Acute myeloid leukemia (AML) is a malignant clonal disorder of hematopoietic stem and progenitor cells characterized by uncontrolled proliferation and accumulation of immature myeloid cells (blasts) in the bone marrow, peripheral blood, and other tissues.

The accumulation of abnormal myeloid blasts results in:

• Suppression of normal hematopoiesis causing bone marrow failure

• Infiltration of tissues and organs by leukemic cells

The clinical manifestations are mainly caused by:

1. Bone marrow failure

   • Anaemia

   • Neutropenia

   • Thrombocytopenia

2. Organ infiltration

   • Liver

   • Spleen

   • Lymph nodes

   • Meninges

   • Brain

   • Skin

   • Testes

AML is a rapidly progressive disease requiring urgent diagnosis and initiation of treatment.

Epidemiology

AML is the most common acute leukemia in adults.

Epidemiological characteristics include:

• Occurs predominantly in adults

• Incidence increases with advancing age

• Slight male predominance

• Represents approximately 80% of acute leukemias in adults

• Can occur in children but is less common than acute lymphoblastic leukemia (ALL)

Risk factors

Increasing age

The risk of AML increases significantly with age due to accumulation of genetic mutations.

Previous chemotherapy or radiotherapy

Therapy-related AML may occur following exposure to:

• Alkylating agents

• Topoisomerase II inhibitors

• Radiation therapy

Myelodysplastic syndromes and other hematological disorders

AML may develop from:

• Myelodysplastic syndrome (MDS)

• Myeloproliferative neoplasms

Genetic abnormalities

Associated abnormalities include:

• Chromosomal translocations

• Mutations affecting myeloid cell differentiation and proliferation

Environmental exposure

Risk may increase with exposure to:

• Benzene

• Certain industrial chemicals

Radiation exposure

High-dose radiation exposure increases risk.

Pathophysiology

AML results from malignant transformation of myeloid precursor cells.

The disease process involves:

1. Genetic mutations affecting normal myeloid differentiation

2. Accumulation of immature myeloid blasts

3. Replacement of normal bone marrow cells

4. Reduced production of normal blood cells

5. Spread of leukemic cells to other tissues

Bone marrow replacement leads to:

• Reduced red blood cell production → anaemia

• Reduced neutrophil production → infection risk

• Reduced platelet production → bleeding tendency

Clinical presentation

AML usually presents acutely with symptoms related to marrow failure and leukemic infiltration.

The severity of symptoms depends on:

• Degree of cytopenias

• Leukocyte burden

• Presence of extramedullary disease

Symptoms

Symptoms due to anaemia

• Fatigue

• Weakness

• Shortness of breath

• Dizziness

• Reduced exercise tolerance

Symptoms due to neutropenia

• Recurrent infections

• Fever

• Mouth ulcers

• Sore throat

Symptoms due to thrombocytopenia

• Easy bruising

• Bleeding gums

• Nose bleeding

• Petechiae

• Heavy menstrual bleeding

Symptoms due to organ infiltration

Lymph node involvement

• Enlarged lymph nodes

Hepatosplenic involvement

• Abdominal discomfort

• Abdominal fullness

Central nervous system involvement

• Headache

• Confusion

• Seizures

• Neurological deficits

Skin infiltration

• Skin nodules

• Leukemia cutis

Clinical signs

General examination

• Pallor

• Fever

• Reduced performance status

• Weight loss

Bleeding manifestations

• Petechiae

• Ecchymosis

• Mucosal bleeding

Infection-related findings

• Fever

• Signs of bacterial or fungal infection

Organ enlargement

• Hepatomegaly

• Splenomegaly

• Lymphadenopathy

Neurological findings

May occur with CNS infiltration:

• Cranial nerve abnormalities

• Altered mental status

• Focal neurological signs

Differential diagnosis

• Acute lymphoblastic leukemia (ALL)

• Chronic myeloid leukemia in blast crisis

• Myelodysplastic syndrome

• Aplastic anaemia

• Severe infections causing leukemoid reactions

• Lymphoma with marrow involvement

• Myeloproliferative neoplasms

Diagnostic criteria

Diagnosis of AML requires:

• Evidence of increased myeloid blasts in bone marrow or peripheral blood

• Usually ≥20% myeloid blasts in bone marrow or blood

Diagnosis is confirmed through:

• Bone marrow aspiration and trephine biopsy

• Immunophenotyping

• Cytogenetic and molecular studies

Classification is based on the WHO classification of AML.

Investigations

Laboratory investigations

Full blood count (FBC)

May demonstrate:

• Anaemia

• Thrombocytopenia

• Abnormal white blood cell count

Peripheral blood film

May show:

• Circulating blasts

• Abnormal myeloid cells

• Auer rods in some AML subtypes

Liver function tests (LFT)

To assess baseline organ function before treatment.

Renal function tests (RFT)

Including:

• Urea

• Creatinine

• Electrolytes

Coagulation profile

Important to assess:

• Bleeding risk

• Disseminated intravascular coagulation (DIC)

Bone marrow examination

Bone marrow aspiration and trephine biopsy

Required for:

• Diagnosis

• Classification

• Assessment of remission status

Immunophenotyping and molecular investigations

Flow cytometry

Used to identify:

• Myeloid lineage markers

• Leukemia subtype

Cytogenetic and molecular evaluation

Used for:

• Risk stratification

• Treatment selection

• Prognosis assessment

Cardiac assessment

ECG and echocardiography

Performed before anthracycline chemotherapy to assess cardiac function.

