Acute Myeloid Leukemia (AML)

• 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.
    
    

• Disorders predisposing to AML include:
  • 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.
    
    

• 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.
  • Syndromes like Li-Fraumeni and hereditary cancer predisposition syndromes may feature AML, though solid tumors predominate.
    
    

• 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.
    
    

• 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 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

• Fail to differentiate into functional neutrophils, red blood cells, or platelets.
• Retain a self-renewing leukemic stem cell population that perpetuates the disease.
• Block normal hematopoiesis through overcrowding and secretion of inhibitory cytokines, such as chemokines.
  
  

Key Genetic Abnormalities

• Chromosomal Translocations: Generate fusion oncogenes, such as:
  • t(15;17) (PML–RARA) in acute promyelocytic leukemia.
  • t(8;21) (RUNX1–RUNX1T1) and inv(16) (CBFB–MYH11) in core-binding factor AML.
• Point Mutations: Affect genes regulating transcription, apoptosis, or cell signaling. Common mutations include:
  • NPM1, FLT3, TP53, CEBPA, and IDH2.
• Epigenetic and RNA-splicing Genes: Alter chromatin regulation and RNA processing.
• Chromosomal Aneuploidy: Loss or gain of whole chromosomes, as seen with inv(3) or t(6;9).
  
  

Bone Marrow Dynamics

• The abnormal blasts accumulate in the marrow, blood, and extramedullary sites (e.g., spleen, liver).
• Bone marrow failure results from both physical crowding and biochemical inhibition of normal progenitor cells.
  
  

Clinical Consequences of Bone Marrow Failure

1. Anaemia:
   • Results in pallor, fatigue, dizziness, and dyspnea.
2. Neutropenia:
   • Causes recurrent bacterial and fungal infections (e.g., Candida, Aspergillus).
3. Thrombocytopenia:
   • Leads to mucosal bleeding, bruising, and petechiae.
     
     

Leukemic Cell Proliferation and Infiltration

• Leukemic cells infiltrate various tissues, including lungs, lymph nodes, gums, skin, testicles, and the CNS, particularly when the white blood cell count exceeds 50,000/µL.
• Leukostasis:
  • Extremely high blast counts (>100,000/µL) can obstruct microvasculature, causing:
    • Respiratory distress.
    • Altered mental status.
      
      

Molecular Heterogeneity and Disease Classification

• NPM1, FLT3, TP53, and CEBPA.
• Fusion genes such as PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11.
  This heterogeneity underpins the classification of AML into subtypes that guide prognosis and treatment.
  
  

Prognostic Implications

• Genetic mutations and chromosomal changes significantly influence outcomes. For example:
  • NPM1 mutation without FLT3 confers a favorable prognosis.
  • TP53 mutations or complex karyotypes are associated with poor outcomes.
    
    

Staging and Classification of Acute Myeloid Leukemia (AML)

• M0: Undifferentiated AML
• M1: AML with minimal maturation
• M2: AML with maturation
• M3: Acute promyelocytic leukemia (APL)
• M4: Acute myelomonocytic leukemia
• M5: Acute monocytic leukemia
• M6: Acute erythroid leukemia
• M7: Acute megakaryocytic leukemia
  
  

1. AML with t(8;21) (RUNX1::RUNX1T1)
2. AML with inv(16) or t(16;16) (CBFB::MYH11)
3. APL with t(15;17) (PML::RARA)
4. AML with t(9;11) (MLLT3::KMT2A)
5. AML with t(6;9) (DEK::NUP214)
6. AML with inv(3) or t(3;3) (GATA2, MECOM)
7. AML (megakaryoblastic) with t(1;22) (RBM15::MRTFA)
8. AML with mutated NPM1
9. AML with CEBPA mutations
   
   

• Defined by cytogenetic abnormalities (e.g., del(5q), -7, or complex karyotype) or a history of myelodysplastic syndromes (MDS).

• Resulting from prior chemotherapy, radiotherapy, or toxin exposure.
  
