Acute Promyelocytic Leukaemia
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Direct answer
Acute promyelocytic leukaemia is a subtype of acute myeloid leukaemia caused by the t(15;17) translocation, which fuses the PML and RARA genes. It presents with bleeding from disseminated intravascular coagulation, and the smear often shows bundles of Auer rods. Treatment with all-trans retinoic acid, usually combined with arsenic trioxide, induces remission in most patients, and it is started as soon as the diagnosis is suspected.
What you must remember
- Genetics: t(15;17)(q24;q21) fuses PML with RARA, and the fusion blocks maturation of myeloid cells at the promyelocyte stage.
- Morphology: abundant Auer rods, often bundled as faggot cells, with heavy granules; the microgranular variant has few granules and bilobed nuclei.
- Coagulopathy: DIC with hypofibrinogenaemia is common at presentation, and bleeding is a leading cause of early death.
- All-trans retinoic acid: induces differentiation of the leukaemic promyelocytes and is started empirically, without waiting for molecular confirmation.
- Arsenic trioxide: combined with ATRA for low and intermediate risk disease, and chemotherapy is added for high risk patients.
- Differentiation syndrome: fever, dyspnoea, weight gain, pulmonary infiltrates and hypotension, treated promptly with corticosteroids.
- Risk stratification: a high initial white cell count is a major risk factor for differentiation syndrome and early death.
A stepwise approach from suspicion to remission
A 30-year-old man has fatigue, gum bleeding and petechiae. His platelet count is 18 × 10^9 per litre, his fibrinogen is low, and the smear shows bundled Auer rods in many blasts. Treatment must start before the molecular result returns.
- Suspect immediately: bleeding, DIC and Auer rods make acute promyelocytic leukaemia a medical emergency, and the diagnosis is treated as urgent.
- Start ATRA promptly: all-trans retinoic acid is given at suspicion, because early differentiation reduces early haemorrhagic death.
- Confirm the diagnosis: flow cytometry, karyotype or FISH for t(15;17), and RT-PCR for PML-RARA confirm the subtype and guide therapy.
- Support coagulation: platelets, cryoprecipitate and fresh frozen plasma are given to keep fibrinogen and platelets at safe levels, guided by serial tests.
- Add arsenic trioxide: given with ATRA for low and intermediate risk disease, while high risk patients also receive anthracycline-based chemotherapy.
- Monitor for complications: differentiation syndrome is watched for, and the QT interval is checked with ECG monitoring during arsenic therapy.
Where the exam tries to catch you
Acute promyelocytic leukaemia questions reward recognising the emergency and the drug that treats it.
- Trap: waiting for PML-RARA confirmation before starting ATRA Correct: ATRA is started when the diagnosis is suspected, since early death from bleeding can occur within days.
- Trap: giving heparin for DIC in acute promyelocytic leukaemia Correct: heparin is generally avoided, because bleeding is the greater danger, and treatment relies on blood products and ATRA.
- Trap: mistaking differentiation syndrome for sepsis or respiratory failure alone Correct: fever, dyspnoea and weight gain after ATRA or arsenic suggest it, and dexamethasone is started.
- Trap: treating the white count as the only risk factor Correct: the initial count stratifies risk, but early bleeding is driven by DIC.
Frequently asked questions
Which chromosomal translocation defines acute promyelocytic leukaemia?
The t(15;17)(q24;q21) translocation defines acute promyelocytic leukaemia, fusing the PML gene on chromosome 15 with the RARA gene on chromosome 17. The PML-RARA fusion is detected by karyotype, FISH or RT-PCR. Its presence confirms the diagnosis and guides targeted therapy.
What is the role of all-trans retinoic acid in acute promyelocytic leukaemia?
All-trans retinoic acid causes leukaemic promyelocytes to mature into neutrophils, relieving the differentiation block caused by PML-RARA. It is started as soon as the disease is suspected, because early treatment reduces the risk of haemorrhagic death. Differentiation syndrome is its most important serious toxicity.
Why is arsenic trioxide added to treatment for acute promyelocytic leukaemia?
Arsenic trioxide degrades the PML-RARA fusion protein and induces apoptosis of leukaemic cells. Combined with ATRA, it forms an effective regimen for low and intermediate risk disease, and many such patients avoid standard cytotoxic induction. QT interval monitoring is needed during arsenic therapy.
How is differentiation syndrome recognised during acute promyelocytic leukaemia treatment?
Differentiation syndrome presents with fever, dyspnoea, weight gain, pulmonary infiltrates, pleural effusions and hypotension, usually early in therapy. It is treated promptly with high-dose corticosteroids, and the offending drug is temporarily withheld according to protocol. Early recognition prevents fatal respiratory and renal complications.
Why does acute promyelocytic leukaemia cause bleeding at presentation?
Leukaemic promyelocytes release procoagulant material, which drives consumptive coagulopathy with fibrinolysis and low fibrinogen. This disseminated intravascular coagulation causes bleeding from the gums, skin and mucosa. Early replacement of platelets and fibrinogen, along with ATRA, is the basis of its management.