Search

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p Methods: Patients were randomized 1:1 to moga 1.0 mg/kg administered intravenously on Days 1, 8, 15, and 22 of the first cycle and on Days 1 and 15 of subsequent cycles or vori 400 mg administered orally once daily. Patients randomized to vori were allowed to cross over to moga upon progression or intolerable toxicity. Safety was assessed by reported adverse events (AEs), changes in physical examinations, vital sign measurements, electrocardiograms, and laboratory analyses. Results: In total, 372 patients were randomized (moga, 186; vori, 186), of whom 370 received study drug and were included in the safety analysis (moga, 184; vori, 186). For the final safety analysis, median duration of follow-up was 34.5 months (range, 0.13-70.0) in the randomized part of the study. Median treatment exposure was 170 days (range, 1-1813) for moga and 84 days (4-1230) for vori, which represent the same median values but broader ranges compared to the primary analysis (primary analysis, 170 days [1-1379] for moga and 84 days [4-1058] for vori). The type and frequency of AEs in either the moga or vori treatment groups (Table) were consistent with those reported in the primary analysis. TEAEs, regardless of causality, that were reported at similar rates in the two treatment groups included constipation, peripheral edema, headache, and anemia. TEAEs (all causality) that occurred at higher frequency in the moga vs vori arm included infusion-related reaction (33.2% vs 0.5%) and drug eruption (25.0% vs 1.1%); the majority of these events were grade 1 or 2 (Table). The types and frequencies of AEs attributable to moga (per Investigator assessment) included infusion-related reaction (33.2% [61/184]), drug eruption (23.9% [44/184]), and fatigue (18.5% [34/184]), and for vori, diarrhea (55.4% [103/186]), nausea (38.2% [71/186]), and fatigue (33.3% [62/186]). In patients who crossed over from the vori to moga arm and received study drug (n=135), the most frequently reported AEs attributable to moga were infusion-related reaction (37.8% [51/135]), drug eruption (24.4% [33/135]), fatigue (7.4% [10/135]), increased alanine aminotransferase (7.4% [10/135]), and increased aspartate aminotransferase (7.4% [10/135]). Discontinuation rates due to AEs were similar between treatment arms and in crossover patients (moga, 21.7% [40/184]; vori, 23.7% [44/186]; crossover, 25.9% [35/135]). The most common AEs leading to discontinuation were drug eruption in the moga arm (7.1% [13/184]) and fatigue in the vori arm (4.3% [8/186]). Overall, the rates of drug-related serious TEAEs were similar between treatment arms and in crossover patients (moga, 19.6% [36/184]; vori, 16.7% [31/186]; crossover, 11.9% [16/135]). After the data cutoff for the primary analysis, 1 additional patient randomized to moga (decreased appetite, general physical health deterioration, hypoalbuminemia) and 1 crossover patient (cerebral hemorrhage) experienced TEAEs with an outcome of death, all considered unrelated to study treatment per Investigator. Conclusions: This final safety analysis from the MAVORIC study in patients with previously treated MF and SS demonstrates that moga was generally well tolerated. Longer follow-up and treatment exposure did not identify any new safety signals. The type and incidence of treatment-related AEs among patients receiving moga after crossover were similar to those observed for patients initially randomized to moga. Disclosures Kim: Merck: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Neumedicine: Research Funding; miRagen: Research Funding. Bagot:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Duvic:Seattle Genetics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Shape: Research Funding; UT MD Anderson Cancer Center: Employment; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Spatz Foundation: Research Funding; Tetralogic: Research Funding; Millennium (formerly Takeda): Research Funding; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; PleXus Communications: Speakers Bureau; Guidepoint Global: Consultancy; Evidera, Inc.: Consultancy; Cell Medica Inc.: Consultancy; Allos: Research Funding; Rhizen Pharma: Research Funding; Oncoceuticals: Research Funding; Soligenetics: Research Funding; Cell Medica Ltd.: Honoraria; Therakos: Speakers Bureau; Jonathan Wood & Assoc.: Speakers Bureau; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau. Morris:Guys Hospital: Employment. Kim:Medimmune: Research Funding; Soligenix: Research Funding; Kyowa Kirin: Research Funding; Galderma: Consultancy, Research Funding; Actelion: Consultancy, Research Funding. Musiek:Menlo: Other: Investigator; Helsinn: Membership on an entity's Board of Directors or advisory committees; Soligenix: Other: Investigator; Pfizer: Other: Investigator; Elorac: Other: Investigator; Kyowa: Honoraria, Other: Above honoraria: for Ad Board; miRagen: Other: Investigator. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; miRagen: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees. Eradat:Kyowa: Research Funding; Kite: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding. Magnolo:University Hospital of Muenster, Center of Innovative Dermatology: Employment. Scarisbrick:Kyowa Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Recordat: Consultancy; 4SC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa: Other: Principal Investigator in clinical trials promoted by Kyowa. Fisher:Kyowa Kirin: Consultancy. Poligone:Stemline Therapeutics: Consultancy, Speakers Bureau; Regeneron: Consultancy, Speakers Bureau; Actelion: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Research Funding; Bioniz: Research Funding; Celgene: Consultancy; Helsinn: Research Funding, Speakers Bureau; Innate Pharma: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria, Research Funding, Speakers Bureau; miRagen: Research Funding; Soligenix: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Quaglino:Actelion: Honoraria, Other: Advisory Board; Innate Pharma: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Kyowa Kirin: Honoraria, Other: Advisory Board; Helsinn: Honoraria, Other: Advisory Board; Therakos: Honoraria, Other: Advisory Board. Reddy:AbbVie: Honoraria; Janssen: Honoraria; KITE: Honoraria; Merck: Research Funding; Celgene: Honoraria, Speakers Bureau. Geskin:Merck: Other: Supported/Contracted Research; UpToDate: Patents & Royalties: Royalty, Receipt of Intellectual Property Rights / Patent Holder; Actelion: Other: Supported/Contracted Research; Helsinn: Consultancy, Honoraria, Other: Supported/Contracted Research; Stratpharma: Other: Supported/Contracted Research; Mallinckrodt: Consultancy, Honoraria, Other: Supported/Contracted Research; Medscape: Speakers Bureau; Medivir: Consultancy, Honoraria. Halwani:Amgen: Other: Investigator; Takeda: Other: PI; Seattle Genetics: Other: PI; Pharmacyclics: Other: Investigator; miRagen: Other: PI; Kyowa Hakko Kirin: Other: PI; Immune Design: Other: PI; Genentech, Inc.: Other: Investigator; Bristol-Myers Squibb: Other: PI; AbbVie: Other: PI. Khot:Peter MacCallum Cancer Centre: Employment; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dermira: Research Funding; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Horwitz:Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Astex: Consultancy; Portola: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Astex: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding. Lamar:Seattle Genetics: Consultancy; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding. Wells:Takeda Pharmaceuticals Australia Pty Limited: Membership on an entity's Board of Directors or advisory committees; MSD Australia: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Akilov:Trillium Therapeutics: Consultancy, Other: PI on the clinical trials, Research Funding; Pfizer: Research Funding. Cowan:Kyowa Kirin: Consultancy. Dummer:Merck Sharp & Dohme: Other: Intermittent, project focused consulting and/or advisory relationships; Novartis: Other: Intermittent, project focused consulting and/or advisory relationships; Bristol-Myers Squibb: Other: Intermittent, project focused consulting and/or advisory relationships; Roche: Other: Intermittent, project focused consulting and/or advisory relationships; Amgen: Other: Intermittent, project focused consulting and/or advisory relationships; Takeda: Other: Intermittent, project focused consulting and/or advisory relationships; Pierre Fabre: Other: Intermittent, project focused consulting and/or advisory relationships; Sun Pharma: Other: Intermittent, project focused consulting and/or advisory relationships; Sanofi: Other: Intermittent, project focused consulting and/or advisory relationships; Catalym: Other: Intermittent, project focused consulting and/or advisory relationships; Second Genome: Other: Intermittent, project focused consulting and/or advisory relationships. Lechowicz:Kyowa Kirin Inc: Consultancy; Spectrum: Consultancy. Foss:Eisai: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy; Acrotech: Consultancy; Mallinckrodt: Consultancy; Spectrum: Other: fees for non-CME/CE services . Wilcox:University of Michigan: Employment. Porcu:Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; Viracta: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Vermeer:Kyowa: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Abhyankar:Therakos: Other: Consulting, Speakers Bureau; Incyte: Speakers Bureau. Pacheco:University of Colorado: Employment. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Fukuhara:Kyowa-Hakko Kirin: Honoraria; Bayer: Research Funding; Mundi: Honoraria; Janssen Pharma: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy. Querfeld:Elorac: Other: Investigator, Research Funding; Trillium: Consultancy, Other: Investigator, Research Funding; Medivir: Consultancy; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; City of Hope Cancer Center and Beckman Research Institute: Employment; Celgene: Other: Investigator, Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Uhara:Kyowa Kirin Co., Ltd: Honoraria, Research Funding. Huen:Innate Pharmaceuticals: Research Funding; Galderma Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Glaxo Smith Kline Inc: Research Funding. Tobinai:Meiji Seika: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; AbbVie: Research Funding; Verastem: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Yakult: Honoraria; Solasia: Honoraria. Tokura:Kyowa Kirin Pharmaceutical Development, Inc.: Honoraria. Boh:Actelion: Other: Principal Investigator; Tulane University School of Medicine: Employment; Celgene: Other: Principal Investigator, Speaker, Grants; Sun: Other: Speaker; Janssen: Other: Principal Investigator, Speaker, Grants; Novartis: Other: Principal Investigator, Speaker, Grants; Soligenix: Other: Principal Investigator; Incyte: Other: Principal Investigator; Regeneron: Other: Principal Investigator, Grants; Ortho Dermatologics: Other: Speaker, Grants; Pfizer: Other: Principal Investigator; UCB: Other: Speaker, Grants; Elorac: Other: Principal Investigator; Abbvie: Other: Principal Investigator. Nicolay:Teva Pharmaceutical Industries: Honoraria, Other: Conference participation fees; Novartis AG: Consultancy, Honoraria; Biogen GmbH: Consultancy, Honoraria; Almirall Hermal AG: Consultancy, Honoraria; Actelion Pharmaceuticals: Consultancy, Honoraria; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy. Leoni:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Herr:Kyowa Kirin, Inc.: Employment. Sokol:EUSA: Consultancy.

Background: There is a large unmet need for relapsed/refractory T cell lymphoma. For patients (pts) with recurrent disease, the efficacy of salvage and autologous stem cell transplant (if feasible) is moderate and the 3-year overall survival is less than 30%. Romidepsin is a histone deacetylase inhibitor (HDACi) that is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. Immune checkpoint blockade (CPB) of PD1/PDL-1 has been successful in many malignancies. In a recent report, PDL1 expression was observed 5-17% of tumor cells and 43%-57% in stromal histiocytes in PTCL-NOS or AITL. A phase II single agent study of the PD1 monoclonal antibody (mAB) pembrolizumab in PTCL demonstrated modest responses (Barta et.al). In addition, PTCL often carries multiple gene mutations in epigenetic modifier genes (TET2, IDH2, DNMT3A) and others (RHOA, FYN) that may impair immunogenicity and promote immune escape. This was the rationale for combining HDACi and CPB. We report this single center, single arm, nonrandomized trial of pembrolizumab in combination with romidepsin in subjects with relapsed or refractory PTCL that have failed to achieve a complete response or progressed after at least one systemic treatment regimen (NCT03278782). METHODS: This is a phase I/II study to examine the safety and efficacy of pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W) in combination with romidepsin. The safety of the combination was tested in the lead-in phase I study with a strategy of dose de-escalation, keeping the starting dose of romidepsin 14 mg/m2 on days 1 and 8. This eventually became the dosing for the phase II study. Adverse events were monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary objectives of the trial are to determine safety, tolerability, and overall response rate (ORR) of the combination. Secondary objectives include further analysis of various efficacy parameters [complete remission rate (CRR), progression free survival (PFS), overall survival(OS) and duration of response (DOR)]. Response assessment was performed utilizing Lugano Revised Response Criteria, and PD-L1 expression assessed by immunohistochemistry and exploratory analysis of targeted Next Generation Sequencing in the primary lymphoma tissue. Changes in peripheral blood T-cell repertoire were assessed primarily by flow cytometry. RESULTS: 15 pts were evaluable for the primary endpoint (demographics in figure 1). The phase I part was expanded from 3 to 6 pts, because of a dose limiting toxicity (DLT) of hypotension and renal insufficiency which resolved. The phase II is ongoing with 9 pts enrolled. The overall response rate was 44%; 3 pts. achieved a complete response and 2 achieved PR. The median follow-up was 6 months (3 weeks- 12 months). The 3 complete responders remain in remission > 10 months. One patient with refractory ALCL who achieved CR after 3 cycles is now 6 months post Haplo-identical transplant. Nausea and vomiting was the most common adverse event (Grade 1/2-). The most common ≥ grade 3 treatment-emergent adverse events were Nausea/vomiting and fatigue ( n =1 and n= 2). Two patients experienced hyperprogression within the first 10 days after the treatment. Correlative studies including NGS, expression of PD-L1, CD4+ T lymphocytes counts are in progress. CONCLUSIONS: The combination of Romidepsin and Pembrolizumab has demonstrated acceptable safety and early encouraging results. Table. Disclosures Iyer: Spectrum: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Trillium Therapeutics: Research Funding; Rhizen: Research Funding. Neelapu:BMS: Research Funding; Allogene: Consultancy; Acerta: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Cellectis: Research Funding; Poseida: Research Funding. Nieto:Affimed: Research Funding; Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Consultancy. Westin:Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:Bayer: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding. Duvic:Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau; PleXus Communications: Speakers Bureau; Therakos: Speakers Bureau; Eisai: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Jonathan Wood & Assoc.: Speakers Bureau; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Soligenetics: Research Funding; Evidera, Inc.: Consultancy; Guidepoint Global: Consultancy; Cell Medica Inc.: Consultancy; UT MD Anderson Cancer Center: Employment; Shape: Research Funding; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Oncoceuticals: Research Funding; Millennium (formerly Takeda): Research Funding; Allos: Research Funding; Rhizen Pharma: Research Funding; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; Cell Medica Ltd.: Honoraria; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. OffLabel Disclosure: Pembrolizumab in T cell lymphoma

