The American–British–French classification, commonly known as the FAB classification, represents one of the most significant milestones in the history of hematology. Developed in 1976 by a collaborative working group of expert hematologists from the United States, the United Kingdom, and France, this system made it possible to define acute leukemias and myelodysplastic syndromes through a standardized language based on microscopic appearance. Before FAB was introduced, clinicians in different countries used different names for the same disease, leading to serious inconsistencies in both diagnosis and treatment decisions.
Which Diseases Does the FAB Classification Cover?
The FAB system was designed primarily to classify three disease groups: acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndromes. These three groups share a common ground in that they are all characterized by abnormal cell production in the bone marrow; however, they differ substantially in terms of the cell type from which they originate, their degree of maturation, and their clinical course.
The Foundation of the Classification: Morphology
The fundamental principle underlying the FAB system is morphology — the branch of science that examines the appearance and structural characteristics of cells under the microscope. In the laboratory, peripheral blood smear and bone marrow aspiration samples are prepared, stained with special dyes, and then examined under a microscope by an experienced hematologist or pathologist. The main parameters assessed during this examination include the percentage of blast cells among all nucleated cells, cell size and shape, nuclear structure, the presence of cytoplasmic granules, and the degree of maturation.
A blast cell is an immature, primitive bone marrow cell that has not yet differentiated into a functional blood cell. In a healthy bone marrow, the blast percentage remains below five percent. An increase in this proportion signals a leukemic process.
FAB Subtypes in Acute Myeloid Leukemia
Acute myeloid leukemia is a disease characterized by the uncontrolled proliferation of myeloid precursor cells in the bone marrow. The FAB system divides this disease into eight subtypes, designated M0 through M7.
M0 — Minimally Differentiated AML: The subtype showing the least maturation. Blasts do not provide clear morphological evidence of myeloid origin; diagnosis is confirmed by immunophenotyping.
M1 — Myeloblastic Leukemia Without Maturation: Myeloblasts predominate in the bone marrow, but there is very little evidence of maturation progression among these cells.
M2 — Myeloblastic Leukemia With Maturation: In addition to myeloblasts, cells representing various stages of maturation are also present. This is one of the most frequently encountered subtypes of AML.
M3 — Acute Promyelocytic Leukemia (APL): Perhaps the most clinically significant subtype in the FAB classification. Abnormal promyelocytes and the Auer rods found within them are the hallmark findings of this type. These cells disrupt the coagulation system and carry a serious risk of bleeding. Because it responds exceptionally well to targeted treatment with tretinoin (ATRA), it is managed under a completely different treatment protocol from all other AML subtypes.
M4 — Acute Myelomonocytic Leukemia: The subtype in which both the myeloid and monocytic cell lineages are simultaneously involved. Its variant known as M4Eo, characterized by eosinophilia, is closely associated with inversion of chromosome 16.
M5 — Acute Monoblastic and Monocytic Leukemia: The subtype in which monoblasts and monocytic cells predominate. Extramedullary manifestations such as gingival hyperplasia and skin involvement are more frequently encountered.
M6 — Acute Erythroid Leukemia: A rare subtype in which abnormal erythroid precursor cells predominate. Dysplastic erythroid cells and multinucleated giant cells are seen in the bone marrow.
M7 — Acute Megakaryoblastic Leukemia: The subtype involving the megakaryocyte lineage, the precursor of platelets. It is relatively more common in children with Down syndrome.
FAB Subtypes in Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia is characterized by the uncontrolled proliferation of lymphoid precursor cells and can occur in all age groups, most commonly in children. The FAB system divides this disease into three subtypes.
L1: The subtype in which small, uniform blasts predominate. It is the most common form in children and carries a relatively more favorable prognosis.
L2: The subtype featuring larger and more heterogeneous blasts. It is encountered more frequently in adult patients.
