Abstract
Acute myeloid leukemia (AML) is an intrinsically resistant disease. Prognosis is poor for the majority of AML patients, based on age and/or adverse biologic features. Standard therapy for AML is highly toxic and poorly tolerated, particularly by the group of older patients for whom few useful therapies exist. Allogeneic hematopoietic stem cell transplantation is an important option for patients with high-risk AML during first remission, as well as for any patient in second or subsequent remission. Use of reduced intensity conditioning transplantations has made allogeneic stem cell transplantation available for a wider group of individuals, but the impact of this novel procedure on the natural history of AML is unknown. The major thrust of novel therapeutics in AML is development of so-called targeted therapies, which are based on exploitation of newly understood pathophysiological events critical for leukemogenesis. Such events include unbridled proliferation, failure to differentiate, stromal cell-mediated survival factors, and failure to undergo normal programmed cell death. Therapies developed to deal with these problems include inhibitors of ras physiology and activated tyrosine kinases, such as fms-like tyrosine kinase 3; histone deacetylase inhibitors, and DNA-hypomethylating agents, which promote transcription of silenced genes; angiogenesis inhibitors; and anti-bcl-2 agents, respectively. Challenges in therapeutic development include the likelihood that only a subset of AML patients will respond to any of these therapies, based on the patient's intrinsic pathophysiology as well as the fact that many of these agents will only work in conjunction with chemotherapy or other viable antileukemic therapies.
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