A phase 2 multicenter trial was performed to evaluate single-agent lenalidomide in advanced, refractory mycosis fungoides/Sézary syndrome. Thirty-two patients were enrolled with a median of 6 prior treatment regimens, including a median of 4 systemic therapies. Patients achieved an overall response rate of 28% (9 patients), and all were partial responses. Median overall survival was 43 months, median progression-free survival was 8 months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events included fatigue (22%), infection (9%), and leukopenia (3%). Patients were frequently unable to tolerate the 25-mg starting dose of lenalidomide used in other hematologic malignancies due to fatigue, pain, and transient flare reaction (TFR) as a contributory factor. TFR appeared to correlate with clinical response, but the small sample size limited definitive conclusions, and the underlying mechanisms of this reaction are not known. Data from correlative studies on peripheral blood samples suggest that the effects of lenalidomide could be associated with decreased circulating CD25(+) T cells and CD4(+) T-cell numbers. Skin lesions showed a trend for increased CD8, CD25, and FoxP3 expression with decreased CD4:CD8 ratio. In conclusion, lenalidomide monotherapy demonstrated activity in refractory cutaneous T-cell lymphomas, along with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT00466921.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy with a historical overall survival (OS) of ~8-14 months from diagnosis and no approved therapies or standard of care. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on BPDCN and other malignancies. Tagraxofusp was granted Breakthrough Therapy Designation for the treatment of patients with BPDCN, and a rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) was completed in June 2018. Detailed results from the pivotal trial of tagraxofusp in BPDCN will be presented. Methods: This pivotal Phase 2 clinical trial is a multicenter, open label, non-randomized, single-arm trial designed to determine safety and efficacy of tagraxofusp in patients with BPDCN. In Stage 1 (lead-in), first line (1L) and relapsed/refractory (r/r) patients with BPDCN received tagraxofusp as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-5 of a 21-day cycle. Patients with BPDCN enrolled in subsequent stages received tagraxofusp at the dose determined in Stage 1 (12 mcg/kg). Stage 2 (expansion) enrolled 1L and r/r patients, and Stage 3 (pivotal, confirmatory) enrolled only 1L patients. Results: 45 patients with BPDCN (Stages 1 and 2, n=32; Stage 3, n=13) were enrolled at 7 sites in the US, including 32 (71%) patients as 1L. Median age was 70 years (range, 22-84); 82% male. Median follow-up for all 1L patients treated at 12 mcg/kg (n=29) was 13.8 months (range 0.2-37.4+). The most common treatment-related adverse events (TRAEs) at 12 mcg/kg in 148 patients treated in four clinical trials with tagraxofusp were transaminitis (44%), hypoalbuminemia (44%), and thrombocytopenia (26%). Capillary leak syndrome (CLS), all grades, occurred in 17% of patients across all indications at 12 mcg/kg; 0.7% (1/148) and 1.6% (3/182) of cases resulted in death across all indications at 12 mcg/kg and all doses, respectively. The Stage 3 pivotal cohort met its primary endpoint with a 54% (7/13) rate of CR+CRc (95% CI: 25.1, 80.8). Across Stages 1, 2 and 3, in 1L patients dosed at 12 mcg/kg (n=29), ORR was 90% (26/29) with a 72% (21/29) rate of CR+CRc+CRi (ORR=overall response rate; CR=complete response; CRc=clinical CR: absence of gross disease with minimal residual skin abnormality; CRi=CR with incomplete hematologic recovery). 45% (13/29) of first-line patients treated with 12 mcg/kg were bridged to stem cell transplant (SCT) (10 allo+3 auto). In r/r patients, ORR was 69% (9/13) with a 38% (5/13) rate of CR+CRc+CRi. Additional patient follow-up will be provided. Conclusions: The pivotal trial of tagraxofusp was the largest prospectively designed, multi-center trial specifically dedicated to patients with BPDCN. This study has met its primary endpoint, and also demonstrated high response rates that were generally achieved early in the course of treatment and maintained over multiple cycles of therapy. Safety profile demonstrated most common toxicities of transaminitis, hypoalbuminemia, and thrombocytopenia; occurrence of CLS was the most serious TRAE, which was overall manageable in this population. Patients with BPDCN are being enrolled in an additional cohort, Stage 4, to ensure ongoing access. Tagraxofusp is also being evaluated in other trials including in patients with chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF). Disclosures Pemmaraju: celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; abbvie: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; BMS: Honoraria; Phizer: Consultancy; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Blum:Tolero: Research Funding; Forma: Research Funding; Astellas: Consultancy; Xencor: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Consultancy. Rizzieri:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Duvic:Guidepoint Global: Consultancy; Eisai: Research Funding; Allos: Research Funding; Clinical Care Options: Consultancy; Array Biopharma: Consultancy, Honoraria; Spatz Foundation: Research Funding; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; MEDACorp: Consultancy; Taiwan Liposome Company LTD: Consultancy; Medscape: Other: Speaker/Preceptor; Concert Pharmaceuticals, Inc.: Consultancy; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya Bioscience Int'l: Consultancy; Shape: Research Funding; Kiniksa Pharmaceuticals: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Huron Consulting Group: Consultancy; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; UT MD Anderson Cancer Center: Employment; The Lynx Group: Consultancy; Evidera, Inc.: Consultancy; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Oncoceuticals: Research Funding; Jonathan Wood & Associates: Other: Speaker; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen Pharma: Research Funding. Spence:Stemline Therapeutics: Consultancy. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Sloan:Stemline Therapeutics: Consultancy. Konopleva:Stemline Therapeutics: Research Funding.

Background: CTCL represents a rare group of non-Hodgkin lymphomas with substantial negative impact on patient (pt) quality of life and mortality in advanced-stage disease. Mycosis fungoides (MF), the most common subtype of CTCL, and the rarer leukemic variant Sézary syndrome (SS) are distinct subtypes of CTCL. Mogamulizumab is a first-in-class, defucosylated monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), which is highly expressed on malignant T-cells in CTCL. Primary results from the MAVORIC study (data cut-off December 2016), a phase 3 trial comparing mogamulizumab to FDA-approved vorinostat in adults with relapsed/refractory MF/SS, showed mogamulizumab significantly prolonged median progression-free survival compared with vorinostat (7.7 vs 3.1 months, P Methods: This was an open-label, randomized, international, phase 3 study (NCT01728805). Pts with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive mogamulizumab (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral vorinostat (400 mg daily). In this follow-up analysis (data cut-off September 2017), exposure quartiles were determined, and baseline demographics, confirmed global response rate, and safety were analyzed by exposure group. To detect linear trends across exposure quartiles, frequencies were analyzed using Chi-square test and continuous data were assessed by analysis of variance. Results: A total of 184 pts randomized to mogamulizumab were included in this analysis. Mean time of mogamulizumab exposure was 275 days (d; standard deviation [SD]: 292 d; range: 1-1617). Based on quartile assessment, >351 d was defined as cut-off for long-term exposure. Baseline characteristics across exposure groups are shown in the Table. Significant trends were observed for baseline Eastern Cooperative Oncology Group performance status (ECOG PS; P=0.04), disease type (P=0.03), and blood involvement (defined as ≥B1 per Olsen et al J Clin Oncol 2011; P351 d, 76% had a confirmed global response (ie, either complete or partial response). The percentage of pts reporting a treatment-emergent adverse event (AE) or serious AE did not vary with increasing exposure to mogamulizumab (351 d: 21% and 4%, respectively). The most common treatment-related AEs reported by pts after >351 d of exposure to mogamulizumab were drug eruption (9/45 [20%]), thrombocytopenia (5/45 [11%]), stomatitis (4/45 [9%]), and anemia (4/45 [9%]). Conclusions: This follow-up analysis of the phase 3 MAVORIC study demonstrated mogamulizumab treatment of pts with MF/SS for approximately 1 year was not associated with an increased safety risk. Significant long-term clinical benefit was observed in pts with blood involvement at baseline, regardless of CCR4 expression status. A higher proportion of pts who had long-term (>351 days) exposure attained confirmed global response versus those who had less exposure. Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Tsianakas:Kyowa Kirin: Research Funding. Musiek:Seattle Genetics: Honoraria; Kyowa Kirin: Honoraria; Actelion: Other: Scientific Advisory Committee . Ortiz-Romero:Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding; Actelion: Consultancy; 4SC: Consultancy. Poligone:Johnson and Johnson: Research Funding; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding; Mallinckrodt: Speakers Bureau; Stemline Therapeutics: Honoraria; Seattle Genetics: Honoraria. Duvic:Clinical Care Options: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huron Consulting Group: Consultancy; Taiwan Liposome Company LTD: Consultancy; Rhizen Pharma: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; UT MD Anderson Cancer Center: Employment; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: Speaker/Preceptor; Guidepoint Global: Consultancy; Jonathan Wood & Associates: Other: Speaker; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Evidera, Inc.: Consultancy; Kiniksa Pharmaceuticals: Consultancy; MEDACorp: Consultancy; The Lynx Group: Consultancy; Spatz Foundation: Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Allos: Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals, Inc.: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Array Biopharma: Consultancy, Honoraria; Oncoceuticals: Research Funding; Tetralogics: Research Funding. Elmets:NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Association: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Leo Pharma: Other: Data and Safety Monitoring Board. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Kim:miRagen: Research Funding; Forty Seven Inc: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding.

Because syndecan-4 (SD-4) on effector and memory T cells inhibits T-cell activation by binding dendritic cell–associated heparan sulfate proteoglycan-integrin ligand (DC-HIL) on antigen presenting cells and because malignant cells of the cutaneous T-cell lymphoma (CTCL) subset, Sézary syndrome (SS), exhibit memory T-cell phenotype, we posited SS cells to express SD-4. Indeed, malignant T cells from patients with SS and from CTCL cell lines constitutively expressed SD-4 at high levels, in contrast to T cells from healthy volunteers and patients with other inflammatory skin diseases and to non-CTCL cell lines that did not. SS cells also bound to DC-HIL at a level higher than normal T cells activated in vitro, resulting in their inhibited proliferation to anti–CD3 antibody. SD-4 on SS cells also trapped transforming growth factor-β1 to their cell surface, enhancing their ability to inhibit activation of syngeneic and allogeneic normal T cells. All of these inhibitory properties were dependent on overexpression of distinct heparan sulfate (HS) moieties by SD-4 on SS cells. Finally, we showed toxin-conjugated DC-HIL to abrogate the ability of SS cells to proliferate in vitro. These findings indicate that SD-4 bearing distinct HS moieties plays a pathogenic role in SS and may be targeted for treatment.

Cutaneous T-cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in the skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing 3 patient clusters. Of these, 2 clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB patients appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower-stage/treatment-responsive CTCL versus higher-stage/treatment-resistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted.

The ISCL/EORTC recommends revisions to the Mycosis Fungoides Cooperative Group classification and staging system for cutaneous T-cell lymphoma (CTCL). These revisions are made to incorporate advances related to tumor cell biology and diagnostic techniques as pertains to mycosis fungoides (MF) and Sézary syndrome (SS) since the 1979 publication of the original guidelines, to clarify certain variables that currently impede effective interinstitution and interinvestigator communication and/or the development of standardized clinical trials in MF and SS, and to provide a platform for tracking other variables of potential prognostic significance. Moreover, given the difference in prognosis and clinical characteristics of the non-MF/non-SS subtypes of cutaneous lymphoma, this revision pertains specifically to MF and SS. The evidence supporting the revisions is discussed as well as recommendations for evaluation and staging procedures based on these revisions.

The activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) were evaluated in patients with refractory cutaneous T-cell lymphoma (CTCL). Group 1 received vorinostat 400 mg daily, group 2 received vorinostat 300 mg twice daily for 3 days with 4 days rest, and group 3 received vorinostat 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily. Treatment continued until disease progression or intolerable toxicity. The primary objective was to determine the complete and partial response (PR) rate. Time to response (TTR), time to progressive disease (TTP), response duration (DOR), pruritus relief, and safety were determined. Thirty-three patients who had received a median of 5 prior therapies were enrolled. Eight patients achieved a PR, including 7 with advanced disease and 4 with Sézary syndrome. The median TTR, DOR, and TTP for responders were 11.9, 15.1, and 30.2 weeks, respectively. Fourteen of 31 evaluable patients had pruritus relief. The most common drug-related AEs were fatigue, thrombocytopenia, diarrhea, and nausea. The most common grade 3 or 4 drug-related AEs were thrombocytopenia and dehydration. Vorinostat demonstrated activity in heavily pretreated patients with CTCL. The 400 mg daily regimen had the most favorable safety profile and is being further evaluated.

