Acute Myeloid Leukemia (AML)

Exposure to Environmental and Chemical Agents

• Radiation and benzene exposure: Prolonged exposure to radiation and benzene increases the risk of AML. Cytogenetic abnormalities associated with radiation and benzene exposure typically involve chromosomes 5 and 7. Alkylating agents, such as cyclophosphamide, melphalan, and mechlorethamine, are linked to these changes and often result in a latency period of 5–10 years before AML development.
• Topoisomerase II inhibitors: Agents such as etoposide and anthracyclines (e.g., doxorubicin) are associated with cytogenetic abnormalities like 11q23 rearrangements (KMT2A). AML from these agents typically arises after 1–5 years.

Antecedent Hematologic Disorders

• Myelodysplastic syndrome (MDS): High-risk forms of MDS frequently evolve into AML.
• Myeloproliferative neoplasms: Conditions such as myelofibrosis, polycythemia vera, and essential thrombocythemia may progress to secondary AML.
• Aplastic anemia and chronic hematologic disorders: Conditions like paroxysmal nocturnal hemoglobinuria and chronic myeloid leukemia are also associated with AML progression.

Inherited Genetic Conditions and Familial Syndromes

• Congenital syndromes: Bloom syndrome, Fanconi anemia, Wiskott-Aldrich syndrome, and neurofibromatosis predispose to AML, often manifesting during childhood.
• Germline mutations: RUNX1, CEBPA, and GATA2 mutations are well-documented familial genetic anomalies contributing to AML.
• Hereditary cancer predisposition syndromes: Syndromes like Li-Fraumeni may feature AML, though solid tumors predominate.

Constitutional Chromosomal Abnormalities

• Trisomy syndromes: Conditions like Down syndrome (trisomy 21), Klinefelter syndrome (XXY), and Patau syndrome (trisomy 13) are strongly linked to AML. In those with Down syndrome, additional chromosomal abnormalities such as del(6q) or dup(7q) contribute to the risk.

Environmental Exposures

• Additional environmental exposures linked to AML include smoking, pesticides, alcohol, and occupational hazards (e.g., abattoir workers and those exposed to diesel fumes or hair dyes).

Cytogenetic Abnormalities and Genetic Mutations

• Cytogenetic changes: Abnormalities may be balanced (e.g., t(8;21), t(15;17)) or unbalanced (e.g., deletions of chromosomes 5q, 7q, or 11q).
• Genetic mutations: Key mutations include FLT3, TP53, NPM1, ASXL1, and CEBPA. These mutations carry prognostic implications and guide therapeutic decisions.

Core Pathogenesis

• AML arises from the malignant transformation of hematopoietic precursor cells, leading to clonal expansion and arrested maturation.
• Immature myeloid cells (blasts):
  • Fail to differentiate into functional neutrophils, red blood cells, or platelets.
  • Retain a self-renewing leukemic stem cell population.
  • Block normal haematopoiesis via overcrowding and secretion of inhibitory cytokines.

Key Genetic Abnormalities

• Chromosomal translocations:
  • t(15;17) (PML–RARA) in acute promyelocytic leukaemia.
  • t(8;21) (RUNX1–RUNX1T1), inv(16) (CBFB–MYH11) in core-binding factor AML.
• Point mutations:
  • Commonly affect NPM1, FLT3, TP53, CEBPA, and IDH2.
• Epigenetic and RNA-splicing genes:
  • Alter chromatin regulation and RNA processing.
• Chromosomal aneuploidy:
  • Includes inv(3), t(6;9), and other whole chromosome gains/losses.

Bone Marrow Dynamics

• Blasts accumulate in marrow, blood, and extramedullary tissues (e.g. spleen, liver).
• Bone marrow failure results from:
  • Physical crowding by blasts.
  • Biochemical inhibition of progenitor cells.

Clinical Consequences of Bone Marrow Failure

• Anaemia:
  • Pallor, fatigue, dizziness, dyspnoea.
• Neutropenia:
  • Recurrent bacterial/fungal infections (e.g. Candida, Aspergillus).
• Thrombocytopenia:
  • Mucosal bleeding, bruising, petechiae.

Leukaemic Cell Proliferation and Infiltration

• Tissue infiltration:
  • Lungs, lymph nodes, gums, skin, testicles, CNS.
• Leukostasis (WBC >100,000/μL):
  • Respiratory distress.
  • Altered mental status.

