Acute Myeloid Leukemia (AML) is a rapidly progressing malignancy that originates in the blood and bone marrow. This cancer is characterized by the uncontrolled growth of immature white blood cells, called blasts, which then interfere with the production of normal blood cells. Unlike many other cancers, AML is not a single disease but a highly diverse group of disorders arising from various genetic and biological abnormalities. The profound differences in how the disease presents and responds to treatment make a unified approach to diagnosis and therapy impossible. To manage this variability, the World Health Organization (WHO) provides a standardized framework for grouping these diverse forms of leukemia.
The Necessity of Standardized Grouping
The WHO classification system exists to ensure that a diagnosis of Acute Myeloid Leukemia means the same thing to doctors and researchers across the globe. This standardization is fundamental for reliably comparing treatment outcomes in clinical trials and for establishing consistent medical guidelines. Before the WHO system, different centers used varying criteria, which made it difficult to assess which treatments were truly effective for specific patient populations.
A precise classification directly informs a patient’s prognostic assessment. Certain genetic features linked to specific WHO categories are known to predict a more favorable or less favorable response to standard chemotherapy. By classifying the leukemia based on these inherent characteristics, clinicians can align patients with the most appropriate and targeted treatment strategies from the outset. This systematic grouping is the first and most important step in moving toward personalized medicine for individuals with AML.
Defining the Major Categories
The most recent WHO Classification, updated in 2022, emphasizes the genetic drivers of AML, shifting the focus away from morphology alone, which was the previous standard. The categories are now primarily defined by the presence of specific genetic changes, recognizing that these abnormalities often dictate the clinical behavior of the disease. The classification separates AML into two main families: AML with defining genetic abnormalities and AML defined by differentiation.
The first and largest family is AML with Defining Genetic Abnormalities, which includes cases where a specific mutation or chromosomal change is the defining feature, regardless of the blast percentage. For example, the presence of an NPM1 gene mutation is a common finding, frequently associated with a better prognosis when not accompanied by certain other adverse mutations. Specific rearrangements involving the CEBPA gene often indicate a favorable outcome. The WHO no longer requires the traditional 20% blast threshold for diagnosis if one of these defining genetic abnormalities is present, such as in Acute Promyelocytic Leukemia (APL), which is characterized by the PML::RARA fusion.
A separate and complex category is AML, Myelodysplasia-Related (AML-MR), which replaces the previous term “AML with myelodysplasia-related changes”. This grouping is defined by the presence of cytogenetic abnormalities or gene mutations typically found in myelodysplastic neoplasms, which are conditions that often precede AML. Examples of these defining gene mutations include ASXL1, SF3B1, and SRSF2, among others. This category generally carries a less favorable prognosis and now requires the integration of molecular findings, rather than just morphological evidence of dysplasia, for diagnosis.
Another category is the Myeloid Neoplasm Post Cytotoxic Therapy (MN-pCT), which encompasses cases that arise after a patient has been treated with chemotherapy or radiation for an unrelated prior condition. The WHO now views the therapy-related aspect as a disease qualifier rather than a diagnosis, but it remains a clinical distinction because these leukemias often present with aggressive features and complex genetic signatures. The category of AML Defined by Differentiation is used for cases that meet the general criteria for AML but lack any of the specific genetic abnormalities required for the other groups. This is the modern replacement for the older “AML, Not Otherwise Specified (NOS)” category, and diagnosis here relies more on cell maturity and morphology.
Essential Diagnostic Methods for Subtyping
Placing a patient into one of the WHO categories requires a combination of sophisticated laboratory techniques that analyze the leukemia cells from multiple perspectives. The integration of these methods provides the comprehensive profile necessary for a definitive diagnosis and subtyping.
Cytogenetics involves analyzing the structure and number of chromosomes within the leukemic cells. This technique is used to detect large-scale chromosomal rearrangements, such as translocations where parts of two different chromosomes swap places, or deletions where a segment of a chromosome is missing. Identifying these abnormalities, like the common translocation between chromosomes 8 and 21, is important because they define several WHO subtypes and significantly influence prognosis.
Molecular Testing focuses on identifying specific gene mutations that are too small to be seen through conventional cytogenetics. This is primarily done using advanced sequencing methods, such as Next-Generation Sequencing (NGS), which can rapidly screen for mutations in genes like NPM1, CEBPA, and FLT3. The presence or absence of these molecular alterations is now a cornerstone of the WHO classification, determining which genetic-defined subtype the patient has.
Immunophenotyping, typically performed using flow cytometry, identifies specific proteins, or surface markers, expressed on the leukemia cells. By tagging cells with fluorescent antibodies, this method helps confirm the myeloid lineage of the cells and determines their stage of maturation. This technique is also important for distinguishing AML from other types of acute leukemia and can sometimes suggest the presence of an underlying genetic abnormality.