The current World Health Organization (WHO) classification of hematopoietic malignancies defines several types of mature T-cell leukemia including T-cell prolymphocytic leukemia (T-PLL), Sezary syndrome (SS), and T-cell large granular lymphocytic (T-LGL) leukemia. These neoplasms can show overlapping features with each other and with T-cell lymphomas involving peripheral blood (PB). We analyzed the spectrum of clinicopatho-logic features in 102 mature T-cell leukemias and compared them to 10 hepatosplenic T-cell lymphomas that involved PB. T-PLL, defined as a T-cell leukemia showing rapidly rising PB lymphocyte counts, was the only tumor type expressing the oncoprotein TCL1 (71% of cases) and could present with relatively low lymphocyte levels or small tumor cell morphology. SS, defined by accompanying erythrodermic skin disease, was frequently associated with peripheral eosinophilia but could also develop high numbers of prolymphocytes, especially late in the disease course. T-LGL leukemia, defined by accompanying cytopenias or autoimmune phenomena (or both), had the best clinical outcome and generally showed the lowest circulating lymphocyte levels with only a few cases developing marked lymphocytosis. Using the dominant clinical or phenotypic feature, we describe here the degree of overlap among currently recognized WHO categories and identify areas where further clarification is needed. Our results indicate that incorporation of additional criteria, such as TCL1 expression status and hematologic parameters, can assist in a more accurate classification. (Blood. 2004;104:328-335)

Background: SL-401 is a targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies. BPDCN is an aggressive hematologic malignancy of unmet medical need that often presents in bone marrow and skin, and may also involve lymph nodes and viscera. Long-term outcomes after treatment with chemotherapy have been very poor, with median overall survival from diagnosis of ~12 months, highlighting the need for novel therapies. Results from the Phase 2 trial of SL-401 in patients with BPDCN are reported here. Methods:This multicenter, single-arm Phase 2 trial of patients with BPDCN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients with BPDCN or relapsed or refractory (r/r) AML received SL-401 as a daily IV infusion at 7, 9, 12, or 16 ug/kg/day for days 1-5 of a 21 day cycle. In stage 2, patients with BPDCN receive SL-401 at the dose determined in stage 1. Results: As of 7/25/16, 29 patients with BPDCN have received SL-401, including 16 first-line and 10 relapsed/refractory (r/r) adults and 3 pediatric patients (under compassionate use). The 26 adult patients (9+17 in stages 1&2) received SL-401 at 7 ug/kg (n=3 [stage 1]) or 12 ug/kg (n=23 [6+17 in stages 1&2]). The median adult age was 69 years (range: 29-82 years). In stage 1, 12 ug/kg was the highest tested dose for BPDCN; MTD was not reached in BPDCN. Results in AML (r/r) patients will be reported separately. The most common treatment-related AEs, all grades, were transient transaminase elevation (54%) and hypoalbuminemia (38%). Transient thrombocytopenia was also noted (19%). The most common ≥ Grade 3 treatment-related AEs were transient transaminase elevation (42%) and thrombocytopenia (19%). Two stage 1 patients developed capillary leak syndrome (CLS): gr 5 (7 ug/kg) and gr 4 (12 ug/kg). Safety precautions, including monitoring of albumin levels and body weight, were successfully implemented to minimize risk of severe CLS, which has not occurred in patients with BPDCN since adoption. Twenty-one of 26 adult patients were evaluable for response (response assessment from 3 recently treated patients are pending; 1 patient was discontinued for as yet unspecified reasons; and 1 patient treated at 7 ug/kg was not evaluable for response due to AE); median follow-up for evaluable patients was 6.9 months (range: 0.6-17.6 months). An 86% (18/21) ORR was observed in evaluable adult BPDCN patients. ORR in evaluable patients was 100% (14/14) in first-line and 57% (4/7) in r/r BPDCN. Of these, 92% (11/12) of first-line patients treated at 12 ug/kg had a CR (n=8) or clinical CR (CRc: a CR in non-skin organs with gross reduction in cutaneous lesions and residual microscopic skin disease) (n=3). 75% (9/12) of these patients remain progression free for 3+ to 16+ months (ongoing), including 4 patients who remain on SL-401 in remission (for 3+ to 12+ months [up to 16+ cycles], ongoing) and 5 additional patients who experienced a major response on SL-401 (3 CR, 1 CRc, 1 PR) and were then successfully bridged to stem cell transplant (SCT; 3 auto-SCT and 2 allo-SCT) and all remain progression free for 3+ to 16+months (ongoing) since first SL-401 dose. Notably, a patient with r/r BPDCN was recently bridged to allo-SCT following CRc on SL-401. Conclusions: SL-401 demonstrates robust single agent activity in BPDCN, including 86% ORR in all-lines, with multiple CRs, in evaluable patients. Six patients, including 1 r/r patient, have proceeded to SCT after achieving a major response from SL-401, and an additional 7 patients remain on SL-401 for up to 12+ months, ongoing. The SL-401 side effect profile remains manageable, and no unexpected AEs have emerged with increased treatment duration, drug exposure, and patient enrollment. Response duration, progression-free and overall survival data continue to be encouraging and updated data will be presented. Clinical trial information: NCT02113982. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Novartis: Consultancy, Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Lancet:Quantum First: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Biopath Holdings: Consultancy; ERYtech: Consultancy; Karyopharm: Consultancy; Baxalta: Consultancy; Kalo Bios: Consultancy; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Boehringer-Ingelheim: Consultancy; Amgen: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

KIR3DL2 is expressed in all subtypes of cutaneous T-cell lymphomas (CTCL), irrespective of clinical stage, with the highest prevalence of expression in Sézary syndrome (SS) and transformed mycosis fungoides (MF), two subgroups of patients with a high unmet need for clinically impactful therapies. KIR3DL2 belongs to the killer immunoglobulin-like receptor (KIRs) family and is expressed on minor subpopulations of normal NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It selectively depletes KIR3DL2-expressing cells by recruiting immune effectors. Its main modes of action include antibody-dependent cell-cytotoxicity (ADCC) and -phagocytosis (ADCP). IPH4102 has shown potent efficacy in preclinical models, in particular ex vivo autologous assays using primary CTCL cells. IPH4102 is currently being investigated in a first-in-human dose-finding phase 1 study (NCT02593045) evaluating repeated administrations of single-agent IPH4102 in relapsed/refractory CTCL patients. The primary objective is to assess the safety and tolerability of increasing doses of IPH4102. Secondary objectives include PK, immunogenicity and signals of anti-tumor clinical activity. Exploratory biomarkers aim to characterize KIR3DL2-expressing and non-expressing cells in involved tissue/disease compartments and to monitor changes during IPH4102 treatment. Minimal residual disease (MRD) is measured in the skin, blood and/or lymph nodes. Assessment of ex vivo NK cell-mediated ADCC against autologous tumor cells is also performed pre-dose on SS patient samples. The study has two sequential portions, a dose-escalation followed by a cohort expansion. The dose-escalation portion has a 3+3 design with accelerated titration and aims to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D). In the cohort expansion portion, two CTCL subtype-specific cohorts will be studied, each to include 10 additional patients to further explore MTD or RP2D. Eligible CTCL patients must have received at least 2 lines of anti-neoplastic systemic therapy. Centrally assessed KIR3DL2 expression on malignant cells in skin or blood is required for inclusion. Patients receive IPH4102 administrations until progression or unacceptable toxicity. Intra-patient dose-escalation is allowed, only past the first complete clinical assessment at week 5 and provided the upper next dose-level is declared safe by the safety committee. Enrollment into study IPH4102-101 started in November 2015 and is currently ongoing. At time of abstract submission, dose-levels #1 to #6 have been completed. A total of 13 patients have been treated at these 6 dose-levels and are evaluable for safety and clinical activity. These patients comprise 10 SS (including 1 with evidence of large-cell transformation), 2 MF and 1 "not-otherwise-specified" CD4+ CTCL. Median age is 71 years (range 50 - 90). For these 13 patients, only grade 1 or 2 related adverse events (AEs) have been reported with IPH4102 treatment. No patient experienced a DLT or a related AE of grade ≥3. No IPH4102-related skin rashes or infections have been observed so far. Results of immuno-phenotyping of patients' blood lymphocytes show consistency of local and central assessments. In addition, ex vivo functional assay results confirm that SS patients' NK cells are functional and able to kill autologous tumor cells through ADCC with IPH4102. Our preliminary data from the phase 1 study of a novel targeted immune therapy show excellent tolerability in advanced CTCL patients. Updated results including exploratory biomarker assessment results will be presented and discussed at the meeting. Disclosures Bagot: Millenium: Other: Investigator in a clinical trial; Kiowa Hakko Kirin: Other: Investigator in a clinical trial; Innate Pharma: Equity Ownership, Other: Investigator in a clinical trial, Patents & Royalties, Research Funding. Porcu:celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Ram-Wolff:Innate Pharma: Other: Investigator in a clinical trial. Battistella:Innate Pharma: Consultancy, Research Funding. Marie-Cardine:Innate Pharma: Research Funding. Mathieu:Innate Pharma: Other: Investigator in a clinical trial. Vermeer:Innate Pharma: Other: Investigator in a clinical trial. Whittaker:Seattle Genetics: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Takeda: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding. Duvic:Kiowa Hakko Kirin: Other: investigator in a clinical trial, Research Funding; Rhizen Pharmaceuticals: Other: Investigator in a clinical trial; Innate Pharma: Consultancy, Other: Investigator in a clinical trial; Millenium: Other: Investigator in a clinical trial; Angimmune LLC: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial. Bensussan:Innate Pharma: Patents & Royalties, Research Funding. Paturel:Innate Pharma: Employment, Equity Ownership. Bonnafous:Innate Pharma: Employment, Equity Ownership. Widemann:Innate Pharma: Employment. Bonin:Innate Pharma: Employment. Sicard:Innate Pharma: Employment, Equity Ownership. Paiva:Innate Pharma: Employment. Pilz:Innate Pharma: Consultancy. Kim:Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Consultancy, Other: Investigator in a clinical trial; Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Genentech: Other: Investigator in a clinical trial; MiRagen: Consultancy; Neumedicine: Consultancy; Soligenix: Consultancy; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; Galderma: Consultancy; Horizon: Consultancy.

Background Cutaneous T cell lymphoma (CTCL) is a chronic disease that negatively impacts quality of life (QoL) and, in advanced stages, has poor prognosis. Current systemic therapies rarely provide reliable and durable responses, and to date, no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate (MTX) or bexarotene (Bex). CD30-directed antibody-drug conjugate brentuximab vedotin (BV) has demonstrated marked clinical activity in two phase 2 single-arm trials in CTCL with overall response rates (ORR) of about 70%. These results led to ALCANZA, a randomized, open-label, multicenter phase 3 trial of the efficacy and safety of BV vs physician's choice (PC) of MTX or Bex, in previously treated patients with CD30-expressing CTCL (NCT01578499). This is the first reported randomized phase 3 trial testing a new agent against standard-of-care therapy in CTCL. Methods Adults with CD30-expressing (≥10% of infiltrate by central review) mycosis fungoides (MF) who received ≥1 prior systemic therapy or primary cutaneous anaplastic large cell lymphoma (pcALCL) who received ≥1 prior systemic therapy or radiotherapy were enrolled. Patients were stratified by diagnosis and randomized 1:1 to receive BV 1.8 mg/kg IV, once every 3 weeks, or PC of either MTX 5-50 mg PO, once weekly, or Bex 300 mg/m² (target dose) PO, once daily, for up to 16 three-week cycles, until disease progression or unacceptable toxicity. Primary endpoint was ORR4, defined as ORR lasting ≥4 months, an endpoint that captures response rate and duration as a single measurement. ORR4 was determined by independent review of global response using the ISCL/EORTC consensus guidelines. Global response is a composite of skin evaluation (modified severity weighted assessment tool), radiographic assessment, and Sézary cell enumeration. Key secondary endpoints were CR rate, PFS, and symptom burden measured by the symptom domain of the Skindex-29 QoL tool. Sample size was calculated to provide 90% power to detect a 30% improvement in ORR4. Treatment-emergent adverse events (AEs) were evaluated according to NCI CTCAE v4.03. Results 131 patients were randomized with 128 patients in the intent-to-treat population (97 MF, 31 pcALCL; 3 excluded for insufficient CD30 expression) and assigned to BV (n=64) or PC (n=64). Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the BV arm (Table). In BV vs PC arms, respectively, median age was 62 (22-83) vs 58 (22-83) years; ECOG performance status 0-1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies. At a median follow-up of 17.5 months, ORR4 (primary endpoint) and PFS strongly favored BV vs PC with ORR4 of 56% vs 13% (p Patients received a median of 12 (1-16) cycles of BV vs 5.5 (1-16) Bex and 3 (1-16) cycles of MTX. Grade 3-4 AEs, all cause / drug-related, were seen in 41% / 29% with BV vs 47% / 29% with PC. Serious AEs were seen in 29% of patients in each arm. Peripheral neuropathy (PN), any grade, was seen in 67% in the BV arm (32% grade 2, 9% grade 3) and 6% in the PC arm. At last follow-up, 36/44 (82%) patients in the BV arm had improvement or resolution of PN. Discontinuation due to AEs occurred in 24% (BV) vs 8% (PC). Four deaths in the BV arm (3 unrelated to study drug) occurred within 30 days of the last dose. Other AEs were consistent with reported safety profiles for the individual agents. Conclusions In this first report of a randomized phase 3 trial evaluating a new agent vs standard-of-care options in CTCL, the clinical outcome of BV was far superior to PC (MTX or Bex). Highly statistically significant improvements in ORR4 (44%) and median PFS (13.2 months) were observed with BV. Greater ORR with higher CR rate and reduction in symptoms per Skindex-29 symptom domain were also observed in the BV arm. Safety data for BV were consistent with the established tolerability profile. The data from this randomized trial provide compelling evidence favoring BV over PC of Bex or MTX in CD30-expressing CTCL. Disclosures Kim: Kyowa Kirin Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Merck: Research Funding; Soligenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Innate: Research Funding; Portola: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding. Whittaker:Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Other: Investigator in a clinical trial; Seattle Genetics: Other: Investigator in a clinical trial; Galderma: Research Funding. Horwitz:ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Takeda: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy. Dummer:Allos: Research Funding; Shape: Research Funding; Jonathan Wood & Assoc: Speakers Bureau; Soligenetics: Research Funding; Cell Medica: Consultancy, Honoraria; Therakos: Speakers Bureau; Mallinckrodt Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Covance Laboratory Services: Consultancy; Oncoceuticals: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya: Consultancy; Eisai: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scarisbrick:Millennium: Consultancy; 4SC: Consultancy. Zinzani:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Wang:Seattle Genetics: Employment, Equity Ownership. Palanca-Wessels:Seattle Genetics: Employment, Equity Ownership. Zagadailov:Takeda Pharmaceuticals: Employment, Equity Ownership; Amerisource Bergen: Equity Ownership. Trepicchio:Takeda Pharmaceuticals: Employment. Liu:Takeda Pharmaceuticals: Employment, Equity Ownership. Little:Takeda Pharmaceuticals: Employment, Equity Ownership.