Molecular Heterogeneity and Disease Classification

• Genomic studies show numerous driver mutations across 76 genes.
• Commonly mutated genes:
  • NPM1, FLT3, TP53, CEBPA.
• Fusion genes:
  • PML–RARA, RUNX1–RUNX1T1, CBFB–MYH11.
• Classification based on mutations guides prognosis and treatment.

Prognostic Implications

• Favourable:
  • NPM1 mutation without FLT3.
• Poor:
  • TP53 mutation.
  • Complex karyotypes.

Staging and Classification of Acute Myeloid Leukaemia (AML)

French-American-British (FAB) Classification

• Based on morphology and cytochemistry.
• Subtypes:
  • M0: Undifferentiated AML
  • M1: AML with minimal maturation
  • M2: AML with maturation
  • M3: Acute promyelocytic leukaemia (APL)
  • M4: Acute myelomonocytic leukaemia
  • M5: Acute monocytic leukaemia
  • M6: Acute erythroid leukaemia
  • M7: Acute megakaryocytic leukaemia

World Health Organization (WHO) Classification

• Integrates genetic and molecular findings.
• Groups:
• AML with defining genetic abnormalities
  • AML with t(8;21) (RUNX1::RUNX1T1)
  • AML with inv(16) or t(16;16) (CBFB::MYH11)
  • APL with t(15;17) (PML::RARA)
  • AML with t(9;11) (MLLT3::KMT2A)
  • AML with t(6;9) (DEK::NUP214)
  • AML with inv(3) or t(3;3) (GATA2, MECOM)
  • AML (megakaryoblastic) with t(1;22) (RBM15::MRTFA)
  • AML with mutated NPM1
  • AML with CEBPA mutations
• AML with myelodysplasia-related changes
  • Defined by MDS history or cytogenetic abnormalities (e.g. del(5q), -7).
• Therapy-related myeloid neoplasms
  • Occur post chemotherapy, radiotherapy, or toxin exposure.
• AML not otherwise specified (NOS)
  • AML with minimal differentiation
  • AML without maturation
  • AML with maturation
  • Acute myelomonocytic leukaemia
  • Acute monocytic leukaemia
  • Acute erythroid leukaemia
  • Acute megakaryoblastic leukaemia
  • Acute basophilic leukaemia
  • Acute panmyelosis with myelofibrosis
• Other categories
  • Myeloid sarcoma
  • Myeloid proliferations related to Down syndrome

International Consensus Classification (ICC)

• Uses hierarchical structure and diagnostic qualifiers.
• Key subtypes:
  • AML with t(8;21) (RUNX1::RUNX1T1)
  • AML with inv(16) or t(16;16) (CBFB::MYH11)
  • AML with t(9;11) (MLLT3::KMT2A)
  • AML with t(6;9) (DEK::NUP214)
  • AML with t(15;17) (PML::RARA)
  • AML with mutated NPM1 or CEBPA
  • AML with BCR::ABL1 (≥20% blasts)
  • AML with myelodysplasia-related mutations or cytogenetic abnormalities

Aetiological Classification

• De novo AML:
  • Occurs without prior haematologic disorder or therapy.
• Secondary AML (s-AML):
  • Evolves from MDS or myeloproliferative neoplasms.
• Therapy-related AML (t-AML):
  • Caused by prior chemotherapy, radiation, or toxins.

Recent Updates in AML Classification

• ELN 2022:
  • Introduced ≥10% blast threshold for AML with specific genetics.
  • Recognised in-frame CEBPA mutations as a distinct entity.
• WHO 2022 (5th edition):
  • Expanded genetic definitions.
  • Emphasised integrated cytogenetic and molecular diagnosis.
• ICC qualifiers:
  • Identifies therapy-related AML, MDS/MPN progression, or germline predisposition.

Incidence and Prevalence

• In the United States, the American Cancer Society (ACS) estimates 20,800 new cases of AML in 2024:
  • 11,600 in men
  • 9,200 in women
• In the UK, approximately 2,945 new cases were reported annually based on 2017–2018 data.
• AML incidence increases with age:
  • Median age at diagnosis is ~68–70 years.
  • In the US, 61% of cases occur in individuals aged ≥65 years.
  • In the UK, 66% of cases are diagnosed in this age group.

