latest treatment advances for acute myelogenous leukemia, The

Medicine and Health Rhode Island,  Aug 2003  by Colvin, Gerald A,  Elfenbein, Gerald J

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A cute leukemia is a stem cell disease that usually falls into two sub-types, myeloid or lymphoid. A total of 11,000 new cases of acute leukemia are diagnosed per year in the United States. Overall, acute leukemia is diagnosed in approximately 5 per 100,000 people each year. The incidence of acute myeloid leukemia (AML) is 3.6 per 100,000 people with the remainder having acute lymphoid leukemia (ALL).1 The median age of patients developing all is 4 years old, contrasted with 65 years for AML. The incidence of AML rises from 1.8 per 100,000 individuals below age 65 to 16.3 per 100,000 individuals at age 65 and over. This fact highlights the problem in treating patients with AML; most are too old for aggressive, potentially curative therapy such as a standard bone marrow transplant using a matched sibling or unrelated donor. Untreated, 95% of patients with acute leukemia will die within one year of diagnosis. Because the vast majority of acute leukemias are myeloid, we will focus on AML.

ACUTE MYELOID LEUKEMIA: CLASSIFICATION AND ETIOLOGY

New treatment strategies for AML have been, and continue to be, developed as a consequence of advances in the understanding of both cytogenetic and molecular pathogenesis. These new treatments have significantly improved the survival rate. Before 1970, the 5 year survival rate for AML was less than 15%; the current 5 year survival rate is about 40%. In older adults (>65 years of age), however, the 5 year survival rates are less than 10%.2

Eighty to 100% of newly diagnosed patients with AML have a chromosomal abnormality in myeloid cells.3 Most cases of AML are the result of genetic mutations that occur in hematopoietic progenitor cells and the majority of these mutations are acquired rather than inherited. The current French-American-British (FAB) classification of AML types M1 through M3 depends upon the varying degrees of granulocytic differentiation and maturation. Monocytic and granulocytic differentiation defects characterize AML-M4, whereas monocyte differentiation is the predominant feature of AML-M5. AML-M6 is characterized by erythroid morphology and AML-M7 by megakaryocytic features.

A recent retrospective analysis of nearly 2,000 patients has shown that the 5-year survival is directly related to the cytogenetic status of the hematopoietic cells at presentation.4 Patients with normal cytogenetics or with favorable cytogenetic abnormalities, such as t(8;21), t(15;17), and t(16;16), have better prognoses. Patients with deletions in the long arm of chromosome 7 and chromosome 5, deletions or inversions of chromosome 3, t(6;9), and the Philadelphia chromosome t(9;22), as well as abnormalities of chromosome 11q23, have relatively poor prognoses.5 Genetic deletions seem to be more characteristic of older AML patients, with 5q and 7q deletions found in approximately 17% of patients in this age group. In general, patients with AML whose cells have translocations seem to fare better than those whose cells have deletions. The poor prognosis associated with increased age may be related to the higher incidence of genetic deletions.

In AML, genes located at translocation breakpoints are typically responsible for cellular transcription and transduction of growth signals. Most translocations in de novo AML result in a fusion of the affected genes, with production of hybrid proteins. The (15; 17) translocation found in most promyelocytic leukemia (PML, M3) illustrates this mechanism where the promyelocytic leukemia (PML) gene on chromosome 15 is fused to the retinoic acid receptor (RAR) alpha gene on chromosome 17, leading to production of a nonfunctional RAR that does not respond to normal physiologic levels of circulating retinoic acid. Cell transcription and differentiation is thus arrested by the inability of the RAR to activate normal target genes. The PML gene seems to function as a histone deacetylator, which also serves to suppress gene transcription and cellular maturation. The administration of all-trans-retinoic acid (ATRA) allows the histone deacetylation complex to dissociate from the RAR-PML fusion protein, enabling the RAR to function appropriately, which, in turn, leads to cellular differentiation.

Another well-characterized gene rearrangement in AML involves the transcription factor complex core-binding factor (CBF). CBF is composed of an alpha subunit that directly contacts DNA and a CBF-beta subunit that facilitates binding of AML1 to DNA. Three genes (AML1, AML2, and AML3) encode the alpha subunit. It is thought that translocations involving the CBF result in the loss of normal CBF properties, converting CBF from transcriptional activator to inhibitor, thus leading to suppression of transcription of several target genes, including genes for interleukin-3 myeloperoxidase, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the T-cell receptor beta.6

The (8;21) translocation, seen in approximately 46% of AML-M2 patients, results in the production of a fusion protein known as ETO/AML, of which the ETO portion from chromosome 8 is involved in histone deacetylation.7 This, in turn, serves to block activation of AML1 gene expression, resulting in lack of IL-3 and GMCSF receptor activation and loss of cellular differentiation/maturation. Inv(16), found in AML-M4 with eosinophilia, is associated with fusion of CBFb to the smooth muscle myosin heavy chain (MYH11) gene. This CBFb-MYH11 chimeric protein directly represses AML1-mediated transcriptional activity by forming inactive complexes in the cellular cytoplasm.8