title: Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.
abstract: Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
authors.affiliation: Developmental Therapeutics Branch, NCI, NIH, Bethesda, MD, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.affiliation: Developmental Therapeutics Branch, NCI, NIH, Bethesda, MD, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Eisch
authors.affiliation: Department of Radiology, Warren G Magnuson Clinical Center, NIH, Bethesda, MD, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ling
authors.affiliation: Consultative Cardiology, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Rosing
authors.affiliation: Dermatology Branch, NCI, Bethesda, MD, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Turner
authors.affiliation: Laboratory of Pathology, CCR, NCI, Bethesda, MD, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.
authors.forename: H Miles
authors.initials: HM
authors.lastname: Prince
authors.affiliation: Hematological Malignancies, Penn State Hershey Medical Center, Hershey, PA, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kirschbaum
authors.affiliation: Hofstra North Shore-LIJ School of Medicine and Monter Cancer Center, Lake Success, NY, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Zain
authors.affiliation: Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Larisa J
authors.initials: LJ
authors.lastname: Geskin
authors.affiliation: Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Joske
authors.affiliation: City of Hope National Cancer Center, Duarte, CA, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.affiliation: Dermatology Branch, NCI, Bethesda, MD, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Cowen
authors.affiliation: Laboratory of Pathology, CCR, NCI, Bethesda, MD, USA.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Celgene Corporation, Cambridge, MA, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Nichols
authors.affiliation: Independent Pharmaceutical Consultant, Boston, MA, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Biostatistics and Data Management, NCI, Bethesda, MD, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Biostatistics and Data Management, NCI, Bethesda, MD, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.affiliation: Center for Cancer Research, NCI, Bethesda, MD, USA.
authors.forename: Caryn
authors.initials: C
authors.lastname: Steakley
authors.affiliation: Cancer Therapy Evaluation Program, DCTDC, NCI, Bethesda, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.affiliation: Center for Cancer Research, NCI, Bethesda, MD, USA.
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.affiliation: LEO Pharma A/S, Ballerup, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Litman
authors.affiliation: Cancer Therapy Evaluation Program, DCTDC, NCI, Bethesda, MD, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D047630:Depsipeptides / Q000009:adverse effects / Q000627:therapeutic use*; D057890:Epigenomics; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin
keywords: T-cell lymphoma; chromatin; epigenetic therapy; histone deacetylase inhibitor; romidepsin