Gender and Racial Disparities

• AML is more common in men than women:
  • Male-to-female ratio is 1.5:1 in the US.
  • In the UK, 56% of cases occur in males and 44% in females.
• Higher incidence reported in non-Hispanic White populations compared to other racial and ethnic groups.

Mortality

• AML is a major contributor to cancer-related deaths.
• The ACS estimates 11,220 AML-related deaths in the US in 2024:
  • 6,290 in men
  • 4,930 in women

Environmental and Genetic Factors

• Recognised environmental risk factors include:
  • Genotoxic chemicals
  • Ionising radiation
  • Tobacco use
  • Prior cytotoxic chemotherapy
• AML may develop after clonal hematopoiesis or antecedent haematologic disorders such as:
  • Myelodysplastic syndromes (MDS)
  • Myeloproliferative neoplasms (MPNs)
  • Clonal cytopenias of unknown significance
• Rarely, AML arises from inherited genetic mutations in tumour suppressor or DNA repair genes (e.g., RUNX1, CEBPA, DDX41).
• Familial predisposition may be associated with coexisting haematologic disorders or other malignancies.

Regional Insights

• AML is more frequently diagnosed in developed nations:
  • Likely due to greater diagnostic availability and environmental exposures.
• Occupational hazards, especially in male-dominated industries, may contribute to the higher male incidence of AML.

Key Historical Findings

Symptoms of Bone Marrow Failure

• Fatigue: Often a progressive symptom attributed to anaemia or the systemic effects of inflammatory cytokines.
• Dizziness: Frequently reported due to anaemia or systemic inflammation.
• Dyspnea: Can result from anaemia or secondary to pulmonary infections.
• Palpitations: Reflect the body's response to anaemia.
• Fever: A common initial symptom caused by infections due to neutropenia or, less commonly, systemic inflammatory cytokines.
• Bleeding: Manifesting as mucosal bleeding (e.g., gums, nose), menorrhagia, or petechiae, often attributed to thrombocytopenia.
• Recurrent Infections: Infections are frequent due to neutropenia, with common sites including the mouth, dental abscesses, nasopharynx, perianal region, and lungs.

Symptoms of Leukemic Infiltration

• Bone Pain: Often described in the sternum or long bones, resulting from marrow expansion.
• Abdominal Fullness: Associated with splenomegaly or hepatomegaly due to leukemic infiltration.
• Oral Symptoms: Gingival hypertrophy or bleeding, particularly in monocytic AML subtypes.
• Skin Changes: May include rashes, nodules, or symptoms associated with Sweet’s syndrome or leukemia cutis.
• Neurologic Symptoms: Headaches, confusion, or focal neurologic deficits may indicate central nervous system involvement or leukostasis in hyperleukocytosis.

Risk Factor History

• Age: AML incidence increases significantly with age, most commonly diagnosed in patients over 65 years.
• Previous Cancer Therapy: Exposure to alkylating agents or topoisomerase inhibitors can predispose to secondary AML, typically with a latency period of 1–10 years.
• Preexisting Hematologic Disorders: A history of myelodysplastic syndrome, myeloproliferative disorders, or aplastic anaemia suggests a higher risk of developing AML.
• Inherited Genetic Conditions: Patients may report family histories of syndromes such as Li-Fraumeni, Down syndrome, or Fanconi anaemia.
• Environmental Exposures: Previous occupational exposure to benzene or a history of smoking could be relevant.

Medical Emergencies Presenting in History

• Hyperleukocytosis/Leukostasis: Symptoms include acute respiratory distress and altered mental status. These typically occur in patients with very high white blood cell counts (>100,000/μL).
• Severe Infection: Febrile neutropenia may present with symptoms of infection without specific localisation, requiring immediate intervention.
• Severe Bleeding: History of significant bruising or mucosal bleeding may indicate a coagulopathy, particularly in acute promyelocytic leukemia (APL) due to disseminated intravascular coagulation (DIC).

Common Findings

Signs of Bone Marrow Failure

• Pallor: Reflecting underlying anaemia.
• Petechiae and Ecchymoses:
  • Small, non-palpable, haemorrhagic rashes on the lower extremities (petechiae).
  • Larger dermal bruises (ecchymoses) indicating significant thrombocytopenia.
• Purpura: Intermediate-sized bruises due to thrombocytopenia or disseminated intravascular coagulation (DIC).
• Fever: Often related to infections secondary to neutropenia.

