Abstract
Several new therapeutic strategies are now considered for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, including modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). These enzymes alter the acetylation of several proteins, including histones and transcription factors, as well as several other proteins directly involved in the regulation of cell proliferation, differentiation and apoptosis. Valproic acid (VPA) is a HDAC inhibitor that has been investigated in several clinical AML studies, usually in combination with all-trans retinoic acid (ATRA) for treatment of patients unfit for intensive chemotherapy, for example older patients, and many of these patients have relapsed or primary resistant leukemia. The toxicity of VPA in these patients is low and complete hematological remission lasting for several months has been reported for a few patients (<5% of included patients), but increased peripheral blood platelet counts are seen for 30 to 40% of patients and may last for up to 1 to 2 years. We review the biological effects of VPA on human AML cells, the results from clinical studies of VPA in the treatment of AML and the evidence for combining VPA with new targeted therapy. However, it should be emphasized that VPA has not been investigated in randomized clinical studies. Despite this lack of randomized studies, we conclude that disease-stabilizing treatment including VPA should be considered especially in unfit patients, because the possibility of improving normal blood values has been documented in several studies and the risk of clinically relevant toxicity is minimal.
Highlights
Acute myeloid leukemia (AML) is caused by clonal expansion of myeloblasts that have lost the normal regulation of differentiation and proliferation; this causes bone marrow accumulation of the leukemic cells, and thereby general bone marrow failure, and eventually leukemization and organ infiltration [1]
The prognosis of acute myeloid leukemia (AML) has improved during the last decade, this is mainly true for younger adults who can receive the most intensive
The responders had a median survival of 171 days and most of this time was spent outside hospital. These results suggest that a subset of patients will benefit from this treatment, and this is supported by a third study [20]
Summary
Acute myeloid leukemia (AML) is caused by clonal expansion of myeloblasts that have lost the normal regulation of differentiation and proliferation; this causes bone marrow accumulation of the leukemic cells, and thereby general bone marrow failure, and eventually leukemization and organ infiltration [1]. Biological and clinical effects of combining VPA and demethylating agents The epigenetic changes in AML include altered DNA methylation and histone acetylation leading to gene silencing. Additional biological studies of these patients demonstrated that DNA hypomethylation and histone H3/H4 acetylation can be induced by this treatment [66] Taken together, these studies suggest that the toxicity of this regimen is acceptable even in older patients; encephalopathy/confusion has been described in a relatively high number of patients in certain studies, but this would be an expected dose-dependent effect of VPA.
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