title: Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome.
abstract: Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.
authors.affiliation: Department of Clinical Laboratories, New York, NY, USA. maslakp@mskcc.org
authors.forename: P
authors.initials: P
authors.lastname: Maslak
authors.forename: S
authors.initials: S
authors.lastname: Chanel
authors.forename: L H
authors.initials: LH
authors.lastname: Camacho
authors.forename: S
authors.initials: S
authors.lastname: Soignet
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: I
authors.initials: I
authors.lastname: Guernah
authors.forename: R
authors.initials: R
authors.lastname: Warrell
authors.forename: S
authors.initials: S
authors.lastname: Nimer
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000627:therapeutic use*; D019175:DNA Methylation; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D010654:Phenylbutyrates / Q000627:therapeutic use*; D010865:Pilot Projects; D014158:Transcription, Genetic / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D006657:Histones; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D001374:Azacitidine