Signs of Leukemic Infiltration

• Hepatosplenomegaly: May be palpable and associated with abdominal discomfort.
• Lymphadenopathy: Rare but present in cases of leukemic infiltration into lymph nodes.
• Leukemia Cutis:
  • Nodular, violaceous, or gray-blue infiltrative skin lesions, particularly in monocytic AML subtypes.
• Chloromas (Myeloid Sarcomas):
  • Extramedullary deposits of leukemic cells, which may involve soft tissues, bones, or organs.
• Gingival Hypertrophy:
  • Common in monocytic AML, causing swollen and bleeding gums.

Signs of Leukostasis

• Respiratory Distress: Caused by impaired pulmonary perfusion due to high leukocyte counts (>100,000/μL).
• Altered Mental Status: Resulting from reduced CNS perfusion.

Other Findings

• Oropharyngeal Lesions: Fungal infections, gingival bleeding, or hypertrophy.
• Skin Changes: Tender nodules, plaques (Sweet’s syndrome), or ulcers (e.g., pyoderma gangrenosum).
• Neurological Signs: Focal deficits or confusion due to CNS involvement.
• Abdominal Findings: Rare acute abdomen due to leukemic infiltration or infection.

Medical Emergencies Identifiable on Examination

• Leukostasis: Respiratory distress or altered consciousness necessitating urgent intervention.
• Febrile Neutropenia: Suggests infection and requires immediate broad-spectrum antibiotics.
• DIC: Bruising, petechiae, or overt bleeding, especially in acute promyelocytic leukaemia (APL).

First-Line Investigations

Complete Blood Count (CBC) with Differential

• Findings:
  • Most patients show anaemia, neutropenia, and/or thrombocytopenia.
  • Leukocytosis (>100,000/µL) in hyperleukocytosis may predispose to tumour lysis syndrome (TLS), leukostasis, and CNS involvement.
  • Severe neutropenia (<500 granulocytes/µL) increases the risk of infections.
• Clinical Significance:
  • Helps identify complications such as TLS and guides urgent interventions for hyperleukocytosis.

Peripheral Blood Smear

• Findings:
  • Presence of myeloid blasts with Auer rods or Phi bodies is diagnostic of AML.
  • Acute promyelocytic leukaemia (APL) shows hypergranular promyelocytes, often with bundles of Auer rods.
• Clinical Significance:
  • Differentiates AML subtypes, particularly APL, which requires distinct treatment.

Coagulation Panel

• Findings:
  • Disseminated intravascular coagulation (DIC) indicators include prolonged PT and aPTT, low fibrinogen, and elevated D-dimer.
• Clinical Significance:
  • DIC is most common in APL and requires urgent management.

Serum Biochemistry

• Electrolytes:
  • Hyperkalaemia, hypocalcaemia, hyperphosphataemia, and hyperuricaemia suggest TLS.
• Liver Function Tests:
  • May be abnormal due to hepatic infiltration or drug toxicity.
• Renal Function Tests:
  • Elevated blood urea nitrogen (BUN) and creatinine may indicate renal impairment from TLS.
• Serum Lactate Dehydrogenase (LDH):
  • Elevated levels correlate with tumour burden and disease severity.
• Clinical Significance:
  • Identifies TLS, a potential oncological emergency.

Bone Marrow Evaluation

• Techniques:
  • Bone marrow aspiration and biopsy with cytomorphology.
  • Flow cytometry for immunophenotyping (e.g., CD34, CD33, myeloperoxidase).
  • Immunohistochemistry when aspirates are inadequate.
• Findings:
  • Hypercellularity with >20% myeloid blasts.
  • APL shows hypergranular promyelocytes or hypogranular variants.
• Clinical Significance:
  • Confirms AML and differentiates it from acute lymphoblastic leukaemia (ALL).

Genetic Testing

• Techniques:
  • Cytogenetics (karyotyping, FISH).
  • Molecular analysis (e.g., NGS panels).
• Findings:
  • Specific mutations (e.g., NPM1, FLT3, TP53) and chromosomal rearrangements (e.g., t(15;17), t(8;21)).
• Clinical Significance:
  • Guides risk stratification and targeted therapies.

Additional Investigations

Central Nervous System (CNS) Assessment

• Imaging:
  • MRI or CT for neurological symptoms.
• Lumbar Puncture:
  • Identifies CNS leukemic involvement; may guide intrathecal chemotherapy.

