#57 – Acute Myeloid Leukemia



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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

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

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

Emergency Presentations

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

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

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

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

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

The Cottage Physician (1893)



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]

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