A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: A New York Cancer Consortium

Silverman, L.R.; Verma, Anupam; Odchimar-Reissig, Rosalie; Cozza, Amanda; Najfeld, Vesna; Licht, Jonathan D.; Zwiebel, James A.

doi:10.1200/jco.2008.26.15_suppl.7000

Cited by 36 publications

(19 citation statements)

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“…This observation is consistent with previous randomized studies in high-risk MDS but is the first demonstration that HDAC inhibitors have no impact on clinical outcomes in patients with newly diagnosed or relapsed AMLtreated with AZA (10)(11)(12). Why might our study have failed to replicate earlier single arm studies of strikingly increased clinical activity of combined AZA and HDAC inhibitor treatment (8,9,22)? Clinical and molecular characterization demonstrates comparability between study arms and confirms that the trial population was broadly representative of older patients with high-risk AML and MDS.…”

Section: Discussioncontrasting

confidence: 33%

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

Craddock

Houlton

Quek

et al. 2017

Clinical Cancer Research

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Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n ¼ 217) and MDS (n ¼ 42) randomized to receive either AZA monotherapy (75 mg/m 2 Â 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P ¼ 0.84) or overall survival (OS; P ¼ 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P ¼ 0.0001), IDH1 (P ¼ 0.004), and TP53 (P ¼ 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity.

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Section: Discussioncontrasting

confidence: 33%

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

Craddock

Houlton

Quek

et al. 2017

Clinical Cancer Research

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“…In patients with advanced hematological or solid malignancies the combination of DNMTi and HDACi was well tolerated and showed biological effects such as DNA hypomethylation and histone acetylation (68 -74). Importantly, this combination strategy showed clinical activity and in at least one preliminary study vorinostat in combination with azacitidine seems to be more effective compared with azacitidine alone (74). Although these data support further investigation, especially to evaluate the clinical efficacy of these combinations in randomized trials, it has to be noted that this strategy also resulted in some unfavorable outcomes and HDACi combined with DNMTi was dose-limited by encephalopathy (75).…”

Section: Clinical Studies Using Hdaci In Combinationmentioning

confidence: 92%

Rational Combinations Using HDAC Inhibitors

Bots

Johnstone

2009

Clinical Cancer Research

204

167

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In addition to well-characterized genetic abnormalities that lead to cancer onset and progression, it is now recognized that alterations to the epigenome may also play a significant role in oncogenesis. As a result, epigenetic-modulating agents such as histone deacetylase inhibitors (HDACi) have attracted enormous attention as anticancer drugs. In numerous in vitro and preclinical settings, these compounds have shown their vast potential as single agent anticancer therapies, but unfortunately equivalent responses have not always been observed in patients. Given the pleiotropic effects HDACi have on malignant cells, their true therapeutic potential most likely lies in combination with other anticancer drugs. In this review we will focus on the anticancer effects of HDACi when combined with other cancer therapeutics with an emphasis on those combinations based on a strong molecular rationale.

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“…Combination therapies using DNA methyl-transferase inhibitors and other epidrugs, such as HDACi, are currently investigated with promising results, 32 such as the Vorinostat-based combination treatment in high-risk myelodysplastic syndromes. 33 However, in AMLs, the data are limited and the results controversial. 31,34 Clearly, new approaches are needed.…”

Section: Discussionmentioning

confidence: 99%

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

et al. 2011

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Epigenetic deregulation is involved in acute myeloid leukemia (AML) pathogenesis and epigenetic targeting drugs are in clinical trial. Since the first results with histone-deacetylase inhibitors in AML are controversial, novel single and combined treatments need to be explored. It is tempting to combine chromatin-targeting drugs. SUV39H1, the main methyl-transferase for lysine 9 tri-methylation on histone H3, interacts with oncogenes involved in AML and acts as a transcriptional repressor for hematopoietic differentiation and immortalization. We report here that pharmacological inhibition of SUV39H1 by chaetocin induces apoptosis in leukemia cell lines in vitro and primary AML cells ex vivo, and that it interferes with leukemia growth in vivo. Chaetocin treatment upregulates reactive oxygen species (ROS) production as well as the transcription of death-receptor-related genes, in a ROS-dependent manner, leading to death receptor-dependent apoptosis. In addition to its direct inhibition by chaetocin, SUV39H1 is indirectly modulated by chaetocin-induced ROS. Accordingly, chaetocin potentiates other anti-AML drugs, in a ROS-dependent manner. The decryption of a dual mechanism of action against AML involving both direct and indirect SUV39H1 modulation represents an innovative read-out for the anticancer activity of chaetocin and for its synergy with other anti-AML drugs, suggesting new therapeutic combination strategies in AML.

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A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: A New York Cancer Consortium

Cited by 36 publications

References 0 publications

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

Rational Combinations Using HDAC Inhibitors

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

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