title: Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome).
abstract: BACKGROUND
  Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).
  
  
  METHODS
  In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.
  
  
  RESULTS
  All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.
  
  
  CONCLUSIONS
  Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. Electronic address: reinhard.dummer@usz.ch.
authors.forename: R
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, MD Anderson Cancer Center, Houston, USA.
authors.forename: M
authors.initials: M
authors.lastname: Duvic
authors.affiliation: Department Dermatology, Hospital Birmingham, Birmingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Scarisbrick
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Olsen
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Rozati
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Eggmann
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: S M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Clinical Research, AMS Ltd, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Hutchinson
authors.affiliation: Department of Dermatology, University of Pittsburgh, Pittsburgh, USA.
authors.forename: L
authors.initials: L
authors.lastname: Geskin
authors.affiliation: School of Cancer and Imaging Sciences, University of Manchester, Manchester, UK.
authors.forename: T M
authors.initials: TM
authors.lastname: Illidge
authors.affiliation: Clinical Development, BioCryst Pharmaceuticals, Inc., Durham.
authors.forename: E
authors.initials: E
authors.lastname: Giuliano
authors.affiliation: Statistics, PharPoint Research, Inc., Chapel Hill.
authors.forename: J
authors.initials: J
authors.lastname: Elder
authors.affiliation: Clinical Research, Stanford Cancer Center, Stanford, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000188:drug therapy*; D011684:Purine Nucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D012751:Sezary Syndrome / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000188:drug therapy*; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase
keywords: Sézary syndrome; cutaneous T-cell lymphomas; forodesine; mycosis fungoides; purine nucleoside phosphorylase inhibitor