Acute promyelocytic leukaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

APL is a distinct, highly curable AML driven by PML::RARA, but the first hours are dominated by haemorrhagic mortality. Suspect it from bleeding, thrombocytopenia, low fibrinogen, prolonged coagulation and abnormal promyelocytes. The classic hypergranular form has bilobed nuclei and bundles of Auer rods; the microgranular variant can present with marked leukocytosis and deceptively sparse granules. Send rapid PML::RARA testing and start tretinoin immediately. The risk of a short empirical course is outweighed by the danger of waiting in a compatible presentation.

Support haemostasis intensively. Check platelets, fibrinogen, PT and APTT at least six-hourly while unstable. Transfuse platelets and cryoprecipitate or fibrinogen concentrate according to the centre APL protocol, commonly targeting platelets above 30–50 × 10⁹/L and fibrinogen above 1.5 g/L, with higher targets for active CNS or pulmonary bleeding. Maintain haemoglobin and correct temperature and calcium. Avoid routine heparin and antifibrinolytics because the syndrome contains both bleeding and thrombosis and evidence does not support empirical use. Avoid invasive procedures and intramuscular injections until control.

Risk classification uses presenting WBC. Low-to-intermediate risk is 10 × 10⁹/L or below; the licensed chemotherapy-free regimen combines ATRA and arsenic trioxide. High-risk disease above this threshold requires prompt cytoreduction and a specialist regimen incorporating ATRA with arsenic and an anthracycline or gemtuzumab-based strategy according to current UK availability and protocol. Do not lower the count by leukapheresis. Hydroxycarbamide or protocol chemotherapy can control treatment-emergent leukocytosis while differentiation therapy continues.

ATRA is usually 45 mg/m²/day orally in two divided doses and starts at suspicion. Headache, liver dysfunction, hypertriglyceridaemia, leukocytosis and teratogenicity require monitoring. Arsenic is 0.15 mg/kg IV daily until complete remission for up to 60 days in newly diagnosed low-to-intermediate-risk disease; consolidation is 0.15 mg/kg five days per week for four weeks on and four weeks off for four cycles. Administration must follow the exact ATRA–arsenic schedule rather than combining isolated SmPC doses without protocol coordination.

Differentiation syndrome is a clinical diagnosis: fever, weight gain, oedema, hypotension, dyspnoea, pulmonary infiltrates, pleural or pericardial effusion and renal injury may appear alone or together. Give dexamethasone 10 mg IV every 12 hours immediately when suspected and continue until resolution. Treat infection simultaneously because presentations overlap. Withhold ATRA or arsenic only in severe syndrome, then restart after recovery according to the protocol. Cytoreduce rising WBC and monitor fluid balance closely.

Arsenic prolongs QT and can cause torsades. Obtain baseline ECG and electrolytes, stop avoidable QT-prolonging drugs and correct potassium and magnesium before dosing. Repeat ECG at least twice weekly and more often when unstable or interacting medicines are unavoidable. If QTc exceeds the SmPC threshold, interrupt arsenic, correct contributors and resume through the staged protocol after normalisation. Monitor liver tests, glucose, renal function and neuropathy. APL therapy is highly teratogenic: urgent pregnancy testing and specialist reproductive discussion must not delay life-saving ATRA.

Response is molecular. Confirm marrow remission and PML::RARA negativity at protocol-defined end points; early post-induction molecular positivity can reflect differentiating cells and should not be labelled resistance prematurely. Continue molecular surveillance in higher-risk or protocol-defined groups. Molecular relapse needs urgent confirmation in a specialist laboratory and treatment before overt cytopenia when possible. Survivorship includes cardiac and metabolic effects of regimen, fertility, secondary malignancy and psychological recovery from the initial emergency.