Introduction: The δ isoform of PI3K is highly expressed in cells of hematopoietic origin. The γ isoform is associated with T-lymphocytes and neutrophils and plays a distinct role in T-cell function. Since δ/γ isoforms are synergistic in the growth and survival of certain T-cell malignancies, dual targeting of PI3K δ/γ is an attractive intervention strategy in patients with T-cell lymphoma. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency for both isotypes. It has shown acceptable safety profile and efficacy in patients (pts) with advanced hematologic malignancies in a Phase 1 study (ASH 2015). Herein, we present the preliminary results from an ongoing Phase 1/1b, dose escalation study of RP6530 in 11 pts with mature T-cell neoplasms (NCT02567656). Methods: The study consists of dose escalation cohorts to determine the MTD of RP6530 using a standard 3+3 design, followed by two expansion cohorts enrolling 20 pts with peripheral T-cell lymphoma (PTCL) and 20 pts with cutaneous T-cell lymphoma (CTCL). Pts with a diagnosis of PTCL or CTCL who have received at least one prior systemic therapy, ECOG performance status ≤ 2 and measurable/evaluable disease are eligible. This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of RP6530 administered twice daily (BID) in 28-day cycles. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2014) and the modified Severity Weighted Assessment Tool (mSWAT) respectively. Dose limiting toxicity (DLT) was defined by a toxicity of grade 3/4 that is considered related to treatment during the first cycle of treatment. Results: To date eleven pts (6 PTCL and 5 CTCL) (5 males and six females) have been enrolled at three dose levels: 200 mg BID, 400 mg BID and 800 mg BID. ECOG performance status score was 0/1/2 in 10/1/0 pts, respectively, with a mean age of 68 yrs (range 52-76). Pts had a median of 3 (range: 3-6) prior treatment regimens, and 5 pts had refractory disease and 6 relapsed on prior treatments. RP6530 was well tolerated without any DLT or related serious adverse event reported to date. A total of 52 non-serious adverse events were reported: 41 Grade 1/2 and 11 Grade 3/4. The most common adverse events included mild vomiting (18%), diarrhoea (18%), fatigue (18%), and rash (18%). No Grade 3/4 adverse events were deemed related to RP6530 except for ALT/AST elevation in one pt. No pt discontinued treatment due to a safety issue. Dose-proportional increases in plasma concentrations were observed in PKs. Dose escalation is currently ongoing at 800 mg BID. Five pts were evaluated for responses at Cycle 3, Day1. Two pts (1 PTCL and 1 CTCL) experienced PR (40%) that are ongoing >5 months, and three pts experienced stable disease lasting for >3 months (60%). Three pts experienced rapid disease progression during first cycle, and discontinued treatment prematurely. Conclusion: This ongoing study of RP6530 demonstrated an acceptable safety profile at doses evaluated, with a promising clinical activity. The results support further evaluation of RP6530 in pts with mature T-cell neoplasms. Disclosures Oki: Novartis: Research Funding. Barde:Rhizen Pharmaceuticals SA: Employment. Penmetsa:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen Therapeutics: Employment.

Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection. Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor Vβ repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific Vβ gene, whereas 10 had oligoclonal or polyclonal expansion of several Vβ families. All patients with TSST-1+S aureus had overexpansion of Vβ 2 in blood and/or skin lesions. These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL, especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.

Human interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10), a C-X- C chemokine, is secreted by IFN-gamma-stimulated keratinocytes and is chemotactic for CD4+ lymphocytes. We therefore investigated its role in the epidermotropism of cutaneous T-cell lymphoma (CTCL) that is known to express IFN-gamma mRNA in the epidermis and is characterized by an indolent course with multiple relapses that remain confined to the skin for many years. By injecting purified recombinant (r) IP-10 we generated a polyclonal rabbit antiserum that specifically recognized and neutralized rIP-10. With immunoperoxidase staining, IP-10 expression was limited to the basal epidermal keratinocytes of normal skin. In biopsies of CTCL lesions the expression of IP-10 was markedly increased and it extended to the suprabasal keratinocytes in 17 of 18 patients, but it was detectable only faintly in the dermal or epidermal lymphoid infiltrates in 2 of these 18 patients. In 1 patient who had matching biopsies performed before and after treatment, IP-10 was overexpressed before treatment, but was normally expressed in the posttreatment biopsy that showed resolution of the CTCL. Increased IP- 10 expression was not detected in any of 4 patients with B-cell lymphoma involving the dermis. On the basis of these findings and a review of the literature, we propose that secretion of IFN-gamma by the lymphoid infiltrate in CTCL induces the epidermal keratinocytes to secrete IP-10 that, in turn, is chemotactic for CTCL, accounting for its epidermotropism. This model may be used as a basis for future investigations of the pathogenesis of CTCL.

INTRODUCTION AND OBJECTIVES: Mycosis Fungoides (MF) andlymphomatoid papulosis (LyP) are relatively rare and itchy skin disorders. The cosmetic disfigurement and severe pruritus dramatically affects the patient's quality of life. The focus is to examine the validity and reliability of the skindex-29, M.D. Anderson symptom inventory (MDASI) and itch-related quality of life (IQOL) questionnaire in 62 patients in a phase II trial of Brentuximab Vedotin. MATERIALS AND METHODS: Patients completed survey questionnaires related to symptoms and quality-of-life several times over the course of Brentuximab Vedotin. We compared patients' baseline scores to their end-of-study (EOS) scores. Patients were grouped by diagnosis into Mycosis Fungoides and Lymphomatoid papulosis group. Questionnaires included skindex-29, focusing on the skin conditions the patient was bothered the most. (MDASI) for patients with cancer and following the symptoms of cancer and the itchy quality of life (I-QoL) questionnaire was developed to measure the symptoms associated with cancer therapeutic agents and their effect on daily activities. Scoring for the Skindex-29, M. D. Anderson Symptom Inventory (MDASI) and the Quality of Life (QOL) survey were done according to the questionnaire specific scoring guide. Responses were compared between 2 groups using the Wilcoxon rank-sum test. RESULTS Questionnaires from 62 patients (23 LyP and 39 MF) were studied at baseline and end of study. Patients were 33 males and 29 females with median age of 60 years (range: 27-86 years). The median overall survival (OS) was significant P = 0.041, when comparing patients with MF to LyP. The median survival time for patients from time of diagnosis with MF was 14.66 years and LyP was not reached. There was no significant difference in progression free survival (PFS) between MF and LyP. The median number of Brentuximab Vedotin cycles was 7 (1-19). Skindex-29 scales, showed change in emotion scale and function scale from baseline to EOS, both groups had a decrease, patients with LyP had a larger decrease in emotion score (P = 0.069) and function score (P =0.096) over the course of the study. There was no difference in the symptom scale from baseline to EOS. The patients with LyP had a larger decrease in function score from baseline to EOS. When comparing patients with MF to those with LyP for MDASI, there is no evidence of a difference, from baseline to EOS, in either symptom severity or symptom interference in daily life. In the IQOL when comparing the LyP patients' QOL responses from baseline to EOS, did not show significant difference. Table 1. Change in Skindex-29 scales, by group Skindex Scale MF LYP p-value Change from baseline to end-of-study: N Median Min Max N Median Min Max Emotion 35 -10 -65 35 20 -22.50 -61.94 12.5 0.0698 Symptoms 35 -7.14 -46.43 42.86 20 -10.71 -53.57 28.57 0.4782 Function 35 -2.08 -50.38 27.08 20 -16.29 -44.70 14.58 0.0962 Table 2. Change in MDASI scales, by Diagnosis MDASI Scale Item MF LYP p-value Change from baseline to end-of-study: N Median Mean Std. Dev Range N Median Mean Std. Dev Range Severity 35 0.23 0.18 1.96 (-5.85, 3.15) 21 0.38 0.46 1.61 (-1.69, 5.0) 0.9595 Interference 35 0.17 0.06 3.07 (-9.17, 5.17) 19 0.0 0.11 1.59 (-3.0, 4.67) 0.6764 CONCLUSIONS A significant improvement in emotions and functional part of skindex-29 was observed when comparing patients with MF to patients with LyP. While both groups had a decrease, the patients with LyP had a larger decrease in emotion and function score over the course of the study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Therakos: Research Funding, Speakers Bureau; Soligenics: Research Funding; Huya Bioscience Int'l: Consultancy; Spatz Foundation: Research Funding; MiRagen Therapeutics: Consultancy; Eisai: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Array Biopharma: Consultancy; Cell Medica Ltd: Consultancy; Tetralogics SHAPE: Research Funding; Innate Pharma: Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with heterogeneous clinical presentation and no available standard therapy. Little is known about the clinical characteristics, molecular characterization, and outcomes of patients (pts) with BPDCN. Methods: We conducted a retrospective review of pts age ≥18 years with a confirmed pathological diagnosis of BPDCN. Results: 37 pts evaluated at our institution between October 1998-June 2015 were identified. Table 1 shows baseline pt characteristics. Bone marrow (BM) was involved in 23 (62%), skin in 26(70%), lymph nodes in 11(30%), central spinal fluid (CSF) in 3 (8%) and 1 (3%) pt each had disease involving brain, uterus/ovary, elbow/soft tissue, and pleural fluid. Tumor immunophenotype demonstrated: CD4+ (31/32), CD56+ (29/32), TCL-1+ (19/21), CD 123+ (22/23). Additionally, CD22 was expressed in 3/9 pts. Frontline therapies received: 19 (51%) HCVAD; 5 (14%) CHOP, 5 (14%) clinical trials, 2 (5%) bortezomib-based, 1 AML induction with daunorubicin+ARAC, 1 oral MTX, 1 IFN-based therapy, 3 other regimens. 5 (14%) pts received radiation (XRT) as part of their therapy. Median follow-up time was 7 months [1-27 mo]. Median number of chemotherapy regimens was 1 [1-6]. Complete remission (CR1) (by standard AML criteria) was achieved in 19 pts (51%) with a median CR1 duration of 19 mo [1-39 mo]. Median overall survival (OS) was 23 mo [6-45 mo]. 23 (69%) pts died, the most common cause of death being multi-organ failure. Among 14 (38%) pts without BM involvement at diagnosis, all 14 had skin involvement. Comparison of pts with BM involvement versus skin-only showed no difference in outcomes. For pts with BM disease, median OS and median CR1 were 23 mo [1-45 mo] and 21 mo [1-39 mo], respectively. For pts with skin-only disease,median OS and median CR1 were 18 mo [1-31 mo] and 19 mo [1-23 mo], respectively, p =0.43 (OS), p=0.78 (CR1). 10 pts (27%) received stem cell transplant (SCT) [7 allogeneic (including 3 cord blood) and 3 autologous). The median OS for pts receiving SCT (n=10) was 18 mo [8-40 mo] versus 23 mo [1-45] for non-SCT group (n=27), p = 0.98. 19 pts (51%) received HCVAD as part of first-line therapy: median OS was 18 mo [1-45 mo] and median CR1: 21 mo [1-39 mo]. Out of 16 pts evaluable for response, 15 achieved CR1; 1 pt died at day 15 (pneumonia). A clinically validated 28-gene molecular panel (next-generation sequencing for commonly mutated genes in myeloid malignancies) is now being performed prospectively on all new pts with BPDCN seen at our institution (thus far, n=9); notably, all 9 have expressed some form of TET2 mutation [ordered mutations=3(c.1648C>T p.R550; c.3781C>T p.R1261C; c.4365del p.M1456fs*2)], ordered+variant=2,variants=4], confirming our earlier finding of occurrence of TET2 mutations in pts with BPDCN (Alayed K, et al Am J Hematol 2013). Thus far, there has been no statistically significant difference in terms of response rates in pts with known TET2 mutations/variants (n=9) vs all others/not done (n=26). Conclusions: Among patients with BPDCN, we observed an older, male predominance, a high incidence of TET2 mutations and, despite intensive chemotherapy and achievement of CR1 in many pts, most still experience relapse and short survival. Therefore, there is an urgent need for novel therapies. Therapies targeting cell surface CD123 and CD56, are available in 2 separate clinical trials at our institution: SL-401 (DT-IL3), which demonstrated 7/9 (78%) major responses including 5 CR, after a single cycle of therapy, (Frankel et al, Blood 2014) is currently being tested in an ongoing multicenter phase I/II trial (Stemline Therapeutics Inc, ClinicalTrials.gov Identifier: NCT02113982, refer to separate abstract ASH 2015) and Lorvotuzumab Mertansine (ImmunoGen, Inc), an antibody-drug conjugate targeting CD56 (ClinicalTrials.gov Identifier: NCT02420873), is in an ongoing ph II trial in CD56-expressing hematologic malignancies, including BPDCN. Table 1. Baseline characteristics (N = 37) Characteristic N (%) / [range] Median age, years 62[20 - 86] Male 33 (89) Median WBC x 109/L 5.9 [1.7-76.5] Median Hemoglobin g/dL 12.9 [6.8-17.1] Median Platelet x 109/L 130 [22-294] Median BM blast 13[0-95] Cytogenetics (n=27)DiploidComplexDeletion 12p13 17 8 1 Miscellaneous 1 28-gene profile (n=9); includes mutations& variantsTET2ASXL1MPLTP53IDH1IDH2 9 3 2 1 1 1 Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Off Label Use: No standard of care available. clinical trial drug therapies/investigation/trial only various cytotoxic chemotherapies used in ALL, AML, other blood cancers. Cortes:BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Duvic:Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Array Biopharma: Consultancy; Oncoceutics: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Therakos: Research Funding, Speakers Bureau; Huya Bioscience Int'l: Consultancy; MiRagen Therapeutics: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Soligenics: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Frankel:Stemline: Consultancy, Patents & Royalties, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Background The term "histiocyte" includes cells of the monocyte/macrophage series as antigen processing cells and the Langerhans cell/DC series as antigen-presenting cells. At least three DC subsets exist in skin: two expressing either CD1a or CD14 are dermal and Langerhans cells expressing CD1a are epidermal. Since the phenotype of histiocytic cells is typically CD3-CD4+, an estimation of the CD4+ histiocytic population can be made by comparing the numbers of CD3+ T cells with CD4+ cells. Programmed Cell Death 1 (PD-1) is an inhibitory receptor expressed on T cells, B cells, and some myeloid cells. During chronic antigen exposure, expression of PD-1 is sustained. Statins, inhibitors of cholesterol biosynthesis, are immunomodulatory agents acting on T cells and DCs, but their effects on skin immunology are unknown. Objectives To investigate whether infiltrates of CD3-CD4+histiocytes in early mycosis fungoides (MF) lesional skin biopsies are associated with any other factors, including history of medication and to reveal their histopathological pattern. Methods From Jan to Dec 2014, we identified cases of early MF from the clinic in which CD4+ cells exceeded CD3+ cells with biopsies to identify increased histiocytic population. Exclusion criteria included Sézary syndrome, granulomatous MF, T cell receptor beta monoclonality, abnormal T cell populations by flow cytometry, retinoid treatment, and progression of disease after treatment (n=12). Clinical and laboratory findings were retrospectively reviewed. Skin biopsies stained for H&E, CD3, CD4, CD7, and CD8 were reviewed. In 3 cases with paraffin blocks available, immunohistochemical stains for CD68, CD1a, CD163, PD-1, and PD-1 ligand PD-L1 were done. Results Clinical manifestations of early MF were pink scaly patches (9/12), capillaritis (2/12), and annular erythema - like patches (1/12). Eleven also had an increased monocytes in peripheral blood. All cases had a medication history of taking statins (atorvastatin 5/12; simvastatin 2/12; rosuvastatin 1/12) for dyslipidemia (hypercholesterolemia 7/12; both hypercholesterolemia and hypertriglyceridemia 3/12). In 9/12, symptoms persisted after MF treatment. A lichenoid or superficial perivascular lymphohistiocytic infiltration was observed in skin lesions. Focal basal vacuolization was found in all 12 patients. Upper dermal perivascular extravasation of RBCs suggesting vasculopathy was also found in 12/12 cases. All twelve cases showed predominant CD4+ T cells compared to CD8+ T cells in dermis and the CD4+ T cells were more prominent in dermis rather than in epidermis. CD7+ T cells were preserved (3/12) or partially lost (9/12). In all 3 cases, macrophage markers CD68 and CD163 were positive in dermal infiltrates. CD1a+ DCs were increased in both epidermis and dermis in all 3/3. Only one case of three showed PD1/PD-L1+ T cells in dermis. Discussion and Conclusion All our cases had a medication history of statins for dyslipidemia. Of interest, skin biopsies showed a vasculopathy previously reported during high-dose atorvastatin treatment (Tehrani et al, 2013) and infiltration of CD4/CD8+ T cells, CD1a+DCs and CD163/CD68+ macrophages. We hypothesize that statins or dyslipidemia in early MF were associated with cutaneous T cell immune reaction. In support of our hypothesis that dyslipidemia is associated with histiocytosis, we found a report of nine cases of granulomatous pigmented purpuric dermatosis with concurrent hyperlipidemia (Battle et al, 2015). Cholesterol induces monocytosis and M1 macrophages in mice. One study showed that predominant migration of mature CD1a+ DC is associated with release of IL-12p70 and efficient expansion of Th 1 cells and functional CD8+ T cells. On the contrary, IL-10 up-regulates migration of immature CD14+ DC, expression of the M2 macrophage marker CD163, poor expansion of CD4+ and CD8+ T cells, and skewing of Th responses conducive to expression of PD-L1. We cannot know whether skin lesions are secondary to hyperlipidemia or to treatment with statins. Although M1 and M2 macrophages can be distinguished by diverse markers, none of these antigens are suitable for single-marker identification by immunohistochemistry in paraffin embedded tissue blocks. Further study of the cutaneous effect and immunologic mechanisms leading to increased expression of DCs and T cell dysfunction after statin medication is necessary. Disclosures Duvic: Oncoceutics: Research Funding; Therakos: Research Funding, Speakers Bureau; Huya Bioscience Int'l: Consultancy; Tetralogics SHAPE: Research Funding; Innate Pharma: Research Funding; Cell Medica Ltd: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; Soligenics: Research Funding; Allos (spectrum): Research Funding; Array Biopharma: Consultancy; Spatz Foundation: Research Funding; Rhizen Pharma: Research Funding; Eisai: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Cutaneous T-cell Lymphomas (CTCL) include several variants of extra-nodal non-Hodgkin's lymphomas characterized by their skin lesions and T-cell surface markers. The most common, mycosis fungoides (MF), often has an indolent course but can transform and rapidly disseminate. While skin-directed therapies are effective for early-stage MF, patients with refractory, transformed or late-stage disease require systemic therapy. Methods: Adult patients with CTCL including MF, transformed MF (T-MF), Sézary syndrome (SS), primary cutaneous anaplastic large cell lymphoma (ALCL), ≥ 1 prior systemic therapy, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were eligible and signed consent. FOL was administered weekly via intravenous push for 3 of 4 weeks; BEX was self-administered orally with food. The standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD), with cohort expansion for dose-limiting toxicities (DLTs). The MTD was the highest dose with < 33% DLT incidence in any cohort. DLTs included the following in Cycle 1: ≥ Grade 3 neutropenia (or G-CSF administered), thrombocytopenia, treatment-related non-hematologic toxicity, hyperlipidemia, or hypothyroidism, and treatment-related adverse events (AEs) causing BEX dose omission for ≥10/28 days or FOL dose omission/reduction. Results: In Cohort 1 (15 mg/m2 FOL + 150 mg/m2 BEX), 0/3 patients had DLTs. In Cohort 2a (15 mg/m2 FOL + 300 mg/m2 BEX), 2/3 patients had DLTs: Grade 3 neutropenia and Grade 2 hypotension (n = 1) and Grade 4 neutropenia and thrombocytopenia (n = 1). Therefore, the combination MTD was identified as 15 mg/m2 + 150 mg/m2. An additional 28 patients were enrolled at the MTD for a total of 34 patients (53% male, 47% female) in the study; all have discontinued treatment. The median age was 66 (range 39-85) years, and the median number of prior therapies was 4 (range 2-14). Histology included MF (53%), T-MF (32%), SS (12%), and ALCL (3%). ECOG PS was 0 (68%), 1 (18%), or 2 (15%). Patients received a median of 6 (range 1-33) cycles of therapy. All patients reported ≥ 1 AE. The most common (>20%) FOL-related AEs were mucositis or mucosal inflammation (68%), fatigue (41%), neutropenia and nausea (32% each), and anemia (24%). The most common (>20%) BEX-related AEs were hypertriglyceridemia (56%), fatigue (44%), neutropenia (32%), nausea (26%), and uncorrected hypothyroidism (24%). Grade 3 and 4 AEs were reported for 79% and 9% of patients, respectively: neutropenia (29% and 6%), hypertriglyceridemia (29% and 0%), and stomatitis (21% and 0%) and one Grade 5 AE of respiratory failure. Serious adverse events (SAEs) were reported for 35% of all patients; SAEs in > 1 patient were neutropenia and hypotension (6% each). Dose omissions and reductions for AEs were required for 74% and 21% of patients, respectively. AEs led to discontinuation for 32% of all patients, most commonly stomatitis (9%) and anemia, fatigue, and neutropenia (6% each). The overall Objective Response Rate was 61% (20/33 evaluable patients); 18/30 [60%] in Cohort 1 and 2/3 [67%] in Cohort 2. Four [12%] patients had a complete response, 16 [48%] partial response, 11 [33%] stable disease, and 2 [6%] progressive disease. Duration of Response ranged from 0-29+ months; median Response Duration was not reached, as 14 patients (3 CRs, 11 PRs) remained in response. Median PFS at the MTD was 12.8 (range 0.5-29.9+) months. Table 1. Response by CTCL Subtype Objective Response Rates CTCL Subtype Overall CR PR All Evaluable, n=33 20 (61%) 4 16 ALCL, n = 1 1 (100%) 1 0 MF, n = 19 12 (63%) 2 10 T-MF, n = 10 5 (50%) 1 4 SS, n = 3 2 (67%) 0 2 Conclusions: The combination of FOL + BEX was well tolerated and efficacious in patients with various CTCL subtypes, as measured by response rates (61% including patients with durable CRs) in this dose-finding study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Therakos: Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Consultancy; Allos (spectrum): Research Funding; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Oncoceutics: Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy. Bhat:Spectrum Pharmaceuticals, Inc: Employment.

