The World Health Organization classifies leukemia primarily by the genetic mutations driving the cancer, not just by how the cells look under a microscope. The current system, published in 2022 as the 5th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5), groups leukemias into broad families and then subdivides them based on specific chromosomal changes and gene mutations found through laboratory testing. This genetics-first approach matters because two patients with leukemia that looks identical under a microscope may have very different diseases, different prognoses, and different treatment options depending on which mutations are present.
How the Classification Is Structured
The WHO system divides blood cancers into myeloid neoplasms (arising from the cell line that produces red blood cells, platelets, and most white blood cells) and lymphoid neoplasms (arising from lymphocytes, the immune cells that include B-cells and T-cells). Leukemia falls into both categories depending on which cell type becomes cancerous. Within each category, the classification layers clinical features, cell appearance, immune markers on the cell surface, chromosome abnormalities, and gene mutations to define distinct disease entities.
A diagnosis under this system requires an integrated workup. That typically means blood counts and a blood smear, bone marrow biopsy, flow cytometry to identify surface proteins on the abnormal cells, conventional chromosome analysis, and molecular genetic testing for specific mutations. No single test is sufficient. The classification was built on the premise that combining all of these tools produces diagnoses that are clinically meaningful, meaning they actually predict how the disease will behave and respond to therapy.
Acute Myeloid Leukemia (AML)
AML is one of the most genetically subdivided leukemias in the WHO system. The 5th edition splits it into two major groups: AML with defining genetic abnormalities and AML defined by differentiation (for cases where no characteristic genetic change is found).
The genetics-first group is where most of the complexity lives. If a patient’s leukemia cells carry certain chromosome rearrangements or gene mutations, those findings alone define the diagnosis. Importantly, many of these subtypes no longer require the traditional threshold of 20% blast cells (immature, cancerous white blood cells) in the blood or bone marrow. For leukemias driven by mutations such as NPM1, or chromosome rearrangements involving PML::RARA, RUNX1::RUNX1T1, or KMT2A, among others, the genetic finding is considered diagnostic even at lower blast counts. This is a significant shift: it means some patients are diagnosed with AML earlier than they would have been under older rules.
The 5th edition also introduced a category called AML with myelodysplasia-related changes, which captures cases linked to a set of specific gene mutations (including ASXL1, BCOR, SRSF2, and several others involved in how cells read and process their own DNA). These mutations signal that the leukemia evolved from a pre-existing bone marrow disorder, which generally carries a less favorable outlook. This category still requires at least 20% blasts for diagnosis.
Several newly recognized chromosome abnormalities were added as well, expanding the list of genetically defined AML subtypes. For cases that don’t fit any defined genetic category and meet the 20% blast threshold, the classification falls back on how the cells differentiate, essentially what type of blood cell they were trying to become before turning cancerous.
Acute Lymphoblastic Leukemia (ALL)
Acute lymphoblastic leukemia is divided first by whether it arises from B-cells or T-cells, then further subdivided by genetic drivers. The B-cell form (B-ALL) has the longest list of recognized subtypes, each tied to a specific genetic event.
Some of these subtypes have been recognized for decades. B-ALL with the Philadelphia chromosome, a fusion between the BCR and ABL1 genes, is one of the most well-known because it was among the first to have a targeted therapy. B-ALL with a rearrangement of the KMT2A gene tends to be aggressive and is common in infants. Hyperdiploid B-ALL, where the leukemia cells have extra chromosomes, generally carries a more favorable prognosis, especially in children.
The current classification has expanded this list considerably. Newer entities include B-ALL with DUX4 rearrangement, MEF2D rearrangement, ZNF384 rearrangement, and several others identified through advanced genomic profiling. A particularly important addition is the “BCR::ABL1-like” category, which describes leukemias that behave like Philadelphia chromosome-positive ALL at the gene expression level but lack the actual BCR::ABL1 fusion. These cases are subdivided further based on whether they activate a specific signaling pathway, because that distinction can influence treatment choices.
T-cell ALL (T-ALL) has a simpler but evolving classification. The most clinically distinct subtype is early T-cell precursor ALL, which arises from very immature T-cells and has a unique genetic profile. The current system recognizes a BCL11B-activated subtype within this group. Beyond that, T-ALL subtypes are organized by which transcription factor or signaling gene is driving the cancer, though many of these remain provisional entities still being validated.
Chronic Myeloid Leukemia (CML)
CML is defined by a single genetic event: the Philadelphia chromosome, which creates the BCR::ABL1 fusion gene. This makes it one of the most straightforward diagnoses in the classification. Detection of this fusion, either through chromosome analysis or molecular testing, is required. Most cases can be identified from a blood sample, but a bone marrow biopsy is needed to confirm the disease phase.
