Acute myeloid leukaemia
Description
- Clonal expansion of myeloid blasts with differentiation block + marrow failure
- >=20% blasts in blood or marrow
- *Except AML with a defining genetic abnormality - t(8;21), inv(16)/t(16;16), PML::RARA, NPM1, KMT2A-r, NUP98-r and others are AML at any blast count* (WHO 5th ed; ICC uses a >=10% floor)
- Only AML with BCR::ABL1 and AML with CEBPA mutation still require >=20%
- Myeloid sarcoma (chloroma) is AML wherever it appears - tissue diagnosis alone is sufficient
Categories that change management
- APML (t(15;17), PML::RARA) - a medical emergency and a chemotherapy-free cure
- AML with myelodysplasia-related changes / secondary AML - worse, and treated differently
- Therapy-related AML
- Germline predisposition - RUNX1, CEBPA, DDX41, GATA2, ANKRD26, ETV6, Fanconi
- Matters before using a family member as a stem cell donor
Epidemiology
- Commonest acute leukaemia in adults; ~1,100 new cases/yr in Australia
- Median age ~68; incidence rises steeply after 60
- M>F slightly
- Childhood AML ~15-20% of paediatric leukaemia (ALL dominates in children, AML in adults)
- APML ~5-10% of AML, younger median age (~40)
Aetiopathogenesis
Two-hit model
- Class I - proliferative signalling: FLT3-ITD/TKD, KIT, NRAS/KRAS, PTPN11
- Class II - differentiation block: RUNX1::RUNX1T1, CBFB::MYH11, PML::RARA, NPM1, CEBPA, KMT2A rearrangement
- Plus epigenetic/spliceosome lesions: DNMT3A, TET2, IDH1/2, ASXL1, SRSF2, U2AF1, EZH2, BCOR, STAG2, ZRSR2, RUNX1
- The last group defines "myelodysplasia-related" AML - adverse regardless of morphology
- Clonal haematopoiesis (CHIP) - DNMT3A/TET2/ASXL1 mutations in normal ageing marrow; the substrate for later AML
Secondary and therapy-related
| Latency | Signature | |
|---|---|---|
| Topoisomerase II inhibitors (anthracyclines, etoposide) | 1-3 yr, no MDS phase | Balanced translocation, KMT2A (11q23) |
| Alkylating agents, radiation | 5-7 yr, preceded by MDS | Complex karyotype, -5/del(5q), -7/del(7q), TP53 |
- Also: antecedent MDS/MPN/aplastic anaemia/PNH, benzene, smoking, Down syndrome, Fanconi anaemia
Why patients die early
- DIC (especially APML) -> catastrophic haemorrhage
- Hyperleucocytosis -> leukostasis (myeloblasts are large and adhesive) -> hypoxaemia, pulmonary infiltrates, CNS symptoms
- Febrile neutropenia -> overwhelming sepsis
- Tumour lysis syndrome
Diagnosis
Blood and marrow
- Anaemia, thrombocytopenia, WCC high, normal or low; blasts in blood in most
- Auer rods - azurophilic crystallised MPO granules. Diagnostic of myeloid lineage
- Seen in AML and in high-grade MDS; never in lymphoid blasts
- Marrow aspirate + trephine: hypercellular, blasts, dysplasia
- Myeloperoxidase or Sudan black positive; non-specific esterase in monocytic subtypes
Flow cytometry
- Myeloid: CD13, CD33, CD117, MPO, CD34, HLA-DR
- Monocytic: CD14, CD64, CD11b, CD4dim
- *APML: CD34 negative, HLA-DR negative, strong MPO, CD33 bright - this pattern on flow should trigger emergency treatment before genetics return*
Genetics - mandatory in every case
- Urgent PML::RARA by FISH/PCR if APML suspected
- Karyotype + FISH + NGS myeloid panel (FLT3, NPM1, IDH1/2, TP53, CEBPA, KIT, ASXL1, RUNX1, KMT2A, NPM1)
- FLT3 must be turned around in days - it changes induction
ELN 2022 genetic risk
| Favourable | t(8;21) RUNX1::RUNX1T1; inv(16)/t(16;16) CBFB::MYH11; mutated NPM1 without FLT3-ITD; bZIP in-frame mutated CEBPA |
| Intermediate | Mutated NPM1 with FLT3-ITD; wild-type NPM1 with FLT3-ITD; t(9;11) KMT2A::MLLT3; cytogenetic/molecular abnormalities not classified elsewhere |
| Adverse | Complex (>=3 abnormalities), monosomal karyotype, -5/del(5q), -7, -17/abn(17p); t(6;9), t(v;11q23) other KMT2A, t(9;22), inv(3); mutated TP53; ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 |
- *Changes from earlier versions: FLT3-ITD allelic ratio no longer used; myelodysplasia-related mutations moved to adverse; NPM1 with adverse cytogenetics is adverse*
- APML is classified and treated separately - excellent prognosis with ATRA-based therapy
MRD
- Flow MRD and molecular MRD (NPM1, CBF fusions) after cycles 1-2 predict relapse and guide transplant decisions
Management
A. Before any chemotherapy - the emergencies
- *Suspected APML: start ATRA immediately on morphological suspicion. Do not wait for cytogenetics*
- Coagulopathy support: fibrinogen >1.5 g/L (cryoprecipitate), platelets >30-50 x10^9/L, FFP for prolonged PT
- Haemorrhagic death in the first days is the main cause of APML mortality, and it is preventable
- Tumour lysis prophylaxis - hydration, allopurinol; rasburicase if high risk, high urate or renal impairment (not in G6PD deficiency)