  

1. AML with minimal differentiation
2. AML without maturation
3. AML with maturation
4. Acute myelomonocytic leukemia
5. Acute monocytic leukemia
6. Acute erythroid leukemia
7. Acute megakaryoblastic leukemia
8. Acute basophilic leukemia
9. Acute panmyelosis with myelofibrosis
   
   

1. Myeloid sarcoma
2. Myeloid proliferations related to Down syndrome
   
   

1. AML with t(8;21) (RUNX1::RUNX1T1)
2. AML with inv(16) or t(16;16) (CBFB::MYH11)
3. AML with t(9;11) (MLLT3::KMT2A)
4. AML with t(6;9) (DEK::NUP214)
5. AML with t(15;17) (PML::RARA)
6. AML with mutated NPM1 or CEBPA
7. AML with BCR::ABL1 (≥20% blasts required for diagnosis)
8. AML with myelodysplasia-related mutations or cytogenetic abnormalities
   
   

• De Novo AML: Occurs without prior hematologic disorders or exposure to therapies.
• Secondary AML (s-AML): Evolves from pre-existing MDS or myeloproliferative neoplasms (MPNs).
• Therapy-Related AML (t-AML): Results from prior chemotherapeutic agents, radiation, or toxins.
  
  

1. ELN 2022 Guidelines:
   • Introduced a blast threshold of ≥10% for defining AML in cases with specific genetic abnormalities.
   • Included new genetic subtypes, such as AML with in-frame CEBPA mutations.
2. WHO 2022 Fifth Edition:
   • Expanded definitions of genetic abnormalities.
   • Emphasised the integration of cytogenetic and molecular data for classification.
3. ICC Diagnostic Qualifiers:
   • Therapy-related, progression from MDS/MPN, or germline predisposition.
     
     

Incidence and Prevalence

• The American Cancer Society (ACS) estimates 20,800 new cases of AML in the United States in 2024, with 11,600 in men and 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, with a median diagnosis age of ~68–70 years. While it can occur at any age, the majority of cases are diagnosed in individuals aged 65 years or older.
  • In the US, 61% of cases occur in those aged 65 and above.
  • Similarly, 66% of cases in the UK are diagnosed in this age group.

Gender and Racial Disparities

• AML is more common in men than women, with a male-to-female ratio of 1.5:1 in the US. In the UK, 56% of cases are in males and 44% in females.
• Non-Hispanic Whites have a higher incidence of AML compared to other racial and ethnic groups.
  
  

Mortality

• AML accounts for significant cancer-related mortality:
  • The ACS estimates 11,220 deaths in the United States in 2024, with 6,290 deaths in men and 4,930 in women.
    
    

Environmental and Genetic Factors

• Environmental exposures such as genotoxic chemicals, radiation, tobacco, and prior cytotoxic chemotherapy are recognised risk factors.
• In some individuals, AML arises after a period of clonal hematopoiesis, often manifesting as myelodysplastic syndromes (MDS), myeloproliferative neoplasms, or clonal cytopenias of unknown significance.
• Uncommon cases are linked to inherited genetic abnormalities, including mutations in tumor suppressor or DNA repair genes (e.g., RUNX1, CEBPA, DDX41). Familial predisposition may also occur in conjunction with hematologic disorders or other malignancies.

Regional Insights

• AML is predominantly diagnosed in developed countries, potentially due to better diagnostic capabilities and environmental exposure differences.
• Occupational exposures, particularly in men, may partially explain the higher male prevalence of AML.
  
  

Key Historical Findings

• 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.
  
  

• 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.
  
  

• 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.
  
  

• 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

• Pallor: Reflecting underlying anaemia.
• Petechiae and Ecchymoses:
  • Small, non-palpable, hemorrhagic 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.
  
  

• 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.
  
  

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

• 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.
  
  

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

First-Line Investigations

• Findings:
  • Most patients show anaemia, neutropenia, and/or thrombocytopenia.
  • Leukocytosis (>100,000/µL) in hyperleukocytosis may predispose to tumor 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.

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

• 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.
    
    

• Electrolytes: Hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia 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 tumor burden and disease severity.
• Clinical Significance:
  • Identifies TLS, a potential oncological emergency.
    
    

• 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 leukemia (ALL).
    
    

• 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

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

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

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

Approach to Emergencies

• Tumor 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).
  
  

• 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.

• 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.

• Clinical Features: History of chronic-phase CML; symptoms similar to 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 be seen in Philadelphia-positive AML.
    