Imaging for Extramedullary Disease

• FDG-PET/CT:
  • Evaluates suspected extramedullary lesions (e.g., myeloid sarcomas).
• Chest X-ray:
  • Identifies pneumonia or mediastinal masses.

Cardiac Assessment

• Echocardiography or MUGA Scan:
  • Evaluates cardiac function in patients with a history of cardiac disease or prior exposure to cardiotoxic drugs.

Approach to Emergencies

• Tumour Lysis Syndrome:
  • Monitor and correct electrolyte imbalances; initiate hydration and allopurinol.
• Hyperleukocytosis:
  • Cytoreduction with hydroxyurea or leukapheresis.
• DIC in APL:
  • Supportive care with fibrinogen replacement and targeted APL therapy (e.g., ATRA).

Acute Lymphoblastic Leukaemia (ALL)

• Clinical Features:
  • Often indistinguishable from AML on clinical grounds alone.
• Key Investigations:
  • Bone marrow analysis reveals lymphoblasts.
  • Immunophenotyping: Positive for terminal deoxynucleotidyl transferase (TdT) and negative for myeloperoxidase.
  • Expression of lymphoid markers such as CD19 and CD20.

Mixed Phenotype Acute Leukaemia (MPAL)

• Clinical Features:
  • Presents with overlapping characteristics of lymphoid and myeloid malignancies.
• Key Investigations:
  • Immunophenotyping shows markers from both myeloid and lymphoid lineages.
  • Genetic testing may reveal Philadelphia chromosome (BCR::ABL1), which supports the diagnosis but does not exclude other conditions.

Chronic Myeloid Leukaemia (CML) in Blast Crisis

• Clinical Features:
  • History of chronic-phase CML; symptoms resemble AML during blast crisis.
• Key Investigations:
  • Peripheral blood smear: Increased basophils and eosinophils may be noted.
  • Presence of Philadelphia chromosome confirms CML, though it can also occur in Philadelphia-positive AML.

Myelodysplastic Syndrome (MDS)

• Clinical Features:
  • Chronic cytopenias and evidence of dysplasia; may progress to AML.
• Key Investigations:
  • Blood smear shows dysplastic features in multiple cell lines.
  • Bone marrow biopsy: Blasts <20% differentiate high-risk MDS from AML.
  • Cytogenetic abnormalities such as deletions in chromosomes 5 or 7.

Aplastic Anaemia

• Clinical Features:
  • Pancytopenia without blasts; no organomegaly or extramedullary involvement.
• Key Investigations:
  • Hypocellular bone marrow biopsy with no increase in blasts.
  • Negative Coombs test; absence of dysplasia or clonal populations.

Myelofibrosis

• Clinical Features:
  • Gradual onset of anaemia and splenomegaly.
• Key Investigations:
  • Peripheral smear shows teardrop-shaped red blood cells.
  • Bone marrow biopsy reveals reticulin fibrosis and no significant blast population.

Drug-Induced Bone Marrow Failure

• Clinical Features:
  • History of drug exposure (e.g., chloramphenicol, methotrexate).
• Key Investigations:
  • Hypocellular bone marrow with no blast excess.
  • Improvement upon drug discontinuation or antidote administration.

Vitamin B12 Deficiency

• Clinical Features:
  • Neurological symptoms such as paraesthesia and ataxia; macrocytic anaemia.
• Key Investigations:
  • Low serum vitamin B12.
  • Peripheral blood smear shows megaloblastic changes.

Leukaemoid Reaction

• Clinical Features:
  • Elevated white blood cell count due to infection or inflammation.
• Key Investigations:
  • Bone marrow biopsy shows no blast excess.
  • Peripheral smear reveals mature neutrophils with toxic granulations.

Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusions

• Clinical Features:
  • Persistent eosinophilia and systemic involvement.
• Key Investigations:
  • Genetic testing for PDGFRA, PDGFRB, and FGFR1 fusion genes.
  • Elevated serum tryptase levels.

Treatment Goals

• Short-term: Achieve complete remission and reduce minimal residual disease (MRD).
• Long-term: Enhance disease-free and overall survival.
  • In younger and fit patients, the goal is a potential cure.
  • In older or frail patients, the focus is on remission, prolonged survival, and quality of life.

