Aml Classification

Although acute leukemia has long been recognized as a hematologic malignancy, it has been only in the last 50 years that AML has been looked at as a distinct entity. Indeed, classification of the acute leukemias was primarily based on age and cell morphology, with the adult form being predominately granulocytic with some variants based primarily on the cell type, such as promyelocytic, monocytic (Schilling), myelomono-cytic (Naegli), or erythroleukemia of DiGuglielmo. However, there was considerable difficulty at times distinguishing between lymphoid and myeloid acute leukemias other than by age at onset. The development of reliable histochemical staining by Hayhoe and colleagues in the 1960s improved our diagnostic accuracy, but did not produce a clear system of classification.

In 1976, some order was introduced into the classification of the morphologically heterogeneous acute leukemias with the establishment of the French-American-British (FAB) system.83 The FAB classification was based on morphology, cellularity, blast percentage, and cytochemistry, and was modified over the next several years with the recognition of AML of megakaryocytic lineage (AML-M7) and of minimally differentiated leukemia (AML-M0).84 85 A limitation of the FAB classification has been the clinical diversity of AML, as well as the emerging genetic diversity of the disease and the lack of correlation to improvement in treatment outcomes. In addition, over the past several decades there has been an increasing recognition of a group of hematologic disorders variously designated as preleukemia or myelodysplasia, which preceded the diagnosis of AML in many, but clearly not all cases. It is important to know and remember the FAB system both for historical purposes and because many important clinical trials still being followed and reported are based on that system.

Beginning in 1995, a project was begun by the World Health Organization (WHO) involving an international group of pathologists, assisted by a clinical advisory committee of expert hematologists, to establish a classification of hematologic malignancies. AMLs are recognized as one of the three main categories of myeloid neoplasms, along with MDSs and myeloproliferative disorders. This classification draws on the combination of morphology, immunopheno-type, genetic features, and clinical syndromes. In particular, this system also more formally incorporates the relationship of AML to the MDSs.

The major goal of the WHO classification was to develop a clinically relevant system that could incorporate the genetic and clinical features of AML with the morphology and newer biological information about the disease. An attempt was made to discriminate between distinct disease entities as opposed to prognostic factors, especially with the increasing information on genetic abnormalities in AML. This has led to recognition of four main groups within the category of AML: (1) AML with recurrent cytogenetic translocations, (2) AML with multilineage dysplasia, (3) AML and MDSs, therapy-related, and (4) AML not otherwise categorized. Within each group are several subcate-gories, as outlined in Table 1.4.

In addition to placing patients with AML into unique clinical and biological subgroups, the other major departure with the FAB system was the lowering of the threshold for the number of blasts in the blood or bone marrow to 20% rather than 30%. This is based on the data showing similar outcomes and biological features in the patients with 20-29% blasts, who were previously classified as having MDS compared to those patients with traditional AML.

Approximately 30% of patients with newly diagnosed AML will have one of the four well-defined cyto-genetic abnormalities listed in Table 1.4. Because patients with these abnormalities have a somewhat distinctive phenotype and a relatively favorable response to treatment, they can be considered distinct clinicopathological entities. While other balanced translocations are considered recurring genetic abnormalities, it is felt that these abnormalities have more prognostic import. Undoubtedly, as we learn more

Table 1.4 WHO classification of AMLs

A. AML with recurrent cytogenetic translocations

■ AML with t(15;17)(q22;q11-12) and variants (PML/RARa)

■ AML with abnormal bone marrow eosinophils Inv(16)(p13q22) or t(16;16)(p13;q11), (CBFP/MYH11X)

■ AML with 11q23(MLL) abnormalities

B. AML with multilineage dysplasia

■ with prior myelodysplastic syndrome

■ without prior myelodysplastic syndrome

C. AML and myelodysplastic syndromes, therapy-related

■ alkylating agent-related

■ epipodophyllotoxin-related (some may be lymphoid)

D. AML not otherwise categorized

■ AML minimally differentiated

■ AML without differentiation

■ AML with maturation

■ acute myelomonocytic leukemia

■ acute monocytic leukemia

■ acute erythroid leukemia

■ acute megakaryocyte leukemia

■ acute basophilic leukemia

■ acute panmyelosis with myelofibrosis

E. Acute biphenotypic leukemia

Modified from Jaffe ES, et al.: World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:45-107, Copyright 2001 International Agency for Research on Cancer.

about the significance of these and other genetic abnormalities, the WHO classification will need to be modified.

While many cases of AML present with a well-documented history of myelodysplasia, often there are dys-plastic changes in the blood and bone marrow at the time of diagnosis of AML without an antecedent history of MDS. The WHO attempts to resolve this dilemma of the relationship between these two entities by establishing the classification of AML with mul-tilineage dysplasia. The recognition of AML in this category without prior MDS requires at least 20% blasts in the blood or bone marrow and dysplastic changes in at least 50% of cells in 2 or more myeloid lineages. It is actually felt by some that AML should be divided into the two large categories of true de novo AML and myelodysplasia-related AML.

Exposure to certain therapies, such as alkylating agents and topoisomoerase II inhibitors, has long been known to increase the risk of the subsequent development of AML. The WHO classification places these cases in a separate category, divided into two groups, based on the known agents associated with this risk. While there are common features between these groups, there is sufficient difference to justify each. The topoisomerase II inhibitor-related AML generally has a shorter latency period between exposure to the mutagen and development of AML. This may be as little as 6 months, but can be as long as 6 years, with a median time of 2-3 years compared to 4-7 years for alkylating agent-related AML. In addition, topoiso-merase II inhibitor-related AML typically presents without MDS features, often has a monocytic component, and includes balanced translocations as the genetic abnormality.

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