Acute Myeloid Leukaemia (AML)

📋 Key Information Summary

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Acute Myeloid Leukaemia (AML) is a haematological emergency characterised by clonal proliferation of myeloid blasts leading to bone marrow failure.
Diagnosis requires ≥20% myeloid blasts in bone marrow or blood, with specific WHO classification subtypes.
Presenting features include symptoms of anaemia, infection (neutropenia), and bleeding (thrombocytopenia); Auer rods are pathognomonic.
Immediate management involves urgent referral to a haematology centre, supportive care, and risk stratification for treatment.
Standard intensive induction for eligible patients is "7+3" chemotherapy: 7 days of continuous cytarabine infusion plus 3 days of an anthracycline.
Post-remission therapy is stratified by genetic risk: favourable (consolidation chemotherapy), intermediate/adverse (allogeneic haematopoietic stem cell transplant).
Molecular and cytogenetic analysis (e.g., FLT3, NPM1, TP53, core-binding factor translocations) is essential for risk classification and guiding therapy.
Supportive care is paramount: broad-spectrum antibiotics for febrile neutropenia, blood product support, and tumour lysis prophylaxis.
Special populations (elderly, those with comorbidities) may be considered for lower-intensity therapies like venetoclax with azacitidine.
Aboriginal and Torres Strait Islander patients may face barriers to timely diagnosis and access to transplant; culturally safe care is critical.
Long-term follow-up for survivors includes monitoring for late effects, particularly secondary malignancies and cardiovascular disease.

Introduction & Australian Epidemiology

Acute Myeloid Leukaemia (AML) is an aggressive, clonal haematopoietic malignancy characterised by the uncontrolled proliferation of immature myeloid precursors (blasts) in the bone marrow and peripheral blood. This leads to bone marrow failure, resulting in anaemia, thrombocytopenia, and neutropenia. AML is a medical emergency requiring prompt diagnosis and initiation of treatment.

In Australia, AML accounts for approximately 1,100 new diagnoses annually, with an age-standardised incidence of 4.2 per 100,000. The median age at diagnosis is 67 years. While it can occur at any age, incidence rises sharply after age 50. Outcomes remain poor, particularly for older adults and those with adverse-risk genetics, with 5-year overall survival rates around 30% for all patients combined. Management must be centralised in specialised haematology centres due to the complexity of therapy and high risk of treatment-related morbidity.

Pathogenesis & FAB Classification

AML arises from acquired somatic mutations in haematopoietic stem or progenitor cells. These mutations confer a survival and proliferative advantage, leading to the accumulation of arrested myeloid precursors (blasts) that fail to differentiate. The pathogenesis is often multi-hit, involving cooperating mutations in genes regulating cell proliferation (e.g., FLT3, KIT), differentiation (e.g., RUNX1, CEBPA), and epigenetic regulation (e.g., NPM1, DNMT3A, IDH1/2).

The French-American-British (FAB) classification (M0-M7) was historically used and is based on morphology and cytochemistry. It remains familiar in clinical practice but has been largely superseded by the World Health Organization (WHO) Classification (5th edition, 2022), which integrates morphology, genetics, and clinical features for more refined prognostication and treatment selection.

FAB Subtype	Name	Key Features
M0	Minimally differentiated	Blasts lack morphological and cytochemical myeloid features; requires immunophenotyping for diagnosis.
M1	Without maturation	High blast percentage with minimal granulocytic maturation.
M2	With maturation	Often associated with t(8;21) translocation; Auer rods may be present.
M3	Acute promyelocytic leukaemia (APL)	t(15;17); associated with coagulopathy; specific all-trans retinoic acid (ATRA) therapy.
M4	Myelomonocytic	Both myeloid and monocytic differentiation; may have inv(16).
M5	Monocytic	High risk of tissue infiltration (gums, skin, CNS).
M6	Erythroid	Predominantly erythroid precursors.
M7	Megakaryoblastic	Often associated with Down syndrome in children.

Clinical Features & Auer Rods

Presentation is typically rapid over weeks and directly results from bone marrow failure and organ infiltration.

Symptoms of Anaemia: Fatigue, dyspnoea, pallor, tachycardia.
Symptoms of Neutropenia: Fever, recurrent or severe infections (e.g., pneumonia, cellulitis, sepsis).
Symptoms of Thrombocytopenia: Spontaneous bruising, petechiae, gingival bleeding, epistaxis, menorrhagia.
Constitutional Symptoms: Fever, night sweats, weight loss, anorexia.
Organ Infiltration: Hepatosplenomegaly, lymphadenopathy, bone pain, gingival hypertrophy (especially monocytic subtypes), skin infiltration (leukaemia cutis).