Treatment Phases

Induction Therapy

• Aim: Achieve complete remission (CR).
• Standard regimen: Cytarabine (7 days) plus an anthracycline (daunorubicin or idarubicin for 3 days) – the "7+3" regimen.
• Alternatives:
  • Liposomal daunorubicin/cytarabine (CPX-351) for therapy-related AML or AML with myelodysplasia-related changes (AML-MRC).
  • FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) in select cases.
• CR rates:
  • Approximately 70–80% in patients under 60 years.
  • Around 60–70% in patients aged 60 or older, depending on disease biology.
• Patients failing to achieve remission are classified as refractory.

Consolidation Therapy

• Aim: Eliminate residual disease and prevent relapse.
• High-dose cytarabine (HiDAC) is typically administered over several cycles.
• CPX-351 may be continued in patients initially treated with it.
• Consolidation may include allogeneic stem cell transplantation (SCT) for high-risk patients.

Stem Cell Transplantation (SCT)

• Allogeneic SCT: Preferred for intermediate- or high-risk AML, or in patients with persistent MRD.
• Autologous SCT: May be considered in select intermediate-risk patients without a donor.
• Reduced-intensity conditioning SCT is used in older or frail individuals.

Targeted Therapies

• CD33-positive AML:
  • Gemtuzumab ozogamicin combined with chemotherapy in favourable/intermediate-risk patients.
• FLT3-mutated AML:
  • Midostaurin or quizartinib during induction/consolidation.
  • Post-consolidation maintenance with FLT3 inhibitors such as sorafenib or gilteritinib.
• IDH1/IDH2-mutated AML:
  • Ivosidenib (IDH1) or enasidenib (IDH2), often combined with azacitidine.
• TP53-mutated AML:
  • Associated with poor prognosis; low-intensity regimens or clinical trials are preferred (e.g., venetoclax with azacitidine).

Maintenance Therapy

• Oral azacitidine for patients in remission who are ineligible for intensive consolidation or SCT.
• FLT3 inhibitors (e.g., sorafenib or gilteritinib) as post-SCT maintenance.

Low-Intensity Therapy

• For patients unfit for intensive induction:
  • Venetoclax with azacitidine, decitabine, or low-dose cytarabine.
  • Glasdegib with low-dose cytarabine.
  • Ivosidenib or enasidenib for IDH-mutated AML.

Management of Acute Promyelocytic Leukaemia (APL)

• Defined by the PML::RARA fusion gene, APL is a haematological emergency due to high risk of coagulopathy.
• Induction:
  • ATRA with arsenic trioxide in non-high-risk APL.
  • ATRA with arsenic trioxide and chemotherapy in high-risk cases.
• Consolidation and maintenance:
  • ATRA-based regimens continued; maintenance often omitted in low-risk cases with MRD monitoring.

Relapsed or Refractory AML

• Salvage options:
  • High-dose cytarabine or FLAG-IDA.
  • Gilteritinib for FLT3-mutated AML.
  • Ivosidenib or enasidenib for IDH-mutated AML.
• Allogeneic SCT is recommended if remission is achieved.
• Palliative care for patients not suitable for intensive therapy.

Supportive Care

• Infection prevention: Antibiotic and antifungal prophylaxis during neutropenia.
• Transfusions: Red blood cell and platelet support as needed.
• Tumour lysis syndrome: Prophylaxis with hydration, allopurinol, or rasburicase.
• Differentiation syndrome: Dexamethasone promptly initiated for fever, hypoxia, or fluid overload.

Overall Survival Rates

• The 5-year survival rate for AML in the US (2014–2020) is 31.9%.
• Survival varies by age:
  • Patients aged <50 years: 63.7% 5-year survival.
  • Patients aged 50–64 years: 38.9% 5-year survival.
  • Patients aged >65 years: 11.2% 5-year survival.

Prognostic Factors

Age

• Younger patients (<60 years):
  • Cure rates are approximately 35–40% with intensive chemotherapy.
  • Outcomes are better with favourable-risk cytogenetics (e.g., t(8;21), t(15;17), inv(16)).
• Older patients (≥60 years):
  • Prognosis is worse due to higher rates of adverse cytogenetics, antecedent MDS, multidrug resistance, and comorbidities.
  • Only around 10% achieve long-term survival.

Cytogenetics and Molecular Abnormalities

• Favourable cytogenetics:
  • Long-term survival approximately 65%.
  • Includes:
    • t(8;21) (RUNX1::RUNX1T1)
    • t(15;17) (PML::RARA)
    • inv(16) or t(16;16) (CBFB::MYH11)
• Intermediate cytogenetics:
  • Includes normal cytogenetics.
  • Associated with ~35% survival.
• Adverse cytogenetics:
  • Includes -5, -7, monosomal karyotype, or complex karyotypes.
  • Survival below 10%.