Key points

APL is the acute leukaemia where treatment begins on morphological suspicion: give ATRA immediately and stop it later if genetics excludes the diagnosis.
Confirm with urgent PML::RARA RT-PCR or FISH; conventional karyotyping is useful but is too slow as the only first-hour test.
Monitor platelets, PT, APTT and fibrinogen at least every 6 hours initially and transfuse actively to the centre target, commonly platelets above 30–50 × 10⁹/L and fibrinogen above 1.5 g/L.
Avoid lumbar puncture, central line placement, bronchoscopy and other invasive procedures until coagulopathy is controlled unless life-saving access or intervention is unavoidable.
Do not use leukapheresis for hyperleukocytic APL because manipulation can worsen coagulopathy and early mortality; use protocol cytoreduction.
Low-to-intermediate-risk newly diagnosed APL, defined by WBC 10 × 10⁹/L or below, can receive ATRA plus arsenic trioxide without conventional chemotherapy under specialist protocol.
High-risk APL has WBC above 10 × 10⁹/L and needs ATRA plus arsenic or chemotherapy with prompt protocol cytoreduction and enhanced differentiation-syndrome prevention.
At the first suspicion of differentiation syndrome give dexamethasone 10 mg IV every 12 hours; withhold ATRA or arsenic only for severe syndrome under the protocol.
Arsenic requires baseline and frequent ECG, potassium, magnesium, calcium, liver and renal monitoring; correct potassium above 4 mmol/L and magnesium above 0.7 mmol/L and avoid QT-prolonging combinations.
Molecular PML::RARA monitoring defines remission and detects relapse; morphological improvement cannot substitute for protocol molecular assessment.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

PML::RARA fusion

The balanced t(15;17) rearrangement fuses PML and RARA, creating an abnormal transcriptional repressor that blocks promyelocyte differentiation.

Additional acquired lesions

Cooperating mutations, including FLT3 alterations in some patients, influence leukocytosis and biology but do not replace demonstration of the defining fusion.

Rare variant rearrangements

Uncommon RARA partners can resemble APL morphologically yet respond differently to ATRA or arsenic, making rapid expert genetic characterisation essential.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Promyelocyte accumulation
PML::RARA suppresses retinoic-acid-responsive genes, arresting myeloid maturation and producing an abnormal promyelocyte clone in marrow and blood.
2
Hyperfibrinolytic coagulopathy
Leukaemic promyelocytes express procoagulant and fibrinolytic mediators, causing simultaneous thrombin generation, fibrinogen consumption and accelerated clot breakdown.
3
Differentiation response
Pharmacological ATRA degrades the fusion-driven transcriptional block and arsenic targets PML::RARA, allowing maturation and eventual elimination of the clone.
4
Differentiation syndrome
Activated maturing cells release cytokines and infiltrate tissues, producing capillary leak, pulmonary dysfunction, hypotension, renal injury and weight gain.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Coagulopathic presentation

Ecchymoses, mucosal bleeding, haemoptysis, heavy uterine bleeding or neurological symptoms occur with thrombocytopenia, falling fibrinogen and raised D-dimer.

Characteristic morphology

Abnormal promyelocytes may be heavily granulated with bundles of Auer rods or microgranular with bilobed nuclei and marked leukocytosis.

High-risk count

A presenting WBC above 10 × 10⁹/L predicts greater differentiation and early complication risk and changes the treatment backbone.

Differentiation syndromeRed flag

Unexplained fever, weight gain, oedema, pulmonary infiltrates, hypotension or renal injury during ATRA or arsenic requires immediate dexamethasone.

Arsenic cardiac toxicityRed flag

Palpitations, syncope, ventricular ectopy or prolonged QT with low potassium or magnesium requires urgent interruption and correction.

Red flags requiring action

Headache, focal neurology, reduced consciousness, haemoptysis, hypoxia, melaena or haemodynamic bleeding requires immediate imaging, transfusion and source-control escalation alongside APL therapy.
Fever, weight gain, oedema, dyspnoea, pulmonary infiltrates, hypotension or renal dysfunction after ATRA or arsenic suggests differentiation syndrome and requires immediate dexamethasone.
Rapid leukocytosis during differentiation therapy increases differentiation and coagulopathic risk and requires protocol cytoreduction, not automatic discontinuation of life-saving ATRA.
QTc prolongation, ventricular ectopy, potassium or magnesium depletion during arsenic treatment requires interruption and urgent correction through the SmPC protocol.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: FBC, film and coagulationFirst stepFirst line
Why
Recognise morphology and quantify the haemorrhagic emergency.
Interpretation and limitations
Send PT, APTT, fibrinogen and D-dimer with serial platelets. Do not allow a modest WBC or atypical microgranular appearance to delay empirical ATRA.
02
Confirmatory: rapid PML::RARA RT-PCR or FISHConfirmatory
Why
Demonstrate the defining fusion quickly and establish a molecular marker.
Interpretation and limitations
A positive result confirms APL. A negative result with convincing morphology requires urgent expert review for sample quality and rare variant RARA rearrangements.
03
Marrow morphology and genetics
Why
Define baseline burden, additional lesions and later remission status.
Interpretation and limitations
Obtain aspirate when haemostasis permits; defer non-essential invasive trephine or line placement during severe coagulopathy if safer blood material is diagnostic.
04
Arsenic safety baseline
Why
Prevent avoidable arrhythmia and organ toxicity.
Interpretation and limitations
Use ECG with QTc, potassium, magnesium, calcium, renal and liver tests and a full interaction screen; correct electrolytes and withdraw avoidable QT-prolonging agents.
05
Molecular response monitoring
Why
Confirm molecular remission and detect preclinical relapse.
Interpretation and limitations
Use the same accredited quantitative PML::RARA assay at protocol end points; interpret early post-induction positivity carefully because maturation can delay clearance.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Non-APL AML