Introduction: Lymphomatoid papulosis (LyP) is a CD30+ lymphoproliferative disorder, with a self-regressing clinical course and malignant histopathology. Objective: The aim of the study was to evaluate characteristics, risk factors, associated malignancies, long-term outcome and treatment of LyP in a large cohort representing the experience of the MD Anderson Cancer Center. Methods: This was a retrospective study of patients with LyP seen between 1999 and 2015. Patient charts, clinical and histopathological data were evaluated, searching the MD Anderson Cancer Center cutaneous T-cell lymphoma database. A total of 237 patients with the diagnosis of LyP were identified, with 180 patients meeting the inclusion criteria of both clinical diagnosis of LyP and confirmatory biopsy. Results: A total of56.6% of patients were male and 43.3% were female. The majority of patients were Caucasians (77.7%, n=139). The mean age at diagnosis was 52.7±17.2 years. The mean time from symptom onset to a biopsy proven diagnosis of LyP was 45.0±75.4 months. The majority of patients (51.6%, n=83) had less than twelve lesions at the worst time point. Histologic subtype A was found in 47.2%, type B in 17.2%, type C in 22.8%, type D in 7.8%, type E in 0.6% and mixed subtype in 4.4% of the patients. Associated lymphomas (n=114) were observed in 93 patients with mycosis fungoides (61.4%, n=70) and anaplastic large cell lymphoma (26.3%, n=30) being the most common forms (Table). Men were 2.85 times (95%CI: 1.55-5.24) more likely to develop a secondary lymphoma than women. Other risk factors for development of lymphoma included histologic subtypes B and C and older age. Number of lesions, symptom severity and ethnicity were not associated with lymphoma development. Patients with type D (CD8+) were less likely to develop lymphomas. Despite the high number of detected secondary malignancies, the prognosis of LyP is excellent. Only eight out of 180 evaluated patients died of their disease. A broad variety of treatment options are available for symptomatic relief only, since no treatment modality was found to prevent progression to lymphoma. Conclusion: We could demonstrate that LyP is associated with other cutaneous and extra-cutaneous malignancies, the most common being MF and ALCL. To date the risk of developing associated lymphomas cannot be altered by medication. Long term follow-up exams and proper patient counseling are required to ensure early detection of evolving secondary malignancies. Table 1. A total of 114 hematologic malignancies were observed in 93 patients with lymphomatoid papulosis diagnosed before, concomitant and after diagnosis of lymphomatoid papulosis Hematologic malignancy Before (n=39) Concomitant (n=28) After (n=47) All (n=114) %(n) %(n) %(n) %(n) MF (all stages) 17.5% (20) 17.5%(20) 26.3%(30) 61.4% (70) MFIA 9.6% (11) 7.0% (8) 20.2%(23) 36.8%(42) MFIB 4.4% (5) 4.4% (5) 2.6%(3) 11.4%(13) MFIIA 1.0% (1) - - 1.0%(1) MFIIB 1.0% (1) 1.0% (1) 1.0%(1) 2.6%(3) MFIVA - 1.0% (1) - 1.0% (1) FMFIA - 1.8% (2) 1.0%(1) 2.6%(3) FMFIB 1.8%(2) 1.0% (1) - 2.6%(3) FMFIIB - 1.0% (1) - 1.0% (1) FMFIVA - - 1.0%(1) 1.0% (1) Hypopigmented MF - - 1.0%(1) 1.0% (1) Granulomatous MF - 1.0% (1) - 1.0% (1) ALCL 12.3%(14) 7.0% (8) 7,0%(8) 26.3% (30) HD 1.0%(1) - 2.6%(3) 3.5%(4) CLL 2.6%(3) - 1.0%(1) 3.5%(4) AML - - 1.0%(1) 1.0% (1) B-cell lymphoma - - 1.8%(2) 1.8% (2) LGL 1.0%(1) - 1.0%(1) 1.8% (2) Multiple Myeloma - - 1.0%(1) 1.0% (1) Abbreviations: ALCL, anaplastic large cell lymphoma; AML, acute myeloid leukemia; CLL, chronic lymphatic leukemia; FMF, folliculotropic mycosis fungoides; HD, Hodgkin disease; LGL, T-cell large granular lymphocytic leukemia; MF, mycosis fungoides; n, number of lymphoma cases. Disclosures Duvic: Therakos: Research Funding.