Molecular Markers

• FLT3 mutations:
  • Associated with poor prognosis due to high relapse rates.
  • FLT3 inhibitors are improving outcomes.
• NPM1 mutations:
  • Favourable prognosis if FLT3-ITD is absent.
• TP53 mutations:
  • Very poor outcomes; often resistant to conventional therapy.
• CEBPA biallelic mutations:
  • Linked to improved survival.
• TET2 mutations:
  • Associated with adverse outcomes even in otherwise favourable-risk patients.

Disease Subtypes

• De novo AML:
  • Best outcomes.
• Secondary AML (s-AML):
  • Worse outcomes, especially when evolving from MDS or MPNs.
• Therapy-related AML (t-AML):
  • Linked to prior chemotherapy or radiation.
  • 5-year survival approximately 10%.

Acute Promyelocytic Leukaemia (APL)

• Cure rates exceed 80% with modern regimens (e.g., ATRA and arsenic trioxide).
• Prognosis is highly favourable compared to other AML types.

Role of Minimal Residual Disease (MRD)

• PCR and flow cytometry detect MRD in patients in remission.
• Persistent MRD is associated with a high relapse risk, especially in t(8;21) AML.

Short-Term Complications

Tumour Lysis Syndrome (TLS)

• Overview: An oncological emergency that can occur spontaneously or shortly after treatment initiation.
• Features:
  • Hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia, and elevated lactate dehydrogenase (LDH).
  • Complications include cardiac arrhythmias, seizures, acute renal failure, and death.
• Management:
  • Vigorous hydration, phosphate binders, and hypouricaemic agents (e.g., allopurinol, rasburicase).
  • Close monitoring and TLS prophylaxis, especially with agents like venetoclax.

Leukostasis (Symptomatic Hyperleukocytosis)

• Overview: Caused by obstruction of microvasculature by leukemic blasts, typically when WBC >100,000/μL.
• Features: Respiratory distress, altered mental status, and end-organ ischaemia.
• Management:
  • Urgent leukoreduction using hydroxyurea or leukapheresis.
  • Supportive care for symptom control.

Neutropenia and Infections

• Overview: A common consequence of disease and treatment, predisposing to life-threatening infections.
• Features: Typically bacterial (gram-negative and gram-positive), though fungal and viral infections may occur.
• Management:
  • Prophylactic antibiotics (e.g., fluoroquinolones) and antifungals (e.g., posaconazole).
  • Reverse isolation, hygiene measures, and dietary modifications.

Pancytopenia

• Overview: Results from marrow infiltration and treatment-induced cytopenias.
• Management:
  • Platelet transfusion for counts <10,000/μL or higher if bleeding or APL is present.
  • Red cell transfusions to maintain haematocrit >25%.

Disseminated Intravascular Coagulation (DIC)

• Overview: Most frequently associated with APL and monocytic subtypes.
• Features: Bleeding and/or thrombosis due to widespread coagulopathy.
• Management:
  • Initiate ATRA in APL promptly.
  • Supportive transfusion with platelets, cryoprecipitate, or FFP to correct coagulation abnormalities.

Central Nervous System (CNS) Leukaemia

• Overview: Rare in adults, but more frequent in children or those with monocytic AML.
• Features: Headache, confusion, seizures.
• Management:
  • Diagnostic lumbar puncture.
  • Intrathecal chemotherapy (e.g., cytarabine, methotrexate).

Differentiation Syndrome

• Overview: Occurs during treatment with ATRA or arsenic trioxide.
• Features: Fever, respiratory symptoms, fluid retention, leukocytosis, pulmonary infiltrates.
• Management:
  • Prompt dexamethasone.
  • Temporary treatment suspension in severe cases.

Long-Term Complications

Therapy-Related Myelodysplasia and Secondary Malignancies

• Overview: Chemotherapy and radiotherapy increase risk of secondary haematological cancers.
• Management: Vigilant follow-up and early intervention.

Endocrine Dysfunction

• Overview: Includes hypothyroidism and other hormonal disturbances.
• Management: Periodic hormonal testing and replacement therapy.

Cardiomyopathy

• Overview: Risk related to cumulative anthracycline exposure.
• Management: Cardiac monitoring with echocardiogram or MUGA scans.

