Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (p < 0.05, q < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignancy [1], and the only possible cure is intensive therapy possibly including stem cell transplantation [2]
We have performed systemic metabolomic profiling of AML patients treated with the combination of all-trans retinoic acid (ATRA), valproic acid, and low doses of conventional cytotoxic drugs, and we examined the effects of both ATRA and valproic acid monotherapy on systemic metabolite profiles of AML patients
Our study suggests that differences in pretreatment amino acid and lipid metabolite profiles are associated with disease aggressiveness, and both ATRA and valproic acid cause further modulation of the systemic metabolic signature
Summary
Acute myeloid leukemia (AML) is an aggressive malignancy [1], and the only possible cure is intensive therapy possibly including stem cell transplantation [2]. 65–70 years [3,4], and the elderly patients above 70–75 years of age have an increased frequency of high-risk disease [4] where remission is unlikely [5,6]. These patients are often not eligible to receive intensive treatment [7]. Intensive chemotherapy is not always recommended for patients with refractory or relapsed disease either [8]. AML-stabilizing treatment, e.g., a histone deacetylase (HDAC) inhibitor combined with all-trans retinoic acid (ATRA) and low-dose cytotoxic drugs [9].
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