechanisms of disease: Molecular pathogenesis of APL and its implications for targeted therapy. Blood Rev. 2009;23(4):167–178.

💡 Teaching tip: ATRA revolutionised APL management — it induces differentiation rather than cytotoxicity. Always anticipate and treat differentiation syndrome early. In reproductive-age patients, pregnancy prevention is critical due to its potent teratogenicity.