Cytogenetic and molecular studies - PML-RARA / t(15;17)

The fusion and why it is an emergency

t(15;17)(q24;q21) -> PML-RARA fusion -> acute promyelocytic leukaemia (APL)
Diagnostic of APL regardless of blast percentage - a defining genetic abnormality, no 20% blast requirement
The one acute leukaemia that is a same-day medical emergency and also the most curable

Hypergranular (classic) - heavily granulated promyelocytes, Auer rods, faggot cells
Microgranular/hypogranular (~20%) - bilobed "butterfly" nuclei, high WCC, granules only on electron microscopy
- Easily mistaken for monocytic AML - the coagulopathy is the clue

~5-10% of adult AML; ~100-150 cases/yr in Australia
Median age ~40 - younger than other AML
M = F
Higher incidence in Hispanic/Latino populations and with obesity
Therapy-related APL after topoisomerase II inhibitors (anthracyclines, etoposide) and mitoxantrone - ~10-20% of cases
Early death remains ~5-15% in population series (vs ~2-5% in trials) - almost all from haemorrhage in the first week

PML (15q24, pro-apoptotic tumour suppressor, nuclear bodies) fused to RARA (17q21, retinoic acid receptor alpha)
PML-RARA binds retinoic acid response elements as a homodimer with greatly increased affinity for nuclear co-repressors (NCoR/SMRT, HDAC, DNA methyltransferases)
- -> transcriptional repression of myeloid differentiation genes
- -> maturation arrest at the promyelocyte stage
Pharmacological-dose ATRA releases the co-repressor -> differentiation resumes
Arsenic trioxide binds the PML moiety -> SUMOylation and degradation of the fusion protein
- -> ATRA and ATO attack the same protein at two different ends -> synergy

APL is the acute leukaemia most strongly associated with DIC at presentation
Promyelocyte granules release:
- Tissue factor and cancer procoagulant -> thrombin generation, consumptive coagulopathy
- Annexin II on the blast surface -> inc plasmin generation -> hyperfibrinolysis
- Elastase and other proteases -> proteolysis of fibrinogen
-> a combined DIC + primary fibrinolysis + thrombocytopenia picture
Cell lysis from chemotherapy makes it worse - which is why ATRA goes in before chemotherapy, not after

Pancytopenia or leucocytosis + bleeding out of proportion to the platelet count
Bruising, mucosal bleeding, intracranial or pulmonary haemorrhage
A young patient with a new leukaemia and a low fibrinogen is APL until disproved

Rapid PML-RARA testing: PML immunofluorescence (microspeckled nuclear pattern, result in hours), FISH for t(15;17), RT-PCR, karyotype
Flow cytometry: CD33 bright, CD13 heterogeneous, MPO strongly positive, HLA-DR NEGATIVE, CD34 negative, CD15 negative/weak
- Microgranular variant may be CD34+ and CD2+

PT, APTT, fibrinogen, D-dimer, platelets - at least twice daily until resolved
Low fibrinogen with high D-dimer

RT-PCR for PML-RARA transcripts - the measurable residual disease marker
- End of consolidation and serially thereafter in high-risk patients
- Molecular relapse precedes haematological relapse -> treat on the molecular result

Start ATRA (45 mg/m2/day in 2 divided doses) immediately - before cytogenetic confirmation
- Do not wait. The delay is what kills.
Aggressive blood product support, continued until coagulopathy resolves
- Platelets > 30-50 x10^9/L
- Fibrinogen > 1.5 g/L (cryoprecipitate or fibrinogen concentrate)
- INR < 1.5 (FFP/prothrombinex)
- Antifibrinolytics and heparin are NOT routine
Avoid: lumbar puncture, central lines, arterial puncture, IM injections until the coagulopathy is corrected

Risk	Regimen
Low/intermediate	ATRA + arsenic trioxide, chemotherapy-free - >95% CR, ~90-95% 5-yr EFS (APL0406, AML17)
High	ATRA + ATO + cytoreduction: gemtuzumab ozogamicin or an anthracycline (idarubicin)

Induction -> consolidation; maintenance largely abandoned in ATO-based regimens
ATRA + ATO outperforms ATRA + chemotherapy and avoids anthracycline cardiotoxicity and secondary MDS/AML

In ~2-25%; typically days 2-21, bimodal
Fever, dyspnoea, hypoxia, pulmonary infiltrates, weight gain >5 kg, oedema, hypotension, AKI, serositis
-> Dexamethasone 10 mg IV bd immediately at first suspicion
- Withhold ATRA/ATO only if severe
- Prophylactic prednisolone in high-WCC patients
Hyperleucocytosis (WCC rising on ATRA) -> hydroxyurea; *leucapheresis is contraindicated* - worsens the coagulopathy

ATO -> QT prolongation - ECG before and during; keep K+ >4.0 and Mg >0.8, avoid other QT-prolonging drugs
ATO: hepatotoxicity, peripheral neuropathy
ATRA: headache, pseudotumour cerebri (esp. children), dry skin, hypertriglyceridaemia, teratogenic
CNS prophylaxis for high-risk disease once safe

ATO-based re-induction if ATO-naive; then autologous HSCT if PCR-negative, allogeneic if PCR-positive
Consider CNS involvement

Therapy-related AML after topoisomerase II inhibitors - etoposide, anthracyclines, mitoxantrone (e.g. after breast cancer or MS treatment)
Disseminated intravascular coagulation
Obesity and Hispanic ancestry
FLT3-ITD - co-occurs in ~30-40%, associated with the microgranular variant and high WCC (prognostic impact largely abolished by ATRA + ATO)
Differentiation syndrome; retinoic acid syndrome is the older name
Secondary MDS/AML after anthracycline-containing APL regimens (an argument for chemotherapy-free treatment)

Before ATRA: uniformly and rapidly fatal. Now the most curable acute leukaemia in adults
>90% cure in low/intermediate risk with ATRA + ATO
Early death (first 30 days) is the dominant residual cause of failure - haemorrhage (mostly intracranial), differentiation syndrome, infection
- Mortality in registry data far exceeds trial data, because trial patients survived long enough to enrol
Relapse ~5-10%, higher in high-risk disease; CNS is a relapse sanctuary
Molecular remission (PCR-negative at end of consolidation) is the goal and the best predictor of cure
Long-term survivors: excellent quality of life; ATO-based regimens avoid the anthracycline late effects

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