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dc.contributor.authorCraddock, C
dc.contributor.authorHoulton, A
dc.contributor.authorQuek, L
dc.contributor.authorFerguson, P
dc.contributor.authorGbandi, E
dc.contributor.authorRoberts, C
dc.contributor.authorMetzner, M
dc.contributor.authorGarcia-Martin, N
dc.contributor.authorKennedy, A
dc.contributor.authorHamblin, A
dc.contributor.authorRaghavan, M
dc.contributor.authorNagra, S
dc.contributor.authorDudley, L
dc.contributor.authorWheatley, K
dc.contributor.authorMcMullin, M
dc.contributor.authorPillai, S
dc.contributor.authorKelly, R
dc.contributor.authorSiddique, S
dc.contributor.authorDennis, Michael
dc.contributor.authorCavenagh, J
dc.contributor.authorVyas, P
dc.date.accessioned2017-09-08T15:12:48Z
dc.date.available2017-09-08T15:12:48Z
dc.date.issued2017-08-01
dc.identifier.citationOutcome of Azacitidine therapy in acute myeloid leukemia is not improved by concurrent Vorinostat therapy but is predicted by a diagnostic molecular signature.. 2017 Clin. Cancer Res.en
dc.identifier.issn1078-0432
dc.identifier.pmid28765326
dc.identifier.doi10.1158/1078-0432.CCR-17-1423
dc.identifier.urihttp://hdl.handle.net/10541/620563
dc.description.abstractPurpose: 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 AML. Experimental Design: We compared outcomes in 259 adults with AML (n=217) and MDS (n=42) randomized to receive either AZA monotherapy (75 mg/m(2) × seven days every 28 days) or AZA combined with VOR 300 mg bd on days 3-9 po. 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=0.84) or overall survival (OS) (P=0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P=0.0001), IDH1 (P=0.004) and TP53 (P=0.003) was associated with reduced OS. Lymphoid multi-potential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusion: 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.
dc.language.isoenen
dc.rightsArchived with thanks to Clinical cancer research : an official journal of the American Association for Cancer Researchen
dc.titleOutcome of Azacitidine therapy in acute myeloid leukemia is not improved by concurrent Vorinostat therapy but is predicted by a diagnostic molecular signature.en
dc.typeArticleen
dc.contributor.departmentSchool of Medicine, University of Birminghamen
dc.identifier.journalClinical Cancer Researchen
refterms.dateFOA2020-04-20T15:19:24Z
html.description.abstractPurpose: 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 AML. Experimental Design: We compared outcomes in 259 adults with AML (n=217) and MDS (n=42) randomized to receive either AZA monotherapy (75 mg/m(2) × seven days every 28 days) or AZA combined with VOR 300 mg bd on days 3-9 po. 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=0.84) or overall survival (OS) (P=0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P=0.0001), IDH1 (P=0.004) and TP53 (P=0.003) was associated with reduced OS. Lymphoid multi-potential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusion: 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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