Acute Myeloid Leukemia (AML)

• Acute myeloid leukemia (AML) is a neoplasm characterized by infiltration of the blood, bone marrow, and other tissues by proliferative, clonal, poorly differentiated cells of the hematopoietic system
• Untreated AML is uniformly fatal
• In 2020, the estimated number of new AML cases in the United States was 19,940
• AML is diagnosed in 1.3% of all cancer cases and 31% of all new acute leukemias
• AML causes 62% of leukemic deaths
• AML is the most common acute leukemia in older patients, with a median age at diagnosis of 67 years
• Long-term survival is infrequent, with only 27% of patients surviving 5 years

Etiology of AML

• Most cases of AML are idiopathic
• Genetic predisposition, radiation, chemical/other occupational exposures, and drugs contribute to the development of AML
• AML cases with established etiology are relatively rare
• No direct evidence suggests a viral etiology
• Most cases of AML arise from a limited number of mutations that accumulate with advancing age
• Genome sequencing is providing advances in understanding leukemogenesis
• The Cancer Genome Atlas (TCGA) and other databases show that 5-6% of normal individuals aged >70 years contain potentially "premalignant" mutations associated with clonal expansion

Clonal Hematopoiesis of Indeterminate Potential (CHIP)

• "Premalignant" mutations represent CHIP, sometimes called age-related clonal hematopoiesis
• The genes most commonly altered include the epigenetic regulators DNMT3A, TET2, and ASXL1
• CHIP has relevance not just to blood cancer evolution but also other medical conditions
• Clonal expansion driven by the acquisition of new mutations is associated with a 10-fold increase in risk for developing a hematologic malignancy, but additional "hits" must occur to drive toward leukemia
• Patients with CHIP have increased risk of cardiovascular mortality
• This may be due to interactions between circulating clonally expanded blood cells and vascular endothelium
• A "proinflammatory" state caused by clonal, infiltrating monocytes leads to accelerated atherosclerotic plaque development and altered cardiac remodeling
• Early CHIP identification may provide therapeutic opportunities
• Modifying cardiovascular risk in patients with CHIP seems prudent
• Mutation-directed therapies to eliminate problematic clones to prevent leukemia are likely to be more elusive

Genetic Predisposition

• Myeloid neoplasms typically occur sporadically in adults
• Inherited predisposition is rare
• Myeloid neoplasms with germline predisposition represent an important and growing subset of disease
• Germline mutations associated with increased risk of developing a myeloid neoplasm include CEBPA, DDX41, RUNX1, ANKRD26, ETV6, and GATA2
• Myeloid neoplasms with germline predisposition are a feature of several well-described clinical syndromes, including bone marrow failure disorders like Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia and telomere biology disorders like dyskeratosis congenita
• Genetic predisposition plays a larger role than has been previously understood
• Down syndrome with trisomy 21 is associated with an increased incidence of AML
• Down syndrome-associated AML in young children (<4 years) is typically of the acute megakaryocytic subtype and is associated with mutation in the GATA1 gene

WHO 2016 Classification of Myeloid Neoplasms with Germline Predisposition

• Myeloid neoplasms with germline predisposition without a preexisting disorder or organ dysfunction:
  • Acute myeloid leukemia with germline CEBPA mutation
  • Myeloid neoplasms with germline DDX41 mutation
• Myeloid neoplasms with germline predisposition and preexisting platelet disorders:
  • Myeloid neoplasms with germline RUNX1 mutation
  • Myeloid neoplasms with germline ANKRD26 mutation
  • Myeloid neoplasms with germline ETV6 mutation
• Myeloid neoplasms with germline predisposition and other organ dysfunction:
  • Myeloid neoplasms with germline GATA2 mutation
  • Myeloid neoplasms associated with bone marrow failure syndromes
  • Myeloid neoplasms associated with telomere biology disorders
  • Myeloid neoplasms associated with Noonan syndrome
  • Myeloid neoplasms associated with Down syndrome

Acute myeloid leukemia (AML) is a neoplasm characterized by infiltration of the blood and bone marrow by poorly differentiated hematopoietic cells. Untreated AML is uniformly fatal. It is the most common acute leukemia in older patients, with a median age at diagnosis of 67 years.