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Auer Rods: These are azurophilic, needle-shaped cytoplasmic inclusions formed from fused primary granules. They are pathognomonic of AML (and high-grade myelodysplastic syndromes) and are never seen in acute lymphoblastic leukaemia (ALL). Their presence confirms a myeloid lineage. They are most readily seen on a peripheral blood or bone marrow film stained with Wright-Giemsa stain.

Investigations & Diagnosis

Urgent investigation is required. Diagnosis is established by the presence of ≥20% myeloid blasts in the peripheral blood or bone marrow, with specific exceptions for certain WHO-defined genetic subtypes (e.g., APL, AML with t(8;21), inv(16), which may have <20% blasts).

Essential

Full Blood Count (FBC) & Peripheral Blood Film

MBS Item 65070. Shows anaemia, thrombocytopenia, and variable WCC (often elevated, sometimes very low). Circulating blasts usually present. Look for Auer rods.

Essential

Bone Marrow Aspirate & Trephine Biopsy

Definitive diagnostic test. Aspirate for morphology, cytochemistry (myeloperoxidase), immunophenotyping (flow cytometry), cytogenetics (FISH, karyotype), and molecular studies. Trephine assesses cellularity and architecture.

Essential

Immunophenotyping (Flow Cytometry)

Confirms myeloid lineage (CD13, CD33, CD117, MPO). Rules out ALL. Identifies aberrant markers.

Essential

Cytogenetics & Molecular Genetics

Conventional karyotype and FISH for core-binding factor translocations. PCR or next-generation sequencing (NGS) for mutations in FLT3-ITD, NPM1, CEBPA, TP53, IDH1, IDH2, RUNX1. Essential for risk stratification.

Available

Coagulation Studies

MBS Item 65125. INR, aPTT, fibrinogen. Critical to identify APL-associated coagulopathy (DIC).

Available

Biochemistry

U&Es, LFTs, LDH (often elevated, marker of tumour burden), uric acid (risk of tumour lysis syndrome).

Available

HLA Typing

For the patient and potential sibling donors, to be performed early for those likely to require allogeneic transplant.

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APL (Acute Promyelocytic Leukaemia) Warning: If morphology or genetics suggest APL (M3 FAB, t(15;17)), this is a medical emergency due to the high risk of fatal coagulopathy. Initiate all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) immediately upon suspicion, before confirmatory results. Do not wait for full karyotype.

Management

All patients should be discussed at a multidisciplinary team meeting at a tertiary haematology centre. Management is stratified by patient fitness, age, and genetic risk.

1. Supportive Care (Immediate)

Febrile Neutropenia: Immediate empirical IV broad-spectrum antibiotics (e.g., piperacillin-tazobactam) per local antibiogram. Refer to Australian Commission on Safety and Quality in Health Care (ACSQHC) standards.
Transfusion Support: Irradiated, leucodepleted blood products. Platelet transfusion for active bleeding or prophylaxis (threshold often <10 x 10⁹/L).
Tumour Lysis Prophylaxis: IV hydration, rasburicase or allopurinol, electrolyte monitoring.
Fertility Counselling: Urgent referral for reproductive counselling before initiating gonadotoxic chemotherapy.

2. Intensive Induction Chemotherapy ("7+3")

For medically fit patients (typically <70-75 years with good performance status).

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Cytarabine

Cytosar® · Antimetabolite

Adult dose (Induction) 100 mg/m²/day via continuous IV infusion for 7 days (Days 1-7).

PBS status ✔ PBS General Benefit

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Idarubicin

Zavedos® · Anthracycline

Adult dose (Induction) 12 mg/m²/day IV bolus for 3 days (Days 1-3). Alternative: Daunorubicin 60 mg/m²/day x3.

PBS status ✔ PBS General Benefit

Expected outcome: Aplasia (nadir) at 7-14 days, with marrow recovery at 21-28 days. Day 14 marrow is performed to assess blast clearance. Complete remission (CR) is defined as <5% marrow blasts, count recovery, and no extramedullary disease.

3. Post-Remission (Consolidation) Therapy

Stratified by ELN 2022 genetic risk:

Favourable Risk

e.g., t(8;21), inv(16), NPM1mut without FLT3-ITD

Intensive consolidation chemotherapy: typically 3-4 cycles of high-dose cytarabine (HiDAC; 3 g/m² x 6 doses).