    

• 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.
    
    

• 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.
    
    

• 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.
    
    

• 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.
    
    

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

• 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.

• 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. For 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

1. 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: ~70–80% in patients <60 years and 60–70% in patients ≥60 years, depending on disease biology.
   • Patients failing to achieve remission are classified as refractory.
2. Consolidation Therapy
   • Aim: Eliminate residual disease and prevent relapse.
   • High-Dose Cytarabine (HiDAC): Typically administered over multiple cycles.
   • CPX-351 is an option for patients who received it during induction.
   • Consolidation strategies may incorporate allogeneic stem cell transplantation (SCT) for high-risk patients.

Stem Cell Transplantation (SCT)

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

Targeted Therapies

• CD33-Positive AML: Gemtuzumab ozogamicin combined with chemotherapy for favorable/intermediate-risk patients.
• FLT3-Mutated AML:
  • Midostaurin or quizartinib combined with induction/consolidation chemotherapy.
  • Post-consolidation maintenance with FLT3 inhibitors (e.g., sorafenib, gilteritinib).
• IDH1/IDH2-Mutated AML: Ivosidenib (IDH1) or enasidenib (IDH2), often combined with azacitidine.
• TP53-Mutated AML: Poor prognosis; clinical trials or low-intensity therapies (e.g., venetoclax with azacitidine) are preferred.
  
  

Maintenance Therapy

• Oral azacitidine is an option for patients in remission but not eligible for intensive consolidation or SCT.
• FLT3 inhibitors like sorafenib or gilteritinib may be used as maintenance post-SCT.
  
  

Low-Intensity Therapy

• For patients unfit for standard induction chemotherapy, options include:
  • Venetoclax with hypomethylating agents (azacitidine/decitabine) or low-dose cytarabine.
  • Glasdegib with low-dose cytarabine.
  • Ivosidenib or enasidenib for IDH-mutated AML.
    
    

Management of Acute Promyelocytic Leukemia (APL)

• APL, characterised by the PML::RARA fusion gene, requires urgent treatment to prevent coagulopathy-related mortality.
• Induction: All-trans-retinoic acid (ATRA) with arsenic trioxide for non-high-risk APL; ATRA with arsenic trioxide and chemotherapy for high-risk APL.
• Consolidation and Maintenance: Continuation of ATRA-based regimens. Maintenance therapy is increasingly omitted in low-risk cases with close MRD monitoring.
  
  

Relapsed or Refractory AML

• Salvage Therapy:
  • High-dose cytarabine or combinations like FLAG-IDA.
  • Gilteritinib for FLT3-mutated AML.
  • Ivosidenib or enasidenib for IDH-mutated AML.
• SCT is recommended if remission is achieved.
• Palliative care may be offered for patients unfit for intensive treatment.
  
  

Supportive Care

• Infection Prevention: Antibiotic and antifungal prophylaxis during neutropenia.
• Transfusions: Red blood cell and platelet transfusions as needed.
• Tumor Lysis Syndrome (TLS): Prophylaxis with hydration, allopurinol, or rasburicase.
• Management of Differentiation Syndrome: Prompt initiation of dexamethasone for symptoms like fever, respiratory distress, and fluid retention.
  
  

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

• Younger Patients (<60 years):
  • Cure rates are approximately 35–40% with intensive chemotherapy.
  • Outcomes are better in the presence of favorable-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 myelodysplastic syndrome (MDS), multidrug resistance, and comorbidities.
  • Only ~10% of older patients achieve long-term survival.

• Favorable Cytogenetics:
  • Long-term survival: ~65%.
  • Includes abnormalities such as:
    • t(8;21) (RUNX1::RUNX1T1).
    • t(15;17) (PML::RARA, characteristic of acute promyelocytic leukemia).
    • inv(16) or t(16;16) (CBFB::MYH11).
• Intermediate Cytogenetics:
  • Normal cytogenetics fall into this category; survival ~35%.
• Adverse Cytogenetics:
  • Includes -5, -7, monosomal karyotype, or complex karyotypes.
  • Survival: <10%.