Extracorporeal photopheresis (ECP) is an effective frontline therapy for patients with leukemic cutaneous T-cell lymphoma (L-CTCL), but the mechanisms of action are not fully understood. To elucidate molecular mechanisms underlying the efficacy of ECP, we used Agilent Whole Human Genome Microarrays to examine blood transcriptional profiles in L-CTCL patients after ECP therapy. Ten L-CTCL patients including 5 clinical responders and 5 non-responders were studied. Their peripheral blood was collected before ECP (baseline), at Day 2, and one month post-ECP. Total RNA extracted from peripheral blood mononuclear cells was assayed with Whole Human Genome Oligo Microarrays (4 × 44 K) (Agilent, Santa Clara, CA). The differentially expressed gene analysis (DGA) was done using the paired t-test with Benjamini- Hochberg correction (P value < 0.05) between post-ECP and baseline. The fold change of gene expression between post-ECP and baseline were calculated from the normalized values. Hierarchical clustering of differentially expressed genes was performed with the Pearson correlation. The DGA between responders and non-responders were cross-compared. Canonical biological pathways were identified using Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Redwood City, CA). Differentially expressed gene profiles were different in responders from non-responders. As indicated in Figure 1, there were more genes differentially regulated in responders than in non-responders post-ECP at both Day 2 (549 genes in responders versus 66 genes in non-responders) and at one month (472 genes in responders versus 95 genes in non-responders). Among 472 differentially expressed genes in responders at one month post-ECP, almost twice as many genes (313) were down-regulated compared to up-regulated genes (159). The top down-regulated genes were IL-1β, EGR1, CCL3, CCL3L3, and CXCL2. The down-regulated genes were mainly related to functions of platelets, immune and/or stress responses, and chromatin remodeling. The upregulated genes were mainly related to functions of the nucleolus and included USP34, POLR3F, ZNF529, C22orf35, and BAT2D1. The ingenuity pathway analysis revealed that the top 5 pathways affected by ECP at one-month in responders were 1) integrin signaling; 2) granulocyte adhesion and diapedesis; 3) signaling by Rho Family GPTases; 4) agranulocytes (lymphocyte, monocyte and macrophage) adhesion and diapedesis; and 5) triggering receptor expressed on myeloid cells 1 (TREM1) signaling (Table 1). In contrast, these pathways and genes were less affected in non-responders. Of note, a comparison of all DGA results indicated that the responder group overlapped in the differentially expressed genes between Day 2 group (RD2) and one month group (RM1), but had few genes in common to the non-responder group (NM1). There were 94 genes consistently downregulated among RD2 and RM1 while only 6 genes were found in common between the RM1 and NM1 group. Similarly, 61 genes were consistently upregulated in group RD2 and RM1 while only 3 genes were found in common between the RM1 and NM1 group. In summary, the blood transcriptional profiling by this study identifies a signature of genes and pathways relevant to clinical response to ECP in L-CTCL patients. These findings expand our understanding of molecular mechanisms of ECP. Further validation of these genes and pathways is warranted in the future studies. Table 1. Top canonical pathways affected by ECP in L-CTCL patients responded to ECP at one-month Canonical Pathways Downregulated genes Upregulated genes Integrin Signaling 15/201 (7%) ITGA2B, MAP3K11, ITGA5, MYLK, ITGB3, MYL9, PARVB, AKT1, RHOB, CAPN1, ACTN4, CTTN, ARPC4, ACTN1, ITGB5 2/201 (1%) ITGB1, PPP1R12A Granulocyte Adhesion and Diapedesis 14/179 (8%) CSF3R, ICAM1, PPBP,ITGA5, CXCL5, SDC4, CCL3, ITGB3, GNAI2, CLDN5, CCL3L3, IL1B, CXCL1, CXCL2 1/179 (1%) ITGB1 Signaling by Rho Family GTPases 13/236 (6%) SEPT5, MAP3K11, ITGA5, MYLK, GNAZ, CDC42EP2, GNAI2, MYL9, GNG11, GNA15, RHOB, GNB2, ARPC4 3/236 (1%) ITGB1, DIAPH3, PPP1R12A Agranulocyte Adhesion and Diapedesis 13/190 (7%) ICAM1, PPBP, ITGA5, CXCL5, SDC4, CCL3, GNAI2, MYL9, CLDN5, CCL3L3, IL1B, CXCL1, CXCL2 1/190 (1%) ITGB1 TREM1 Signaling 7/76 (9%) ICAM1, AKT1, NLRP12, ITGA5, IL1B, CD83, CCL3 2/76 (3%) ITGB1, NLRC3 Figure 1. Differentially expressed genes post-ECP between responders and non-responders Figure 1. Differentially expressed genes post-ECP between responders and non-responders Disclosures Duvic: Therakos: Research Funding. Ni:Therakos: Research Funding.

INTRODUCTION AND OBJECTIVES: Folliculotrophic mycosis fungoides (FMF) is an uncommon and distinct variant of mycosis fungoides (MF) that is often difficult to diagnose and treat. To identify prognostic factors, we analyzed the prognostic relevance of clinical, and histologic features in FMF patients. MATERIALS AND METHODS: We queried the MD Anderson Cancer Center cutaneous T-cell lymphoma database for patients with a diagnosis of folliculotrophic mycosis fungoides (FMF). The patients' charts were reviewed and patients were included if they displayed a biopsy showing histologic and immunohistochemical features consistent with FMF. Clinical and histopathologic features, prognostic features including overall survival (OS), progression free survival (PFS), and disease free survival (DFS), and treatment options were described in 114 patients with biopsy proven F-MF with and without large cell transformation (LCT). Survival outcomes were assessed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS We evaluated 114 patients (54% male, 46% female) 72% were Caucasian with median age at diagnosis of 56 yrs (range 22-86 yrs). Median overall survival (OS) and disease free survival (DFS) was not reached but median time to progression was 7.6 years (95% CI). Histologic LCT in skin or nodes occurred in 24 patients (21%), including 12 within a year of initial diagnosis of FMF. Median survival for patients diagnosed with large cell transformation (LCT) at time of diagnosis of FMF was only 2.4 yrs (0.4, 6.3; 95% CI). Median time to progression was 1.5 yrs (0.4, 6.3: years; 95% CI and median PFS for patients diagnosed with LCT diagnosed at 1-year was 5.6 (1.9, 6.3) years. Patients > 65 years were about 4.5 times more likely to die than In Univariate analysis: Increased risk of death was associated with lymph node stage (2x), Stage IV vs Stage IA, increased white cell count (WBC) (5x), visceral involvement (M0) (20 x), erythroderma (T4)(4.7 x), involvement on the chest (3.6 x), pruritus (7.8x), and increased lactic dehydrogenase ( 2x). Patients with FMF on the chest were 3.6 times more likely to die. Patients with pruritus were about 7.8 times more likely to die. In multivariate analysis: Increased risk of death was associated with LCT at time of diagnosis (13X), increased WBC (8X). The most frequent skin directed therapies were topical steroids (85%), nitrogen mustard (45%), and total body skin electron beam (TBSEB) 32%. The most common systemic therapies were bexarotene (46%), other retinoids (34%) and brentuximab vedotin (7.0%). Patients with FMF on the head/face were more likely to respond to oral bexarotene. Patients receiving local radiation and TBSEB had the highest response rates 79% (23/29) and 68% (25/37), followed by extracorporeal photopheresis (ECP) 56% (5/9), topical steroids 48% (47/97), retinoids 44% (14/32), oral bexarotene 36% (19/53), interferon 31% (4/13), and methotrexate 20% (3/15). Table 1. Univariate analysis of OS, PFS and DSS for FMF Univariate Analysis OS PFS DSS Factors HR [95% CI] p HR [95% CI] p HR [95% CI] P Age >65 4.52 [2.06, 9.88 ] 0.0002 2.20 [1.20, 4.02] 0.01 2.96[0.89, 9.78] 0.07 LCT 618 1.002 [1.001, 1.003] 0.0056 1.00 [1.000,1.002] 0.0076 1.00 [1.00, 1.00] 0.0145 Symptoms Erythroderma 4.73 [1.58, 14.7 ] 0.0054 3.10 [1.21, 7.96] 0.018 1.87 [1.33, 31.87] 0.020 FMF on Chest 3.6 [1.35, 9.59 ] 0.014 3.83 [1.82 , 8.04 ] 0.0004 1.41 [0.882, 19.1] 0.07 Pruritus 7.85 [1.06, 58.0 ] .043 5.069 [1.55, 16.5] 0.007 16.49 [0.00, NE] 0.99 CONCLUSIONS Folliculotropic mycosis fungoides is an important entity requiring proper diagnosis and early treatment with radiation, ECP, topical steroids and retinoids. FMF is clinically more aggressive than classic MF and was associated with large cell transformation in 21% of FMF patients. Prospective studies on the clinical course and treatment responsiveness of FMF are planned. Disclosures Duvic: Innate Pharma: Research Funding; MiRagen Therapeutics: Consultancy; Eisai: Research Funding; Soligenics: Research Funding; Spatz Foundation: Research Funding; Array Biopharma: Consultancy; Huya Bioscience Int'l: Consultancy; Oncoceutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Allos (spectrum): Research Funding; Rhizen Pharma: Research Funding; Therakos: Research Funding, Speakers Bureau; Cell Medica Ltd: Consultancy; Tetralogics SHAPE: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: SL-401 is a novel biologic delivering a truncated diphtheria toxin, a highly potent protein synthesis inhibitor, to the IL-3R that is overexpressed on cancer stem cells and tumor bulk in BPDCN, AML and other hematologic malignancies. The agent is being further evaluated in relapsed/refractory (r/r) BPDCN based on robust activity in BPDCN pts treated with a single cycle at 12 µg/kg/day x 5 (78% ORR, 55% CR; Frankel, Blood 2014). The objectives of the lead-in stage of this trial, which includes a pivotal evaluation in r/r BPDCN, were to evaluate the safety, pharmacokinetics (PK), and preliminary activity of multiple cycles, and confirm the dose for the BPDCN study and further AML studies. Methods & Results: To date, 17 adults (9 BPDCN; 8 AML; median ages: All 63; BPDCN 69; AML 53), 15 of whom are evaluable for dose-limiting toxicity (DLT), have received 57+ cycles (range, 1-12+) of SL-401 as a 15 min infusion daily for up to 5 days every 3 weeks at 7 (6 pts/29+ cycles), 9 (3 pts/9 cycles) & 12 µg/kg/day (8 pts/19+ cycles). Two BPDCN pts had DLTs of capillary leak syndrome (CLS; Gr 5 [7 µg/kg/d]; Gr 4 [12 µg/kg/d]) in cycle 1 as manifested by decreased serum albumin during treatment followed by symptomatic CLS; both had rapid improvement of skin only disease but did not complete formal end-of-cycle assessments and are not evaluable for response. No other DLTs have occurred and the maximum tolerated dose (MTD) has not been identified. Measures, successful to date in preventing CLS, have been implemented to suspend dosing within a cycle for early CLS (manifested by weight gain and/or decreased albumin) and have allowed those pts to proceed to full 5-day dosing in subsequent cycles. Transient Gr 3 transaminase elevations, largely limited to cycle 1, have also occurred. Cumulative side effects have not been observed over multiple cycles. Five (71%) of 7 evaluable BPDCN pts had major objective responses, including complete responses. Four of 5 BPDCN pts with bone marrow involvement (range 15-80% blast count) had normalization to ≤ 5% blasts, and robust resolution of extensive, symptomatic skin lesions, lymphadenopathy, and soft tissue disease have also been noted, often within days of starting treatment. Several BPDCN pts with objective responses are receiving continued therapeutic benefit with successive cycles. Three r/r AML pts had stable disease for 6-12+ cycles, one of whom resolved transfusion dependence. Preliminary PK studies indicate inter-subject variability, increasing exposure from day 1 to 5 of cycle 1, and generally increased exposure in BPDCN relative to AML pts. Conclusions: Multiple cycles of SL-401 are feasible and confer an acceptable safety profile at doses up to 12 µg/kg/day, which, along with safety measures to prevent CLS, will be used in a pivotal stage of this study in r/r BPDCN. Because of limited toxicity and evidence of protracted disease stabilization (up to 9+ mo) in several AML pts, further SL-401 dose escalation in AML is ongoing. Major responses in BPDCN and stabilization in AML indicate that targeting of IL-3R expressing cells via SL-401 has potential for sustained anticancer activity in aggressive myeloid malignancies. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Lane:Stemline Therapeutics, Inc.: Research Funding. Stein:Amgen: Speakers Bureau. Blum:Celator: Consultancy; Celgene: Consultancy; Boerhinger Ingelheim: Consultancy. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Employment. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Disalvatore:Stemline Therapeutics: Employment. Liu:Stemline Therapeutics: Employment. Duvic:Cell Medica Ltd: Consultancy; Array Biopharma: Consultancy; Oncoceutics: Research Funding; Spatz Foundation: Research Funding; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Therakos: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding. Schwartz:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B- cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T- cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.

Introduction and Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (PC-CD4+ SM-PTL) was recently re-classified as a rare provisional subtype in the 2008 World Health Organization (WHO) classification. It is characterized by solitary nodules or plaques located mostly on the head and neck. Multiple lesions are associated with a worse prognosis; however, the paucity of patients has prevented the definition of prognostic factors. Histologically, a dense cutaneous infiltrate of clonal small/medium hyperchromatic lymphocytes admixed with numerous reactive cells is observed, sometimes leading to the diagnosis of pseudolymphoma or other lymphoma: Mycosis Fungoides (MF) or peripheral T cell lymphoma – not otherwise specified (PTCL-NOS). Differential diagnosis with other aggressive cutaneous lymphomas is very important due to the favorable prognosis of PC-CD4+SM-PTL and complete response to conservative therapies. The purpose of this retrospective study was to evaluate and compare clinical and histological features of PC-CD4+ SM-PTL in 48 cases collected from two independent centers, MD Anderson Cancer Center (Houston, TX) and Dermatological Clinic of the University of Milan (Milan, Italy). Results: Forty-eight patients were identified (26 MDACC and 22 Milan cases). Women out-numbered men (women 67% and 55% respectively, and men 33% and 45% respectively). The mean age at onset was 53 and 50 years. The mean follow-up time was 19 months (1-84 months) for the American group and 31 months (3-180 months) for the Italian group. All patients in both groups were alive at the time of last follow up, without evidence of extra-cutaneous disease. Seventy-four percent of American patients and 73% of Italian patients developed single lesions, most common were nodules in the head and neck area. Multifocal lesions were found in other body sites besides head and neck in 6/7 American patients and in all Italian patients. Multifocal disease was characterized by plaques rather than nodules. Histological features showed a dense infiltrate composed of small to medium-sized hyperchromatic “grouped” atypical lymphoid cells occupying superficial and deep dermis. The infiltrate also showed admixed reactive B-cells, plasma cells, macrophages, and few dendritic cells. Vascular hyperplasia was noted. Adnexotropism was frequently found. Focal epidermotropism was also present. The neoplastic cells were CD3+, CD4+, CD5+, PD1+, CD8-, CD30-. A peculiar perivascular and small cluster arrangement of PD-1+ cells was noted. T-bet nuclear expression was recorded in 3 Italian cases. Mib1/Ki-67 proliferation index was between 5 and 30% in all Italian patients. The treatments used for patients with complete responses included surgical excision, local radiotherapy, and high potency topical steroids, occasionally combined with topical nitrogen mustard. Patients who had complete responses without relapse also had single lesions on the head and neck (67% and 68 % respectively), except for one US patient with multifocal disease. A small group of patients (18.5% and 4%, respectively) relapsed one time. Seven percent of American patients and 18% of Italian patients developed multifocal plaques on the trunk and extremities and had dramatic responses to therapy with a “waxing and waning” course. Only one Italian patient developed rapidly progressive tumors confined mainly to the legs and was resistant to cyclophosphamide and oral steroids. Conclusion: This case series demonstrates that PC-CD4+ SM-PTL is characterized by heterogeneous clinical presentations. There are no definite criteria to predict an aggressive course reported rarely in the literature. Histological findings useful, but not sufficient for diagnosis, and not sufficiently underscored by classical description of this tumor, are the arrangement of PD-1+ atypical cells in small clusters or rosettes surrounding reactive cells and the perivascular distribution of the neoplastic cells. Absent or minimal epidermotropism, a mixed B cell infiltrate and the clinical presentation of a solitary dermal nodule, may help to distinguish PC-CD4+ SM-PTL from the other CD4+ PD1+ CTCLs, mycosis fungoides and PTCL-NOS. Disclosures No relevant conflicts of interest to declare.