Allogeneic transplant not indicated in 1st CR.

Intermediate Risk

e.g., Normal karyotype, NPM1mut with FLT3-ITD

Consider allogeneic transplant based on measurable residual disease (MRD) status and donor availability.

Transplant decision individualised.

Adverse Risk

e.g., TP53 mutation, complex karyotype, monosomal karyotype

Proceed to allogeneic haematopoietic stem cell transplant (allo-HSCT) in 1st CR if medically fit and donor available.

Referral to transplant centre for work-up.

4. Allogeneic Haematopoietic Stem Cell Transplant (allo-HSCT)

The only curative option for intermediate and high-risk AML. Utilises donor-derived stem cells to provide a graft-versus-leukaemia effect. Requires HLA-matched sibling or unrelated donor, or haploidentical family donor. Conditioning regimens are myeloablative or reduced-intensity, tailored to patient age and comorbidities. Associated with significant risks of graft-versus-host disease, infection, and treatment-related mortality.

5. Lower-Intensity & Targeted Therapies

For patients not fit for intensive chemotherapy.

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Venetoclax + Azacitidine

Venclexta® + Vidaza® · BCL-2 inhibitor + Hypomethylating agent

Indication Newly diagnosed AML in adults ineligible for intensive chemotherapy.

PBS status ⚠️ PBS Authority Required

Special Populations

🤰 Pregnancy

Urgent Multidisciplinary Input

Requires collaboration between haematology, obstetrics, and neonatology. First trimester diagnosis may warrant discussion regarding termination due to teratogenic risks of chemotherapy. If continuing pregnancy, intensive chemotherapy can be administered in the 2nd/3rd trimester with careful foetal monitoring.

👧 Paediatrics

Specific Protocols

Paediatric AML is treated on specialised protocols (e.g., ANZCHOG). Dosing is based on body surface area. Outcomes are generally better than in adults. Higher incidence of AML in children with Down syndrome, which is highly curable.

👴 Elderly / Unfit

Lower-Intensity Regimens

Patients >75 years or with significant comorbidities are generally not candidates for "7+3". First-line therapy is venetoclax + azacitidine. Goals of care discussions are essential. Hypomethylating agents alone (azacitidine, decitabine) are an alternative.

🩸 Renal Impairment

Dose Adjustment Required

Cytarabine dose adjustment required for CrCl <60 mL/min. Idarubicin/daunorubicin require dose reduction for significant renal impairment. Rasburicase preferred over allopurinol for tumour lysis in renal impairment. Close monitoring of fluid balance.

Aboriginal and Torres Strait Islander Health Considerations

Important Considerations

Aboriginal and Torres Strait Islander peoples may have a higher incidence of AML and poorer outcomes compared to non-Indigenous Australians. This disparity is influenced by complex social, economic, and historical factors.

Access to Care

Geographic remoteness and cultural barriers can delay diagnosis and referral to tertiary centres for intensive chemotherapy and transplant. Telehealth and patient-assisted travel schemes are crucial.

Clinical Trials & Transplant

Lower rates of participation in clinical trials and access to allogeneic transplant due to systemic factors and donor availability. Early HLA typing and family donor searches are vital.

Cultural Safety

Health services must provide culturally safe environments, engage with Aboriginal Health Workers and Liaison Officers, and respect family structures in communication and decision-making.

📚 References

1. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377.
2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719.
3. Cancer Australia. Acute Myeloid Leukaemia (AML) in Australia. Available at: [https://www.cancer.gov.au](https://www.cancer.gov.au) (Accessed: 2024).
4. Australian Institute of Health and Welfare (AIHW). Cancer in Australia 2021. AIHW, Canberra. 2021.
5. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617-629.
6. Australian Commission on Safety and Quality in Health Care (ACSQHC). National Safety and Quality Health Service Standards. 2nd ed. Sydney: ACSQHC; 2017.
7. Leukaemia Foundation. Understanding Acute Myeloid Leukaemia. Leukaemia Foundation, Australia. 2023.
8. Australasian Leukaemia & Lymphoma Group (ALLG). Clinical Trials. Available at: [https://allg.org.au](https://allg.org.au) (Accessed: 2024).
9. National Health and Medical Research Council (NHMRC). National Statement on Ethical Conduct in Human Research. 2023 Updated. Canberra: NHMRC.
10. Australian Indigenous HealthInfoNet. Summary of Aboriginal and Torres Strait Islander health. 2023. Available at: [https://healthinfonet.ecu.edu.au](https://healthinfonet.ecu.edu.au).