Infertility

• Overview: High risk with intensive chemotherapy or stem cell transplantation.
• Management: Fertility preservation (e.g., sperm or oocyte cryopreservation) before therapy initiation.

1. American Cancer Society. Key Statistics for Acute Myeloid Leukemia. 2024.
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 Revision to the WHO Classification of Myeloid Neoplasms and Acute Leukemia. Blood. 2016;127(20):2391-2405.
3. Bain BJ, Béné MC. Morphological and Immunophenotypic Clues to the WHO Categories of Acute Myeloid Leukaemia. Acta Haematologica. 2019;141(4):232-244.
4. Bhatt VR, Shostrom DC, Rodeghier M, et al. Incidence, Predictors, and Outcomes of Febrile Neutropenia in AML. Supportive Care in Cancer. 2020;28(6):2673-2680.
5. Chelghoum Y, Danaïla C, Belhabri A, et al. Influence of Cigarette Smoking on the Presentation and Course of Acute Myeloid Leukemia. Annals of Oncology. 2002;13(10):1621-1627.
6. Coiffier B, Altman A, Pui CH, et al. Guidelines for the Management of Tumor Lysis Syndrome in Adults and Children with Hematologic Malignancies: An Expert Panel Consensus. Journal of Clinical Oncology. 2008;26(16):2767-2778.
7. Daver N, Schlenk RF, Russell NH, et al. Targeting FLT3 Mutations in AML: Review and Recommendations. Leukemia. 2019;33(2):299-312.
8. DiNardo CD, Pratz KW, Luger SM, et al. Molecular Landscape and Prognostic Implications in AML. Journal of Clinical Oncology. 2019;37(6):512-519.
9. Döhner H, Estey E, Grimwade D, et al. Diagnosis and Management of AML in Adults: Recommendations from the European LeukemiaNet. Blood. 2022;140(12):1345-1377.
10. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and Management of AML in Adults: 2022 Recommendations. Blood. 2022;140(12):1345-1377.
11. Estey EH, Döhner H. Acute Myeloid Leukemia. The Lancet. 2006;368(9550):1894-1907.
12. Gao L, Holme H, et al. GATA2 mutations and familial MDS/AML. Blood. 2017;129(8):1018-1026.
13. Khoury JD, Solary E, Abla O, et al. The 5th Edition of the WHO Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719.
14. Ley TJ, Miller C, Ding L, et al. Genomic and Epigenomic Landscapes of Adult De Novo AML. New England Journal of Medicine. 2013;368(22):2059-2074.
15. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic Acid and Arsenic Trioxide for APL. New England Journal of Medicine. 2013;369(2):111-121.
16. Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA. Optimising Survival Outcomes with Post-Remission Therapy in Acute Myeloid Leukemia. American Journal of Hematology. 2019;94(7):803-811.
17. Metzeler KH, Herold T, Rothenberg-Thurley M, et al. Spectrum and Prognostic Relevance of Driver Gene Mutations in Acute Myeloid Leukemia. Blood. 2016;128(5):686-698.
18. Montesinos P, Sanz MA. The Differentiation Syndrome in Patients with Acute Promyelocytic Leukemia: Experience of the PETHEMA Group and Review of the Literature. Mediterranean Journal of Hematology and Infectious Diseases. 2011;3(1):e2011059.
19. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. New England Journal of Medicine. 2016;374(23):2209-2221.
20. Patel JP, Gönen M, Figueroa ME, et al. Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia. New England Journal of Medicine. 2012;366(12):1079-1089.
21. Shallis RM, Wang R, Zeidan AM. Epidemiology of Acute Myeloid Leukemia: Recent Progress and Enduring Challenges. Blood Reviews. 2019;36:70-87.
22. Tallman MS, Altman JK. How I Treat Acute Promyelocytic Leukemia. Blood. 2009;114(25):5121-5130.
23. Thol F, Ganser A. Treatment of Relapsed Acute Myeloid Leukemia. Current Treatment Options in Oncology. 2020;21(8):66.
24. Vardiman JW, Thiele J, Arber DA, et al. The 2008 Revision of the WHO Classification of Myeloid Neoplasms and Acute Leukemia. Blood. 2009;114(5):937-951.
25. Welch JS, Ley TJ, Link DC, et al. The Origin and Evolution of Mutations in AML. Cell. 2012;150(2):264-278.