Introduction: Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is a rare neoplasm, of unknown etiology, composed of mature, activated, γδ T cells with a cytotoxic phenotype, usually presenting as plaques or nodules with ulceration. PCGD-TCL, which has been classified as a distinct entity in the 2008 World Health Organization classification, often fails to respond to polychemotherapy and radiation therapy with a poor prognosis although some cases demonstrate relatively indolent behavior. Objective: We report a case of cutaneous γδ T-Cell lymphoproliferative disorder following a stingray puncture and mimicking PCGD-TCL. Case report: A 33-year-old man was referred for a generalized skin rash of seven years duration. In 2007, a stingray punctured his right ankle and one week later he developed cellulitis that responded to IV antibiotics. Five months later, multiple small, red spots appeared at the site of the puncture first and then on both ankles and gradually spread to the lower legs and torso. In 2011, arthralgias in knees and hands were successfully treated with oral prednisone, and his rash also improved transiently. Eosinophilia of up to 31% fell to 10% on prednisone but persisted. At presentation to MDACC in Dec 2012, on physical exam there was a red capillaritis-like fixed exanthem from the waist down. Small nodules were present on his right lower leg and back. Flow cytometry of peripheral blood showed CD8+ T cells with partial loss of CD5 and CD7, and partial expression of CD56 and CD57. Bone marrow was negative. PET scan showed a few small skin nodules without lymphadenopathy. Increased serum beta-2-microglobulin (2.6 mg/L) and lactate dehydrogenase (680 IU/L) were noted. Multiple biopsies from capillaritis and nodules showed perivascular, periadnexal, and subcutaneous infiltrates of small to medium sized CD8+ T cells, eosinophils, and CD68+/S100+ histiocytes. Anti-CD1a staining highlighted scattered, small clusters of dendritic cells with a small subset of Langerin+ cells. There were scattered mast cells as highlighted by anti-tryptase. Molecular studies showed T-cell receptor γ chain gene rearrangements identical in skin and peripheral blood. Discussion : This patient developed generalized capillaritis, arthralgias, and neuropathy following a stingray puncture, an injury occurring in approximately 2000 people annually in the USA. In one other patient with a stingray puncture, a skin biopsy taken four days later showed central hemorrhagic necrosis with surrounding infiltrate of eosinophils and lymphoid cells, which were mainly CD3+, CD4+ and TIA+. Both cases suggest a host immunological reaction with eosinophils to stingray toxin venom. In particular, stingray venom contains tetraspanins which are known to activate macrophages and induce chemotaxis of eosinophils. The presence of CD68+/S100+ histiocytes and CD1a+/Langerin+ cells in our patient suggests activation of the classic macrophage- maturation pathway, leading to proliferation of CD8+ T-cells and promotion of anti-tumor immunity. Human Vδ1+ γδ T cells are known to recognize phospholipid antigens presented by CD1a+ cells. We hypothesize that tetraspanins in stingray toxin may have induced chemotaxis for eosinophils and promoted CD8+ immunosurveillance by controlling the antigen presentation process and macrophage activation. Summary: Although this patient's skin lesions had several poor prognostic factors (monoclonal TCR γ in skin and peripheral blood, elevated lactic dehydrogenase and beta-2-microglobulin, and CD8+ cytotoxic markers), unlike PCGD-TCL his clinical course was indolent over 7 years and his lesions responded to oral prednisone. Therefore, we conclude that this patient developed a PCGD-TCL- like immune reaction to stingray venom similar to that reported against tetraspanins. Further studies are needed to confirm this mechanism. Disclosures No relevant conflicts of interest to declare.

Introduction: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A and B and human interleukin-2. E7777 has the same amino acid sequence as denileukin diftitox (DD) (approved as ONTAK in the USA for treatment of persistent or recurrent CTCL) but with improved purity and an increased percentage of active protein monomer species. This study is a pivotal multicenter open-label single-arm study comprising a Lead-In part (approx. 20 pts) to select the E7777 dose for the Main Study (70 patients [pts]) in which primary efficacy and safety of E7777 is assessed. Dose finding is necessary since the specific bioactivity of E7777 is 1.5 – 2 times that of the prior less purified form (ONTAK). The Lead-In study is reported in this abstract. Methods: A Continual Reassessment Method (CRM) is used for dose-finding with E7777 doses ranging from 3 – 18 µg/kg to be tested. The CRM is designed to target a DLT rate of approx. 20%. Inclusion criteria were patients ≥ 18 yr old, with a diagnosis of Mycosis Fungoides (MF) or Sézary Syndrome (SS) with stage I-IV disease at study entry, measurable CD25+ tumor, and who have received at least one prior therapy for CTCL. Prior commercial DD therapy was not allowed. E7777 was administered as monotherapy by iv infusion over 60 min on 5 consecutive days every cycle of 21 days. Pts were be dosed up to 8 cycles; additional dosing is allowed if deemed beneficial by the treating physician. Required premedication included an antihistamine, anti-pyretic, and anti-emetic; in case of infusion-related reaction low-dose systemic steroid premedication was allowed. The aim of the Lead–in study was to establish the maximum tolerated dose (MTD) and the recommended Main Study dose (based on the MTD and clinical judgment), and to assess safety and tumor response. Tumor responses were assessed according to the new ISCL/EORTC criteria (Olsen 2011). Results: Seventeen pts have been treated in the Lead-In. There were 8 males and 9 females, with median age 64 (range 26-81). Thirteen pts had MF (3, 7, 1, and 2 pts with Stage I, II, III, and IV disease, respectively) and 4 had SS (Stage IV). Fourteen or more pts had at least 4 lines of prior therapy. Pts were treated for a median of 4 cycles (range 1-8 cycles) and 8 patients are ongoing. Of the 9 pts who have discontinued from the study, 5 were for disease progression, 2 for AEs, 1 completed treatment per protocol, and 1 was pt choice. Pts were treated at doses ranging from 6 to 15 µg/kg; dose levels were assigned by the CRM based on the cumulative DLT information. The dose levels for each pt are shown in chronological order in the Table below, with the corresponding DLT assessments.TableContinual Reassessment MethodPatient #Dose (µg/kg)DLT16No29No312No415Yes56No6-129No13-1512No1615Yes1712No In the 17 patients treated, there were two DLTs; both occurred at the 15 µg/kg dose level and were capillary leak syndrome (CLS) (one Gr 2 with hospitalization, and one Gr 4). Based on preliminary results from these 17 pts, the highest dose with a DLT rate of ≤ 20% is 12 µg/kg. The most frequent AEs occurring in ≥ 3 pts were nausea (6 pts), ALT increased and AST increased (4 pts each), and vomiting, chills, fatigue, pyrexia, myalgia, rash, staph skin infection (3 pts each). Serious AEs considered related to study drug were CLS (2 pts) and pruritus, rash, diarrhea, vomiting, hypoxemia, and tumor flare (all in 1 pt each). AEs leading to drug discontinuation were CLS (2 pts). There were no deaths on study. Five pts achieved an objective response (OR) as assessed by the investigator, including 1 pt with relapse after allogeneic stem cell transplantation who received 8 courses and achieved a complete remission with associated skin graft-vs-host disease. These responses occurred at dose levels of 6, 9, and 12 µg/kg, including in 3 pts with stage IV disease (2 MF, 1 SS). Conclusion: Dose finding of E7777 in CTCL is proceeding with the CRM method. The toxicity profile is acceptable and so far no new safety signals compared to ONTAK has been identified. Initial signs of activity have been observed. Final data from this Lead-in study will be presented. Disclosures Duvic: Eisai Inc.: Member of safety monitoring committee for trial Other, Research Funding. Kuzel:Eisai Inc.: Research Funding. Dang:Eisai Inc.: Protocol Steering Committee Other, Research Funding. Prince:Eisai Inc.: Research Funding. Foss:Eisai Inc.: Consultancy. Guo:Eisai Inc.: Employment. Ottesen:Eisai: Employment. Ooi:Eisai Inc.: Employment. Kim:Eisai inc.: Protocol Steering Committee Other.

Introduction Brentuximab vedotin, an antibody drug conjugate comprising of an anti-CD30 monoclonal antibody (cAC10) attached by a protease-cleavable linker to a microtubule-disrupting agent monomethyl auristatin E (MMAE), was approved for relapsed Hodgkin lymphoma (ORR 75%) and systemic anaplastic large T-cell lymphoma (ALCL; ORR 86%) and the naked cAC10 antibody was shown active in CD30+ skin lymphomas (ORR 70%). Study design To determine safety and activity of Brentuximab vedotin we completed a Phase II open-label trial of 48 patients with primary cutaneous CD30+ lymphoproliferative disorders including lymphomatoid papulosis (LyP) and primary cutaneous pc-ALCL (pc-ALCL) or CD30+ mycosis fungoides (MF). Eligibility required skin lesion expression of CD30, > 10 Lyp lesions, one or more tumors, and need for systemic therapy. Patients with CD30+ MF were stage IB or higher and had received one or more prior topical or systemic therapies. The antibody conjugate was infused at 1.8 mg/kg every 21 days. Patients achieving a complete response (CR) received two additional doses and those achieving partial responses (PR) after 8 cycles could receive up to 16 doses. Response criteria for LyP were a 50% decrease in lesions, for pc-ALCL were 50 % tumor reduction, and for MF were 50% decrease in modified skin weighted assessment tool mSWAT. CD30 pretreatment skin biopsies and serum sCD30 were correlated with response. Results The 48 evaluable patients who received >2 doses of brentuximab vedotin included 22 females and 26 males with median age of 59.5 years (range 31-86). Their clinical diagnoses are in Table 1: 28 with MF, 2 with pc-ALCL, 9 with only LyP, 7 LyP with MF, and 2 with pc-ALCL/LyP/MF. Overall response rate (ORR) was 71% (34/48) with CR of 35% (17/48). The intent to treat response rate for all 56 patients receiving at least one dose was 61% (34/56). ORR was 50% in 28 MF patients regardless of whether their lesions had low, medium, or high CD30 at baseline. LyP and pc-ALCL patients had a 100% ORR and two pc-ALCL patients had CRs. For LyP, time to response (TTR) was 3 wks (range 3-6) and median duration of response (DOR) of 23 wks (range 6-44). For MF, TTR was 10.5 wks (range 3-39) and DOR was 13.5 wks (range 3-56 wks). Relapse rates in Lyp and pc-ALCL was 40% (8/20) with TTR of 25 wks (range 6-41). In MF responders, 5/14 (36%) relapsed and MTR was 3 wks (range 3-40). Median ORR and disease specific response (DSS) were not reached from date of diagnosis or from first dose. Median progression free survival (PFS) was 9.7 years from diagnosis and 1.68 years from first dose. Soluble CD30 levels from baseline to end of study differed significantly among those patients achieving a CR compared to those with PR or SD (p=.036). The most common related adverse event (AE) of any grade was peripheral neuropathy (PN) in 29/48 (60%): resolved in 14/29 (48%) and ongoing in 15/29 (52%) with 5 grade 2 and 10 grade one. Other AE > 10% were drug rashes (27%), diarrhea (24%), fatigue (30%), alopecia (16%), myalgias (16%), and nausea (14%). Grade 3-4 events included neutropenia (n=5), nausea (n=2), chest pain (n=2), deep vein thrombosis (n=1), transaminitis (n=1) and dehydration (n=1). Dose reductions to 1.2 mg/kg were for grade 2 neuropathy (n=2), transaminitis (n=1) and arthralgia/ fatigue (n=2). There were two deaths from untreated sepsis after one dose. Conclusion This phase II clinical trial demonstrates that brentuximab vedotin is active for mycosis fungoides (ORR 50%) irrespective of level of CD30+ expression. The ORR was 100% for CD30+ pc-ALCL, and LyP patients and was 71% with a CR of 36% for all evaluable patients. Disclosures: Duvic: Seattle Genetics: Research Funding. Off Label Use: This is an open label study for Cutaneous T-cell lymphoma and lymphoproliferative disorder. Brentuximab is approved for relapsed and refractory Hodgkins lymphoma. Tetzlaff:Seattle Genetic: Consultancy.

