P131 Phase I trial of the combination of the epigenetic modulators vorinostat and azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). An update from the NY Cancer Consortium

Silverman, L.R.; Verma, Amit; Odchimar-Reissig, Rosalie; LeBlane, A.; Najfeld, Vesna; Gabrilove, Janice; Isola, Luis; Espinoza‐Delgado, Igor; Zwiebel, James A.

doi:10.1016/s0145-2126(09)70212-7

Cited by 20 publications

(22 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: Discussionsupporting

confidence: 91%

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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: Discussionsupporting

confidence: 91%

“…Coadministration of AZA with histone deacetylase (HDAC) inhibitors augments killing of leukemic cell lines in vitro (7) and single-arm trials have described increased clinical activity of AZA in combination with a number of HDAC inhibitors including sodium valproate and vorinostat (VOR; refs. 4,8,9).…”

Section: Introductionmentioning

confidence: 99%

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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“…Of these, 966 HpaII fragments also reached a methylation difference cutoff of greater than 1.5 ( Figure 5D-E). It has been widely reported that bone marrow response in patients treated with 5AC only occurs after several cycles, 9,12,34 and this trend also occurred in the current study. 35 Therefore, the difference in methylation profile cannot be attributed to normalization of the bone marrow at these early time points.…”

Section: Org Fromsupporting

confidence: 84%

MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation

Figueroa

Skrabanek

et al. 2009

Blood

302

224

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Increasing evidence shows aberrant hypermethylation of genes occurring in and potentially contributing to pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDSs), are responsive to DNA methyltransferase inhibitors. To determine the extent of promoter hypermethylation in such tumors, we compared the distribution of DNA methylation of 14 000 promoters in MDS and secondary acute myeloid leukemia (AML) patients enrolled in a phase 1 trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34 ؉ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34 ؉ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alupoor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. This trial was registered at www.clinicaltrials.gov as J0443.

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“…The outcomes of 40 primarily higher-risk patients enrolled in a phase 2 trial testing the combination of vorinostat and azacitidine highlight the potential of combined epigenetic therapy. 40 Of the 33 patients evaluable, 23 (70%) responded, with a CR (CR/CR with incomplete hematologic recovery) in 14 and an additional 9 with hematologic improvement. The median duration of response was 16 months and the median overall survival was 21 months.…”

Section: Combination Therapiesmentioning

confidence: 99%

Established and novel agents for myelodysplastic syndromes

Sekeres

Gerds

2014

Hematology

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The myelodysplastic syndromes (MDS) are the most commonly diagnosed myeloid malignancy, with Ͼ15 000 new cases identified in the United States yearly. Prognostic scoring systems supplant a formal staging approach and, in general, divide patients into those with lower-risk and those with higher-risk MDS. Although treatment goals for patients with lower-risk disease focus on minimizing transfusions and optimizing quality of life, in higher-risk MDS, the goal is to delay transformation to acute leukemia and to prolong survival. In lower-risk patients, isolated cytopenias are treated with erythropoiesis-stimulating agents or growth factors such as thrombopoietin mimetics. For patients with the del(5q) cytogenetic abnormality or those who fail these initial approaches, lenalidomide may be tried, as can experimental agents. Lower-risk patients with multiple cytopenias may be treated with immunosuppressive drugs or low-dose hypomethylating agents. For patients with higher-risk disease, hypomethylating agents are the preferred initial treatment approach, with evaluation for hematopoietic cell transplantation at diagnosis. Several novel agents are being developed for MDS patients who have failed hypomethylating drugs. Learning Objective• To describe appropriate therapies for lower-and higher-risk myelodysplastic syndromes and novel agents being developed

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P131 Phase I trial of the combination of the epigenetic modulators vorinostat and azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). An update from the NY Cancer Consortium

Cited by 20 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

MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation

Established and novel agents for myelodysplastic syndromes

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