• FLT3 Mutations: Poor prognosis due to high relapse rates, though outcomes are improving with FLT3 inhibitors.
• NPM1 Mutations: Favorable prognosis when not accompanied by FLT3 internal tandem duplications (ITD).
• TP53 Mutations: Extremely poor outcomes; often unresponsive to conventional therapies.
• CEBPA Biallelic Mutations: Associated with improved survival.
• TET2 Mutations: Adverse impact, even in favorable cytogenetic groups.

• De Novo AML: Best outcomes among AML types.
• Secondary AML (s-AML): Evolving from MDS or myeloproliferative neoplasms, has poorer outcomes.
• Therapy-Related AML (t-AML): Associated with prior chemotherapy or radiation; 5-year survival ~10%.
  
  

Acute Promyelocytic Leukemia (APL)

• Cure rates exceed 80% with current treatment protocols (e.g., ATRA and arsenic trioxide).
• Prognosis is highly favorable compared to other AML subtypes.
  
  

Role of Minimal Residual Disease (MRD)

• Advanced techniques like PCR and flow cytometry detect MRD, even in patients in morphological remission.
• Persistently elevated MRD levels are associated with a higher risk of relapse, especially in patients with t(8;21) AML.
  
  

Short-Term Complications

• 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 hypouricemic agents (e.g., allopurinol, rasburicase).
  • Close monitoring and TLS prophylaxis are mandatory, especially with drugs like venetoclax.

• Overview: Occurs when leukemic blasts obstruct microvasculature, particularly with WBC counts >100,000/μL.
• Features: Respiratory distress, altered mental status, and end-organ ischemia.
• Management:
  • Urgent leukoreduction with hydroxyurea or leukapheresis.
  • Supportive care to mitigate symptoms.
    
    

• Overview: Neutropenia arises from both the disease and treatment, leading to increased infection risk.
• Features: Infections are typically bacterial (gram-negative or gram-positive), with fungal and viral infections less common.
• Management:
  • Prophylactic antibiotics (e.g., fluoroquinolones) and antifungals (e.g., posaconazole).
  • Reverse isolation, germ-reduced diets, and rigorous hygiene to prevent infections.
    
    

• Overview: Bone marrow infiltration and treatment-induced cytopenias result in anaemia, thrombocytopenia, and leukopenia.
• Management:
  • Platelet transfusions for counts <10,000/μL, or higher thresholds in bleeding or APL patients.
  • Red blood cell transfusions to maintain hematocrit >25%.
    
    

• Overview: A frequent complication in APL and some monocytic AML subtypes.
• Features: Coagulopathy leading to bleeding or thrombotic complications.
• Management:
  • Initiate differentiation therapy (e.g., all-trans-retinoic acid [ATRA]).
  • Supportive therapy with platelets, cryoprecipitate, or fresh frozen plasma to normalise coagulation parameters.
    
    

• Overview: Rare in adult AML but more common in pediatric cases or high-risk subsets (e.g., monocytic AML).
• Features: Neurological symptoms such as headaches, confusion, or seizures.
• Management:
  • Diagnostic lumbar puncture with cerebrospinal fluid analysis.
  • Intrathecal chemotherapy with cytarabine or methotrexate.
    
    

• Overview: Caused by treatments inducing rapid leukemic cell differentiation, such as ATRA or arsenic trioxide in APL.
• Features: Fever, fluid retention, pulmonary infiltrates, respiratory distress, and leukocytosis.
• Management:
  • Immediate administration of dexamethasone.
  • Temporary discontinuation of causative agents in severe cases.

Long-Term Complications

• Overview: Long-term use of chemotherapy and radiation increases the risk of secondary hematologic malignancies.
• Management: Surveillance and early intervention in symptomatic cases.
  
  

• Overview: Hypothyroidism and other endocrine disorders may develop due to therapy.
• Management: Regular hormonal evaluations and replacement therapies as needed.
  
  

• Overview: Anthracycline-based regimens (e.g., daunorubicin) can lead to cardiac dysfunction.
• Management: Baseline and periodic cardiac function assessments with echocardiograms or MUGA scans.
  
  

• Overview: Common in younger patients undergoing intensive chemotherapy or SCT.
• Management: Fertility preservation options (e.g., cryopreservation) before treatment initiation.
  
  

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