Other AML can contain Auer rods or cause DIC but lacks PML::RARA and follows a different induction pathway.

Sepsis-associated DIC

Infection can cause thrombocytopenia, prolonged coagulation and low fibrinogen; blood-film morphology and rapid fusion testing identify coexisting or alternative APL.

Acute monocytic leukaemia

Monocytic AML may cause high counts, tissue infiltration and bleeding but has a distinct flow and genetic profile and does not receive empirical ATRA long term.

Variant RARA leukaemia

Morphologically similar rare fusions can be ATRA resistant, so a negative standard PML::RARA result needs urgent expert laboratory review rather than simple exclusion.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Morphological suspicionGive ATRA before confirmationFirst stepAbnormal promyelocytes and compatible coagulopathy make APL possible.

1Start tretinoin immediately, admit under acute leukaemia care and send urgent PML::RARA RT-PCR or FISH.
2Monitor coagulation and fibrinogen at least six-hourly and transfuse to the APL platelet and fibrinogen targets.
3Avoid invasive procedures and leukapheresis, then refine treatment when genetics and presenting WBC define risk.

02Confirmed lower-risk APLUse protocol ATRA plus arsenicPML::RARA is confirmed and presenting WBC is 10 × 10⁹/L or below.

1Complete ECG, electrolyte, organ, pregnancy and interaction assessment without interrupting emergency ATRA.
2Give the exact licensed ATRA–arsenic induction and consolidation protocol with ongoing blood support.
3Monitor differentiation syndrome, QT, liver toxicity and molecular response through remission and surveillance.

03Confirmed high-risk APLAdd prompt cytoreductionPresenting WBC exceeds 10 × 10⁹/L or rapidly rises with clinical risk.

1Continue ATRA, haemostatic support and lysis prevention and start protocol cytoreduction without leukapheresis.
2Use the current specialist ATRA-based regimen incorporating arsenic and protocol chemotherapy or targeted cytoreduction.
3Provide intensified differentiation-syndrome surveillance and protocol molecular assessment before consolidation decisions.

04Differentiation syndromeTreat at first suspicionFever, weight gain, respiratory infiltrates, effusions, hypotension or renal injury develops during differentiation therapy.

1Give dexamethasone 10 mg IV every 12 hours immediately and investigate and treat infection in parallel.
2Control fluid balance and leukocytosis and support respiratory, renal and haemodynamic failure.
3Withhold ATRA or arsenic only if severe, then restart through the specialist protocol after resolution.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

First-hour differentiation therapy that begins reversing PML::RARA-driven promyelocyte biology and reduces coagulopathic mortality.

Tretinoin (ATRA)

Give 45 mg/m²/day orally in two divided doses immediately when APL is morphologically suspected; continue within the risk-adapted regimen until complete remission or the protocol maximum, and stop if adequate genetics excludes APL.

Do not delay for molecular confirmation. Monitor differentiation syndrome, WBC, headache, pseudotumour cerebri, liver tests and lipids. It is highly teratogenic: use urgent specialist pregnancy management and effective contraception without delaying life-saving treatment.

PML::RARA-targeted differentiation and apoptosis therapy combined with ATRA in chemotherapy-free lower-risk treatment.

Arsenic trioxide

For newly diagnosed low-to-intermediate-risk APL give 0.15 mg/kg IV daily until complete remission, maximum 60 days; consolidate 0.15 mg/kg five days weekly for four weeks on and four weeks off for four cycles.