The WHO system recognizes CML in chronic phase and blast phase. Chronic phase is the initial, more stable stage where the disease is typically diagnosed and responds well to targeted therapy. Blast phase represents transformation into an acute leukemia, with a sharp increase in immature blast cells. The distinction between phases has practical consequences: chronic phase CML is highly treatable with oral medications, while blast phase is far more difficult to control and often requires intensive chemotherapy.
Chronic Lymphocytic Leukemia (CLL)
CLL is the most common leukemia in adults in Western countries and has straightforward diagnostic criteria in the WHO system. It requires at least 5,000 clonal B-lymphocytes per microliter of blood, sustained for at least three months. These cells must carry the CD5 protein (normally found on T-cells, not B-cells) alongside typical B-cell surface markers. The diagnosis is confirmed through flow cytometry, a test that identifies proteins on individual cells.
CLL cells are mature-looking lymphocytes that accumulate in the blood, bone marrow, lymph nodes, and spleen. When the same disease presents primarily in lymph nodes rather than the blood, it is classified as small lymphocytic lymphoma (SLL). The WHO considers these the same disease entity presenting in different locations. If a patient has fewer than 5,000 clonal B-cells and no other symptoms or enlarged lymph nodes, the condition is classified as monoclonal B-cell lymphocytosis, a precursor state that may or may not progress to CLL.
Blast Count Thresholds and Why They Matter
One of the most consequential aspects of the WHO classification is how it uses blast percentages, the proportion of immature cancer cells in the blood or marrow, to draw lines between diseases. Historically, 20% blasts in the bone marrow was the dividing line between a pre-leukemic condition (myelodysplastic syndrome) and acute myeloid leukemia. That threshold still applies for several AML categories, including AML with myelodysplasia-related changes and AML not otherwise specified.
However, for many genetically defined AML subtypes, the 5th edition dropped this requirement entirely or lowered it. The rationale is that certain genetic mutations define a disease that will behave like AML regardless of how many blasts are currently present. For example, a patient with an NPM1 mutation and 12% blasts has a disease that is biologically and clinically AML, even though the blast count falls below the traditional cutoff. The WHO system now recognizes this by allowing the genetic finding to override the blast count for specific subtypes.
This creates some complexity. AML with a BCR::ABL1 fusion still requires 20% or more blasts, because below that threshold the disease is classified as CML in blast phase instead. AML with a CEBPA mutation also retains the 20% blast requirement in the WHO system, though a parallel classification system (the International Consensus Classification) has provisionally lowered this to 10%.
WHO vs. International Consensus Classification
A notable complication for patients and clinicians is that two classification systems were published nearly simultaneously in 2022: the WHO 5th edition and the International Consensus Classification (ICC). Both systems share the same genetics-first philosophy, and they agree on the majority of disease definitions. But they diverge in some specifics.
The ICC sets a minimum blast threshold of 10% for most genetically defined AML subtypes, while the WHO does not specify a blast cutoff for many of these same entities. This means a patient with, say, 8% blasts and an NPM1 mutation would be diagnosed with AML under the WHO system but with a myelodysplastic syndrome under the ICC. The ICC also recognizes AML with TP53 mutation as a distinct entity requiring over 20% blasts and a variant allele frequency above 10%, a category the WHO handles differently.
In practice, most major cancer centers are aware of both systems and use whichever their institution has adopted, sometimes referencing both. The differences are mostly at the margins, but they can affect eligibility for clinical trials and the timing of treatment decisions.
How Genetic Testing Shapes the Diagnosis
The modern WHO classification makes advanced genetic testing essential, not optional. A complete chromosome analysis (karyotype) remains a baseline requirement for nearly every new leukemia diagnosis. On top of that, targeted molecular panels test for specific gene mutations, and fluorescence in situ hybridization (FISH) can detect chromosome rearrangements that are invisible on standard karyotyping.
For AML, the minimum workup now effectively includes testing for NPM1, CEBPA, and the panel of myelodysplasia-related mutations. For ALL, identifying the specific genetic driver can take days to weeks, and the subtype may be refined as results come in. For CLL, flow cytometry is the cornerstone test. For CML, molecular detection of BCR::ABL1 is definitive.
This reliance on genetic testing has practical implications. In settings where advanced molecular testing is unavailable, a precise WHO classification may not be possible. The system accounts for this with “not otherwise specified” categories, but these are intentionally vague because they represent cases where the full picture is unknown rather than cases where the disease itself is undefined.