What is acute myeloid leukemia (AML)?

What is Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues, representing the most common form of acute leukemia in adults and accounting for the largest number of annual leukemia deaths in the United States. 1

Epidemiology and Incidence

• AML has an annual incidence of 4.1-8 per 100,000 people in the United States and Europe, with approximately 21,450 new cases diagnosed annually. 1, 2
• The median age at diagnosis is 67-71 years, with 54% of patients diagnosed at age ≥65 years and approximately one-third diagnosed at ≥75 years. 1
• The yearly mortality rate is 4-6 cases per 100,000, with an estimated 10,590-10,920 deaths annually in the United States. 1
• The incidence increases steeply with age, reaching 15-25 per 100,000 per year in the population over 70 years old. 1

Pathophysiology and Disease Characteristics

• AML results from genetic variations that cause neoplastic transformation and clonal proliferation of myeloid stem cell precursors, leading to abnormal proliferation with decreased apoptosis and arrested cellular differentiation. 3, 4
• The disease is genetically complex and dynamic, with commonly altered genes including FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. 2
• As immature blast cells accumulate in the bone marrow (>20% blasts defines AML), they replace normal hematopoietic cells, resulting in bone marrow failure with associated bleeding, anemia, and infection. 1, 4

Clinical Presentation

• Patients typically present with symptoms related to bone marrow failure: bleeding complications from thrombocytopenia, fatigue from anemia, and infections from neutropenia. 4
• Laboratory findings include leukocytosis with predominance of immature cells (primarily blasts) in peripheral blood and bone marrow. 4
• Some patients may present with extramedullary disease (myeloid sarcoma), which can occur in skin, gastrointestinal tract, lymph nodes, and bone. 1

Classification Systems

• The World Health Organization (WHO) classification system incorporates morphological criteria, cytogenetic data, molecular genetics, immunophenotype, and clinical information to define clinically significant disease entities. 1
• AML is distinguished from myelodysplastic syndromes (MDS) by the presence of ≥20% blasts in peripheral blood or bone marrow. 1
• Special subtypes include therapy-related AML (t-AML), which accounts for 5-20% of cases and typically follows treatment with alkylating agents or topoisomerase inhibitors. 1
• Distinct entities recognized in the WHO classification include myeloid leukemia associated with Down syndrome and blastic plasmacytoid dendritic cell neoplasm. 1, 5

Prognostic Factors

• Risk stratification is primarily based on cytogenetic and molecular findings, with favorable-risk AML including acute promyelocytic leukemia with t(15;17), and core binding factor AML with t(8;21) or inv(16)/t(16;16). 1, 6
• Normal karyotype AML represents an intermediate risk group, while complex karyotype abnormalities and chromosomal monosomies confer poor prognosis. 1
• In cytogenetically normal AML, NPM1 and bi-allelic CEBPα mutations are favorable when present as single molecular aberrations, while FLT3 alterations predict high relapse risk. 1
• Patient age, initial leukocyte counts, comorbidities, and evolution from pre-existing MDS are important clinical risk factors. 1

Treatment Landscape Evolution

• Since 2017, the treatment paradigm has been revolutionized by incorporation of molecularly targeted therapies, including midostaurin, gilteritinib, and quizartinib for FLT3-mutated AML, and ivosidenib/olutasidenib for IDH1 and enasidenib for IDH2 mutations. 7, 2
• The combination of hypomethylating agents with venetoclax has transformed therapy for older adults, extending survival compared to monotherapy. 2
• Current treatment approaches are customized based on patient comorbidities and AML genomic profile, with more than 80% of acute promyelocytic leukemia patients achieving cure with modern therapy. 6, 2