Use only under an acute-leukaemia specialist. Monitor QTc at least twice weekly, potassium, magnesium, calcium, liver, renal and glucose; avoid QT-prolonging drugs and interrupt and restart through the SmPC threshold protocol. It is teratogenic and breastfeeding must stop.

Rapid suppression of cytokine-driven capillary leak, pulmonary infiltration and organ dysfunction during ATRA or arsenic differentiation.

Dexamethasone for differentiation syndrome

Give 10 mg intravenously every 12 hours immediately at the first clinical suspicion of differentiation syndrome and continue until signs and symptoms resolve, with further taper or duration set by the APL protocol.

Do not wait for radiographic certainty and treat infection simultaneously. Monitor glucose, delirium, infection, gastrointestinal and muscle toxicity; withhold ATRA or arsenic only in severe syndrome under specialist direction.

Prevents early intracranial and pulmonary haemorrhage while differentiation therapy resolves the underlying coagulopathy.

Fibrinogen and platelet support

Give pooled cryoprecipitate or fibrinogen concentrate and platelet components repeatedly to the current APL protocol targets, commonly fibrinogen above 1.5 g/L and platelets above 30–50 × 10⁹/L, with higher targets for critical bleeding.

Base replacement on very frequent results and clinical bleeding, not a once-daily test. Monitor volume, ionised calcium, thrombosis and transfusion reactions; use irradiated or selected components according to transplant and local policy.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Early fatal haemorrhage

Intracranial and pulmonary bleeding from consumption and hyperfibrinolysis remains the dominant preventable early cause of death.

Differentiation syndrome

Untreated capillary leak can progress rapidly to respiratory failure, shock and acute kidney injury during ATRA or arsenic therapy.

Thrombosis

The coagulopathy can produce venous or arterial thrombosis as well as bleeding, complicating transfusion and anticoagulation decisions.

Molecular relapse

Reappearance of PML::RARA transcripts can precede haematological relapse by weeks or months and permits urgent confirmation and pre-emptive specialist treatment before overt marrow failure.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During the unstable first days check clinical bleeding, platelets, PT, APTT and fibrinogen at least every 6 hours and transfuse proactively to the APL protocol targets.
Monitor WBC, temperature, weight, oxygen requirement, chest signs, fluid balance and creatinine at least daily for differentiation syndrome and more frequently when changing.
During arsenic obtain baseline and at least twice-weekly ECG plus frequent potassium, magnesium and calcium; interrupt for clinically important QT prolongation and correct all contributors.
Measure liver function, glucose, triglycerides, neurological symptoms, lysis chemistry and infection throughout induction and consolidation.
Use accredited quantitative PML::RARA testing at protocol-defined remission and surveillance points, with urgent confirmation and MDT action for molecular recurrence.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Treat then disprove

APL reverses the usual sequence because a few early ATRA doses are far less dangerous than hours of untreated fusion-driven coagulopathy.

Both bleeding and clotting

APL is not simple factor depletion. Tissue factor, consumption and hyperfibrinolysis coexist, explaining why empirical heparin or antifibrinolytic treatment can be hazardous.

White count defines regimen

The presenting count, not a peak caused by differentiation, defines conventional low-to-intermediate versus high-risk classification and the need for added cytoreduction.

Syndrome mimics infection

Fever and infiltrates may be differentiation syndrome, sepsis or both. Give dexamethasone immediately while cultures and antimicrobial treatment proceed.

Early PCR can persist

Differentiating cells may retain detectable transcript soon after induction. End-of-consolidation molecular status is more decisive than premature labelling of resistance.

11Common pitfallsFrequent interpretation and management errors.

01
Do not await PML::RARA confirmation before starting tretinoin in a morphologically compatible coagulopathic presentation.
02
Do not perform routine lumbar puncture, central-line placement or leukapheresis during uncontrolled APL coagulopathy.
03
Do not check fibrinogen and platelets only once daily during the unstable phase; rapid consumption requires repeated testing and replacement.
04
Do not stop ATRA automatically for a rising WBC; cytoreduce through the risk-adapted protocol and reserve interruption for severe differentiation syndrome.
05
Do not give arsenic without systematic QT, electrolyte and interaction management.
06
Do not diagnose molecular resistance from an inappropriately early positive PCR without protocol timing and expert laboratory interpretation.