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Epidemiology

• Most common type of acute leukemia and the second most common type in adults
  • 32% of all adult leukemia cases
  • Only 1% of all adult cancers deaths in the US
    • Around 12,000 deaths per year in US
• 3-5 cases per 100,000 population
• Around 20,000 patients per year in the US get diagnosed
  • 2% annual increase in cases from 2007-2016
• Mean age of diagnosis is 65 years and increases with age

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Pathophysiology

• Malignancy of myeloid precursor cells
  • Multipotential hematopoietic stem cell –> common myeloid progenitor –> myeloblast

• 2 main models
  • Occurs at one of several developmental stages
  • Occurs within the primitive multipotent cells
• Two-hit hypothesis of leukemogenesis
  • Class I mutation
    • Confers a proliferative advantage
  • Class II mutation
    • Impairs hematopoietic differentiation
• Mechanisms of Genetic Damage
  • Chemotherapy
    • 3-5 years after alkylating agent-induced damage
  • Ionizing radiation
    • Induces double strand breaks
    • Typically > 20 Gy (grays)
  • Chemical exposure
    • Benzene is classically associated with AML
  • Infections
    • Human T-lymphocyte virus type I (HTLV-1

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Signs and Symptoms

• Constitutional
  • Fatigue, weakness, dyspnea
  • Fever
• Skin (13% of patients)
  • Easy bruisability, ecchymoses
  • Pallor
• HEENT
  • Gingival bleeding, oral candidiasis
  • Papilledema, retinal infiltrates
  • Lymphadenopathy
• Abdomen (10% of patients)
  • Organomegaly
    • Spleen and liver
• Musculoskeletal (4% of patients)
  • Polyarthritis and arthralgias
  • Bone pain

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Emergency Presentations

• Pancytopenia
• Tumor lysis syndrome
  • Hyperkalemia, hyperphosphatemia, hyperuricemia, AKI
• Bleeding
• New onset CNS symptoms

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Diagnostic Studies

• CBC
  • Leukocytosis or leukopenia
    • 20% of patients have > 100,000 cells/microL
    • 25-40% of patients have < 5,000 cells/microL
  • Thrombocytopenia
    • 75% of patients have < 100,000 cells/microL
    • 25% of patient have < 25,000 cells/microL
• Peripheral Blood
  • 95% of patients will have circulating myeloblasts
    • Immature cells with large, prominent nuclei and variable amount of pale blue cytoplasms
    • May have Auer rods present
  • Myeloperoxidase reaction
    • Simple means of determining if the blasts are myeloid

• Flow Cytometry
  • Can assist in detecting circulating myeloblasts
• Bone Marrow Biopsy
  • This is the key component in the diagnosis of AML
  • It gives a general overview of the degree of involvement, allows for cell differential count to determine the percentage of blasts in the marrow, and provides a detailed cytologic evaluation of the blasts
  • Cell Origin
    • Identifies if myeloid, monocytic, erythroid, or megakaryocytic
    • Differentiates the blasts of lymphoid lineage
  • Infiltration
    • Diagnosis of AML is > 20% blasts of the total cellularity
• HLA Typing in patients who are potential candidates for bone marrow transplantation

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Diagnosis

• Requires both of the following criteria:
  • Documentation of bone marrow infiltration
    • > 20% blasts in bone morrow
  • Myeloid origin
    • Presence of Auer rods, (+) myeloperoxidase reaction, or presence of myeloid markers on immunophenotyping

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Treatment

• Goals
  • Complete remission (<5% blasts)
    • Appropriate goal for most AML patients
• Pretreatment evaluation
  • Comorbid conditions
    • Heart disease, renal insufficiency, liver disease
  • Physical function and performance status
    • ECOG Scale most commonly used

• Two distinct treatment phases
  • Induction
    • Combination therapy (7 and 3 regimen)
      • Cytarabine
        • Interferes with DNA synthesis
        • 7 day continuous infusion
      • Anthracycline
        • Daunorubicin, idarubicin
          • Inhibition of topoisomerase II
            • Leads to DNA breaks
        • Day 1, 2, and 3
    • Bone marrow biopsy 7-10 days after induction to re-assess
  • Postremission management
    • Continuing chemotherapy
    • Hematopoietic cell transplant

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Prognosis

• Overall 5-year survival is 15%
  • Decreases with age
    • 53% 5-year survival in 15-24yo to 13% in 70-79yo
• Genetic subtypes
  • Karyotypes
  • Gene mutations

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The Cottage Physician (1893)

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References

1. Acute myeloid leukemia statistics.  Cancer.net.  Accessed on 03/22/2020 [link]
2. Blum W, Bloomfield CD. Acute Myeloid Leukemia. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; . http://accessmedicine.mhmedical.com.ezproxy.uthsc.edu/content.aspx?bookid=2129&sectionid=192017732. Accessed March 22, 2020.
3. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA: a cancer journal for clinicians. 2017; 67(1):7-30. [pubmed]
4. Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis? British journal of haematology. 2005; 128(1):18-34. [pubmed]
5. Levine EG, Bloomfield CD. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Seminars in oncology. 1992; 19(1):47-84. [pubmed]
6. Shuryak I, Sachs RK, Hlatky L, Little MP, Hahnfeldt P, Brenner DJ. Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks. Journal of the National Cancer Institute. 2006; 98(24):1794-806. [pubmed]
7. Austin H, Delzell E, Cole P. Benzene and leukemia. A review of the literature and a risk assessment. American journal of epidemiology. 1988; 127(3):419-39. [pubmed]
8. Shah A, Andersson TM, Rachet B, Björkholm M, Lambert PC. Survival and cure of acute myeloid leukaemia in England, 1971-2006: a population-based study. British journal of haematology. 2013; 162(4):509-16. [pubmed]