- Hyperleucocytosis (>100 x10^9/L with symptoms) - urgent cytoreduction (hydroxyurea, start induction); leukapheresis selectively
- *Avoid red cell transfusion until the count falls - it worsens viscosity*
- Febrile neutropenia - blood cultures then broad-spectrum antibiotics within 1 hour
- Central access, fertility preservation discussion, HLA typing of patient and siblings
B. Fit for intensive therapy
- Induction "7+3": cytarabine 100-200 mg/m2 continuous infusion x7 days + daunorubicin/idarubicin x3 days
- FLT3-mutated: add midostaurin (or quizartinib for FLT3-ITD)
- Core-binding factor AML: add gemtuzumab ozogamicin
- Therapy-related or MDS-related AML: CPX-351 (liposomal daunorubicin/cytarabine)
- Day 14-21 marrow to confirm aplasia/remission
- Consolidation: high-dose cytarabine x2-4 cycles for favourable risk
- Allogeneic SCT in CR1 for intermediate and adverse risk, and for MRD-positive favourable risk
- Oral azacitidine maintenance (QUAZAR) if in CR1 and not proceeding to transplant
C. Unfit for intensive therapy (age, comorbidity, performance status)
- Venetoclax + azacitidine is the standard of care
- VIALE-A: median OS 14.7 vs 9.6 months, CR/CRi ~66% vs 28% - this superseded single-agent azacitidine and low-dose cytarabine
- Ramp-up dosing with TLS prophylaxis; venetoclax dose reduced with azoles (CYP3A4)
- Prolonged cytopenias - dose interruption between cycles is expected
- Ivosidenib + azacitidine if IDH1-mutated; olutasidenib/enasidenib for IDH2
- Low-dose cytarabine, hypomethylating agent alone, or best supportive care where even this is too much
- *Best supportive care alone remains a legitimate choice - discuss it explicitly*
D. APML - the exception
- Non-high-risk (WCC <=10): ATRA + arsenic trioxide, chemotherapy-free - ~95% cure
- High-risk (WCC >10): ATRA + arsenic + gemtuzumab ozogamicin or an anthracycline
- Differentiation syndrome (~25%): fever, dyspnoea, pulmonary infiltrates, hypoxia, weight gain, effusions, hypotension, AKI
- Dexamethasone 10 mg bd immediately on suspicion; hold ATRA/arsenic if severe
- Prophylactic corticosteroid or hydroxyurea if WCC rising
- ATRA: headache, dryness, pseudotumour cerebri (more in children/adolescents - use lower dose), hypertriglyceridaemia
- Arsenic: QT prolongation (ECG and electrolytes before and during), hepatotoxicity
- Molecular monitoring of PML::RARA; molecular relapse is treated before it becomes haematological
E. Relapsed / refractory
- Gilteritinib for FLT3-mutated (ADMIRAL)
- Menin inhibitors (revumenib) for KMT2A-rearranged and NPM1-mutated disease
- IDH inhibitors; salvage chemotherapy (FLAG-Ida) then allogeneic SCT - the only realistic curative route
- Clinical trial
F. Supportive care throughout
- Irradiated, leucodepleted (and CMV-safe if seronegative) blood products
- Antifungal prophylaxis (posaconazole) during induction - remember the venetoclax and vincristine interactions
- Antibacterial and antiviral prophylaxis, PJP cover with hypomethylating agents
- Mucositis care, nutrition, transfusion thresholds (platelets <10, or <20 if febrile)
Associations
- Gingival hypertrophy and infiltration - monocytic subtypes (M4/M5)
- Sweet syndrome - acute febrile neutrophilic dermatosis; also leukaemia cutis
- DIC - classically APML, but also monocytic AML
- Myeloid sarcoma / chloroma
- Antecedent MDS, MPN, aplastic anaemia, PNH
- Down syndrome - transient abnormal myelopoiesis then AMKL (GATA1 mutation), exquisitely chemosensitive
- Germline predisposition syndromes - ask about family history of cytopenias or early cancer
- Prior chemotherapy or radiotherapy, benzene, smoking
Natural history & complications
- Untreated: death within weeks to a few months
- Cure rates: ~35-40% under 60, <10-15% over 60
- APML: >90% cure with ATRA + arsenic - the best outcome in acute leukaemia
Adverse prognostic factors
- Age >60 (and especially >75), poor performance status
- Antecedent MDS/MPN or therapy-related disease
- Adverse cytogenetics - complex karyotype, -5/del(5q), -7, inv(3), TP53
- FLT3-ITD (worse with high allelic burden and absent NPM1)
- Failure to achieve CR after induction; MRD positivity after consolidation
- Hyperleucocytosis at presentation, CNS disease
Favourable
- t(8;21), inv(16), NPM1-mutated without FLT3-ITD, bZIP in-frame CEBPA
Complications
- Relapse - most within 2 years; salvage rarely durable without transplant
- Treatment-related: prolonged cytopenias, invasive fungal infection, anthracycline cardiotoxicity, infertility
- Transplant: GVHD, graft failure, infection, secondary malignancy
- Extramedullary and CNS relapse (more with monocytic and KMT2A-rearranged disease)
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