L3: Also known as Burkitt leukemia, this subtype corresponds to the leukemic form of Burkitt lymphoma. Large blasts containing abundant cytoplasmic vacuoles are characteristic, and it is associated with a translocation involving chromosome 8.
FAB Subtypes in Myelodysplastic Syndromes
Myelodysplastic syndromes encompass a group of clonal bone marrow disorders in which the bone marrow is unable to produce sufficient healthy and functional blood cells. The FAB system divides this group into five subtypes.
Refractory Anemia (RA): The blast percentage in the bone marrow is low, but dysplasia in the red cell lineage is prominent. Treatment-resistant anemia dominates the clinical picture.
Refractory Anemia with Ringed Sideroblasts (RARS): In addition to the features of RA, ringed sideroblasts are present in the bone marrow. These are abnormal erythroblasts in which iron has accumulated around the mitochondria due to a defect in iron metabolism.
Refractory Anemia with Excess Blasts (RAEB): The blast percentage in the bone marrow ranges between five and twenty percent. The risk of transformation to leukemia is substantially increased.
RAEB in Transformation (RAEB-T): In this subtype, the blast percentage ranges between twenty and thirty percent, placing the disease at the very threshold of leukemic transformation.
Chronic Myelomonocytic Leukemia (CMML): This subtype combines features of MDS with a marked monocytosis in the peripheral blood. In the post-FAB era it has come to be regarded as a separate disease category in its own right.
The Clinical Significance of FAB
The contribution of the FAB classification to hematology practice extends well beyond academic standardization. The system clearly demonstrated that certain subtypes follow distinct clinical courses and require different treatment protocols. The adoption of ATRA therapy in the M3 subtype is the most striking example of this: a disease once considered one of the most lethal forms of AML has today become the form with the highest cure rate.
In addition, by establishing a common language for clinical research, FAB made it possible to compare data across different centers. International multicenter studies became feasible as a result, and the accumulation of knowledge in the field of hematology accelerated considerably.
The Limitations of FAB
Despite being a groundbreaking innovation for its time, the FAB system gradually revealed some important shortcomings. The most fundamental criticism was that it was based solely on morphology. As cytogenetic analysis and molecular biology advanced rapidly through the 1980s and 1990s, it became apparent that two patients with identical morphological appearances could have completely different genetic profiles — differences that decisively influence prognosis and treatment response.
Interobserver variability in the assessment of certain morphological features, such as Auer rods, also periodically called the system’s reliability into question. The threshold of twenty percent blasts established for myelodysplastic syndromes was similarly debated in terms of whether it truly reflected biological reality.
Its Relationship to the WHO Classification
In 2001, the World Health Organization published a new classification that substantially revised the FAB system. The WHO system incorporated cytogenetic abnormalities, molecular mutations, immunophenotyping, and clinical features into its classification criteria in addition to morphology. This approach enabled the definition of new disease entities characterized by specific genetic abnormalities.
In the WHO system, for instance, the blast threshold required for an AML diagnosis was lowered from thirty to twenty percent, largely eliminating intermediate categories such as RAEB-T. The ability to diagnose AML regardless of blast percentage in patients carrying specific cytogenetic abnormalities such as t(8;21), inv(16), and t(15;17) was another significant innovation introduced by this revision.
Nevertheless, the WHO system did not render FAB entirely obsolete. Many clinicians continue to use FAB terminology, particularly when describing AML subtypes, and the WHO 2016 and 2022 updates retain explanatory references to the original FAB categories. It is fair to say that the core conceptual legacy of FAB endures to this day.
Conclusion
The American–British–French classification retains its place as one of the founding texts of modern hematology. By systematically defining acute leukemias and myelodysplastic syndromes according to microscopic criteria, this system established standardization in diagnosis, provided a common language for clinical research, and laid the groundwork for the development of targeted therapies. Although it has been largely updated by the WHO classification, the FAB system’s place in the history of hematology and its importance in medical education remain beyond dispute.