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ESSENTIALS OF DIAGNOSIS
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ESSENTIALS OF DIAGNOSIS
Short duration of symptoms, including fatigue, fever, and bleeding.
Cytopenias or pancytopenia.
Blasts in peripheral blood in 90% of patients.
More than 20% blasts in the bone marrow.
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GENERAL CONSIDERATIONS
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Acute leukemia is a malignancy of the hematopoietic progenitor cell. Malignant immature cells proliferate in an uncontrolled fashion and replace normal bone marrow elements. Most cases arise with no clear cause. However, radiation and some toxins (benzene) are leukemogenic. In addition, a number of chemotherapeutic agents (especially cyclophosphamide, melphalan, other alkylating agents, and etoposide) may cause leukemia. The leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are often associated with abnormalities in chromosomes 5 and 7. Those related to etoposide or anthracyclines may have abnormalities in chromosome 11q23 (MLL locus).
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Most of the clinical findings in acute leukemia are due to replacement of normal bone marrow elements by the malignant cells. Less common manifestations result from organ infiltration (skin, GI tract, meninges). Acute leukemia is potentially curable with combination chemotherapy.
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The myeloblastic subtype, AML, is primarily an adult disease with a median age at presentation of 60 years and an increasing incidence with advanced age. Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17), which produces the fusion gene PML-RAR-alpha, leading to a block in differentiation that can be overcome with pharmacologic doses of retinoic acid. The lymphoblastic subtype of acute leukemia, ALL, comprises 80% of the acute leukemias of childhood. The peak incidence is between 3 and 7 years of age. It is also seen in adults, causing approximately 20% of adult acute leukemias.
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CLASSIFICATION OF THE LEUKEMIAS
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A. Acute Myeloid Leukemia (AML)
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AML is primarily categorized based on recurrent structural chromosomal and molecular abnormalities. The cytogenetic abnormalities can be identified on traditional karyotyping or metaphase fluorescence in situ hybridization (FISH) and the molecular abnormalities are identified by either targeted or genome-wide sequencing of tumor DNA. Favorable cytogenetics such as t(8;21) producing a chimeric RUNX1/RUNX1T1 protein and inv(16)(p13;q22) are seen in 15% of cases and are termed the “core-binding factor” leukemias. These patients have a higher chance of achieving both short- and long-term disease control. Unfavorable cytogenetics confer a very poor prognosis. These consist of chromosomal translocations [t(6;9), t(3;3) or inv (3), t(v;11q23)], isolated monosomy 5 or 7, the presence of two or more other monosomies, or three or more separate cytogenetic abnormalities and account for 25% of the cases. The majority of cases of AML are of intermediate risk by traditional cytogenetics and have either a normal karyotype or chromosomal abnormalities that do not confer strong prognostic significance. However, there are several recurrent gene pathogenic variants with prognostic significance in this subgroup. On the one hand, internal tandem duplication in the gene FLT3 occurs in ~30% of AML ...