Staging and classification

AML is classified according to the World Health Organization (WHO) classification based on:

• Genetic abnormalities

• Morphology

• Immunophenotype

• Clinical characteristics

Unlike solid cancers, AML is not staged using TNM staging.

Management

AML requires urgent specialist hematology management.

Treatment depends on:

• Patient age

• Performance status

• Cytogenetic risk category

• Comorbidities

• Disease subtype

Management includes:

1. Initial assessment and stabilization

2. Induction chemotherapy

3. Assessment of remission

4. Consolidation therapy

5. Stem cell transplantation in selected patients

6. Relapsed disease management

Non-pharmacological treatment

Supportive care

Essential components include:

• Management of infections

• Blood product transfusion support

• Nutritional support

• Prevention and management of tumour lysis syndrome

Infection prevention

Includes:

• Prompt antibiotic therapy for febrile neutropenia

• Infection control measures

• Antimicrobial prophylaxis where indicated

Hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-hSCT) may be considered in:

• High-risk AML

• Relapsed AML

• Selected patients achieving remission

Pharmacological treatment

Induction therapy

The aim is to achieve complete remission.

7 + 3 regimen

Cytarabine – 100 mg/m² – intravenous continuous infusion – once daily for 7 days

AND

Daunorubicin – 60 mg/m² – intravenous infusion – once daily for 3 days

Consolidation therapy

For patients achieving remission:

(Blast cells <2% in bone marrow)

High-dose cytarabine(HiDAC) – intravenous – according to protocol schedule

Used to reduce relapse risk.

Relapsed AML

FLAG-IDA regimen

Used for relapsed disease.

Fludarabine

Fludarabine – 30 mg/m² – intravenous – daily for 4 days

AND

High-dose cytarabine

Cytarabine – 2 g/m² – intravenous – daily for 4 days

AND

Filgrastim – 300 mcg/m² – subcutaneous – daily for 5 days

AND

Idarubicin – 10 mg/m² – intravenous – daily for 3 days

If remission is achieved:

• Consider allogeneic hematopoietic stem cell transplantation

Palliative treatment

For patients unsuitable for intensive chemotherapy:

Low-dose cytarabine

Cytarabine – 20 mg – subcutaneous – every 12 hours – for 10 days

OR

Azacitidine – 75 mg/m²/day – subcutaneous – for 7 days

Frequency:

• Repeat every 4–6 weeks

Management according to underlying cause

Acute promyelocytic leukemia (APL)

APL is a hematological emergency because of the high risk of:

• Disseminated intravascular coagulation (DIC)

• Severe bleeding

• Differentiation syndrome

Treatment should begin immediately when APL is suspected based on morphology, without waiting for genetic confirmation.

Differentiation syndrome management

Dexamethasone – 10 mg – intravenous – twice daily – for 3 days or until symptoms resolve

If severe:

• Consider stopping all-trans retinoic acid (ATRA)

Treatment of acute promyelocytic leukemia

Induction phase

All-trans retinoic acid (ATRA)

ATRA – 45 mg/m²/day – intravenous – daily until remission

AND

Arsenic trioxide – 0.15 mg/kg/day – intravenous – daily until bone marrow remission

OR

ATRA – 45 mg/m²/day – intravenous – daily

AND

Daunorubicin – 50 mg/m² – intravenous – for 4 days

PLUS/MINUS

Cytarabine – 200 mg/m² – intravenous – for 7 days

Cytarabine is added in patients with high-risk relapse.

Consolidation phase

Options include:

• ATRA and arsenic trioxide

• ATRA and daunorubicin

• Arsenic trioxide and daunorubicin

• Daunorubicin and cytarabine

Maintenance phase

Options include:

ATRA alone

OR

Combination maintenance

ATRA – 45 mg/m²/day – oral – for 15 days every 3 months

PLUS

6-mercaptopurine – 60 mg/m² – oral – once daily

PLUS

Methotrexate – 20 mg/m² – oral – once weekly

Duration:

• 2 years

Referral

All suspected AML patients should be urgently referred to a specialist hematology centre.

Urgent referral indications

• Suspected leukemia on blood film

• Severe anaemia

• Severe thrombocytopenia with bleeding

• Febrile neutropenia

• Suspected APL

• DIC

• Neurological symptoms

• Hyperleukocytosis

Complications

Disease-related complications

• Severe infection

• Bleeding

• Disseminated intravascular coagulation

• Tumour lysis syndrome

• Leukostasis

• Organ infiltration

Treatment-related complications

• Neutropenia

• Febrile neutropenia

• Mucositis

• Cardiotoxicity

• Infertility

• Secondary malignancies

Prognosis

Prognosis depends on:

• Patient age

• Cytogenetic risk group

• Molecular abnormalities

• Response to induction therapy

• Presence of relapse

Younger patients with favourable-risk genetic abnormalities generally have better outcomes.

Relapsed AML carries a poorer prognosis.

Prevention

Primary prevention

• Minimize unnecessary exposure to radiation and carcinogenic chemicals

• Reduce occupational exposure to benzene

• Avoid unnecessary cytotoxic therapy

Secondary prevention

• Early investigation of persistent cytopenias

• Prompt referral for abnormal blood counts

• Early diagnosis of myelodysplastic syndromes

Tertiary prevention

• Regular monitoring after treatment

• Surveillance for relapse

• Management of long-term chemotherapy complications