Cutaneous T cell lymphoma—CTCL is a malignancy of skin-tropic T cells. CTCL cells have ubiquitous overexpression of CD3. Although uncommon, CTCL has been estimated to affect 1,500 patients per year in the United States. There are multiple approved systemic therapies for CTCL, but responses are brief lasting months. Allogeneic stem cell transplantation may provide long-term remissions, but is suitable for only rare CTCL patients. Overall, CTCL has a long clinical course with relentless progression over months to years with estimated median survival of 3-5 years for stage IB-IIB patients. The CD3 targeted agent, Resimmune, was synthesized and prepared for clinical use. It consists of the catalytic and translocation domains of diphtheria toxin fused to two anti-human CD3 Fv fragments. DNA encoding Resimmune protein was integrated into the Pichia pastoris genome, and recombinant protein was produced in Pichia pastoris via the secretory route (Woo, Protein Expr Purif 25, 270, 2002). Protein was purified by anion exchange and size exclusion chromatography. The CD3+ Jurkat cell line incubated with Resimmune yielded an IC50 for protein synthesis inhibition of 0.017pM. The CD3- Vero cell line incubated with Resimmune showed an IC50 >10pM. Mice, rats, and monkeys given total doses of >200mg/kg over four days showed only transient transaminasemia without histopathologic tissue injury or clinical signs or symptoms (Woo, Cancer Immunol Immunother 57, 1225, 2008). In a mouse model with human CD3e transfected lymphocytes, four logs of antigen positive cells were reproducibly depleted from nodes and spleen with 100mg/kg total dose of Resimmune (Thompson, Protein Eng 14, 1035, 2001). Based on these findings, a phase 1 study was initiated and this report serves to update the results of a single cycle of Resimmune given at 2.5-11.25mg/kg 15 min IV infusion twice daily for 8 doses to 18 CTCL patients. There were 10 females and 8 males with ages 20-81 years. Two patients were naïve to systemic therapies, and all others had failed 1-4 prior treatments including interferon, bexarotene, gemcitabine, vorinostat, chlorambucil, etoposide, pralatrexate, doxil, romidepsin, methotrexate, CHOP, and brentuximab vedotin. None of the Resimmune treated CTCL patients had dose-limiting toxicities. Side effects were mild-moderate and transient with fevers, chills, nausea, transaminasemia, hypoalbuminemia, lymphopenia, reactivation of EBV and CMV, and hypophosphatemia. Toxicities responded to antipyretics, anti-emetics, albumin infusions, rituximab treatment and valgancyclovir. Among measured patients, there was a 3 log decline in normal, circulating T cells by day 5 that recovered by day 14. Because of vascular leak syndrome toxicities in non-CTCL patients, the MTD was defined as 7.5mg/kg x 8 doses. Cmax ranged from 1.9-40.7ng/mL and half-life from 5-66min. Pretreatment anti-DT titers were 0.9-251mg/mL and day 30 post-therapy increased to 5-4059 mg/mL. 17 CTCL patients were evaluable for response. There were six responses for a response rate of 35%. There were four CRs (24% CR rate). Three of the CRs are over 4-years duration. Patients with IB or IIB disease and mSWAT Disclosures: Woo: Angimmune: Patents & Royalties, Research Funding. Foss:celgene: Honoraria, Research Funding; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; eisai: Membership on an entity’s Board of Directors or advisory committees; spectrum: Research Funding; merck: Research Funding; seattle genetics: Research Funding. Neville:Angimmune: Employment, Equity Ownership, Patents & Royalties.

Introduction Pralatrexate is an anti-folate approved for relapsed/refractory peripheral Tcell lymphoma. Pralatrexate also had high activity and acceptable toxicity when used as a single agent in a dose finding phase 1/II study of 54 patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL). The response rate was 45% in 29 patients treated at an optimal dose of 15 mg/m2/week for 3 of 4 weeks. In a second international multicenter Phase I/II dose finding trial, the optimal dose of praletrexate from the first trial was combined 150- 300 mg/m2 bexarotene. Eligibility was based on ECOG < 2 and MF stage > IB with ≥ one prior systemic therapy. Pralatrexate was administered at 15 mg/m2 weekly via intravenous push for 3 of 4 weeks each cycle. The MTD for bexarotene was 150 mg/m2 taken orally daily with food and supplemented with both levothyroxine and atovastatin. All patients on praletrexate received bi-monthly vitamin B12 and daily folic acid supplementation. Response to therapy was determined by a composite score consisting of the modified skin assessment tool (mSWAT), lymph nodes by CT scan, and blood flow cytometry. Results The ORR for both trials at our site was 42% (11/26). The ORR in the Phase I dose finding trial of praletrexate alone was 4/12 (33%). The ORR in the pralatrexate plus bexarotene trial was 7/14 (50%). Ten of 26 patients enrolled in both trials received more than 9 cycles of praletrexate: 3 on pralatrexate and 7 on the pralatrexate/bexatotene combination (Table 1). There were 4 females and 6 males with median age of 71 years (range 41-82 years). Their clinical stagies were 4 with IIB, 1 with IIIB, 4 with IVA, and 1 with IVB. They received a median of 13 cycles (range 9-23). The median number of prior therapies was 4 (range, 2–5). Median time to response was 15.75 weeks (range 4-24 weeks) and the median duration of response was 26.75 weeks (range 8.5-49.5 weeks). Because there are still 4 responding subjects in ongoing therapy, the mean duration of response underestimates the true duration. Two patients (Table 1*) presented with lower leg tumors that responded to therapy leaving residual chronic leg ulcers and are on long term active treatment. The most common related adverse events of any grade were stomatitis (Grade 1-2) (n=8), neutropenia (n=5), headaches (n=3), dizziness (n=3), nausea (n=3), fatigue (n=2). The dosing frequency of three out of four weeks was reduced to every other week at 10 mg/m2 in three of 10 long term responders. Summary/Conclusions Praletrexate alone or in combination with low dose oral bexarotene is active and capable of long term durable responses in CTCL patients with advanced age and stage. The combination of 150 mg/m2 of bexarotene with 15 mg/m2 of praletrexate was well tolerated and had a better profile than praletrexate alone at our center. Disclosures: Off Label Use: Off label study. Duvic:Spectrum: Research Funding.

Introduction and Rationale Sézary Syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma CTCL), is characterized by generalized erythroderma and >1000 circulating central memory T-cells with a CD4+CD26- phenotype, Other clinical features include reactive adenopathy, keratoderma, ectropion, pruritus, and colonization with Staphylococcus aureus. SS can arise de novo or emerge in patients with Mycosis Fungoides (MF). Morphologically, SS cells were first recognized by their convoluted nuclei and karyotype analysis has shown the presence of multiple chromosomal abnormalities and copy number variants, none of which are disease defining; however, the mutational landscape of SS has not been investigated systematically. Here we present initial findings from profiling somatic mutation by whole exome sequencing. Methods In order to delineate the genomic mutation profile of Sézary cells we compared protein coding sequences from CD4+ and CD4- peripheral blood cell DNA to that from autologous cultured fibroblasts derived from ten newly diagnosed SS patients with high percentages of circulating SS cells. CD4+ T-cells were selected by a Miltenyi Biotec CD4+ T Cell Isolation Kit and genomic DNA was extracted from CD4+ T-cells, residual CD4- cells, and autologous fibroblasts from each patient using an All Prep DNA/RNA/Protein Mini Kit (Qiagen). Purity of CD4+ T-cell sorting confirmed by flow cytometry was > 90% purity. Skin biopsies from SS non-lesional skin were explanted, cultured for 5-6 weeks, and used to extract genomic control DNA for each patient. Whole exome DNA was enriched by capture using a Nimblegen VCRome version 2.1 array. Nine billion bases of sequence was generated for each sample on an Illumina HiSeq 2000 run for 101 cycles. This resulted in approximately 95% target covered to a minimum depth of 20 bases, with and overall average coverage of over 130 bases in all samples. Somatic mutations were called by comparing sequence from all tissues to the human reference sequence (GRC37) and then subtracting nucleotide variation found in the fibroblast lines from variation found in the CD4- and CD4+ cell populations. Results We found an average of 82 mutations per patient in the CD4+ cells. TP53 with 4 mutations was the most commonly mutated, three patients harbored MSH3 mutations, which may contribute to higher mutation frequencies in those patients. Singleton mutations in MYC, MLLT4 are among cancer-related transcription factors, and singleton NF1 and Notch4 suggest aberrant signaling. Surprisingly, the CD4- cells also harbored TP53 mutations in 3 of the 4 patients. Conclusions Whole exome sequencing revealed recurrent mutations in two genes: TP53 and MSH3 and hinted at involvement of RAS and Notch pathway signaling, although no RAS mutations were observed. The presence of TP53 mutation in CD4- cells was unanticipated, and may result from mutation of a common progenitor cell population in the CD4- cells. Studies are underway, including analysis of copy number gains and losses to further elucidate the mutational patterns in SS patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 3688 Introduction: Brentuximab vedotin is a conjugate of CD30 monoclonal antibody (cAC10) and the tubulin inhibitor, monomethyl auristatin E (MMAE) which targets the cell surface antigen CD30. Responses in CD30+ relapsed/refractory Hodgkin lymphoma (HL; ORR 75%) and anaplastic large T-cell lymphoma (ALCL; ORR 86%) were reported. Study design: To determine the safety and efficacy of brentuximab vedotin, we conducted a Phase II investigator initiated open label clinical trial in patients with primary cutaneous CD30+ lymphoproliferative disorders (self-regressing lymphomatoid papulosis (LyP) or primary cutaneous pc-ALCL) and CD30+ mycosis fungoides (MF) with or without large cell transformation. Eligibility was based on ECOG < 2, need for systemic therapy, expression of CD30 in baseline skin lesion by immunohistochemistry, > 10 lesions of active or scarring LyP, pc-ALCL without generalized nodes, and CD30+ MF stage > IB with ≥ 1 prior topical or systemic therapy. Brentuximab vedotin at 1.8 mg/kg was infused over 30 min every 21 days up to 8 doses with an option of up to 8 more doses for patients with PR or two cycles past a complete response. Patients receiving at least 2 doses were evaluable for response measured as 50% decrease in active lesion number (LyP), tumor measurements (pc-ALCL), or modified skin weighted assessment tool mSWAT (MF). Biopsies were taken at pre-study, day 1, and to confirm response or disease progression to correlate response with CD30 expression. Results: Among 46 patients receiving at least one dose there are currently 38 evaluable patients: 21 females and 25 males whose median age is 59.5 years (range 31–86 years). Their clinical diagnoses are 27 MF, 3 pc-ALCL, 9 LyP, 6 LyP/MF, and 1 pc-ALCL/LyP/MF. The overall response rate is 63% (24/38) with CR of 32% (12/38) (Table 1). Evaluable MF patients (n=24) divided into three groups based on intensity of CD30+ expression in skin tumor cells at baseline, had response rates of 30% (low < 10%; n=10), 37.5% (medium >10-50%; n=6). Complete responses were noted in all primary and secondary LyP patients as well as CD30+ tumors in pc-ALCL and MF patients. Time to response for LyP and ALCL was 3 wks (range 3–6) with median duration of response (DOR) of 22 wks (range 9–30). Time to response was 12 wks (range 3–25) and median duration of response for MF was 12 wks patients (range 6–32). The most common related adverse events of any grade were neuropathy (38%), drug rash (27%), diarrhea (24%), fatigue (24%), alopecia (16%), myalgias (16%), and nausea (14%). Grade 3–4 events were neutropenia (n=3), nausea (n=2), chest pain (n=2), deep vein thrombosis (n=1), transaminitis (n=1) and dehydration (n=1). Dose reductions to 1.2 mg/kg were made for grade 2 neuropathy (n=2), transaminitis (n=1) and arthralgias and fatigue (n=1). One pc-ALCL patient with tumor regression died from infection after one dose; one withdrew due to infusion reaction. Conclusion: This phase II clinical trial demonstrates that brentuximab vedotin is an effective and safe targeted therapy for the spectrum of CD30+ CTCLs - MF, pc-ALCL, and LyP with an overall response rate of 63% in all evaluable patients and 100% in LyP/pc-ALCL. Although highest response rates correlated with highest CD30+ expression, low expression patch/plaque MF responded following additional treatment cycles. Disclosures: Duvic: seattle genetics: Consultancy, Research Funding. Off Label Use: This is a conjugated antibody approved for HD and ALCL tested in a phase II trial for another indication - CTCL CD30+. Tetzlaff:Seattle Genetics: Consultancy.

Abstract 1638 Background: Lenalidomide is currently being used in various hematological malignancies and solid tumors. The mechanism of action is unknown, but appears to be immune-mediated with stimulation of T- and NK cell function, induction of Th1 cytokine production and cytotoxic activity. The biologic effects of lenalidomide in relapsed CTCL have not been defined. We performed a phase II multicenter trial in relapsed CTCL patients, and investigated the immunomodulatory effects of lenalidomide in a subset of the patients. Methods: Thirty-five heavily pretreated patients (median prior tx 7; range, 1–14) have been enrolled with 28 and 32 patients evaluable for response and toxicity, respectively. The first 18 enrolled patients received 25 mg daily for 21 days with 7 days rest of a 28-day cycle. Because of unacceptable cutaneous flare reactions, the study was amended and subsequent patients received a starting dose of 10 mg and then titrated up to 25 mg as tolerated. A subset of patients underwent immunomodulatory assessment. Blood samples of 6 patients before and 3 weeks into therapy have been analyzed by flow cytometry for various T- and NK cell subsets. Results: Clinical stages were: 7 (24%) stage IB, 2 (7%) stage IIA, 4 (14%) stage IIB; 6 (21%) stage III; 8 (28%) stage IVA, 1 (4%) stage IVB. The overall response rate was 32% (9 pts-all PR with 25 mg daily dose) with median response duration of 5 months (range, 1–12+). The stable-disease rate was 61% (17 pts), and 7% (2 pts) had PD. The median time to first response was 3 months (range, 1–5). Grade 3 adverse events were fatigue (22%), infection (9%), leukopenia (3%), and neutropenia (3%). No grade 4 toxicity occurred. Eight patients (25%) experienced grade 1 or 2 tumor flare after starting treatment with lenalidomide. There was less flare in patients dose escalated. When compared with baseline levels, 4 of 6 patients screened for immunomodulatory changes revealed a decrease in CD4+ T-cells (range, 24% – 68%) with concomitant decrease in CD4+CD25+ T regulatory cells (range, 18% to 87%). When compared to clinical response 2 of these patients achieved PR and 2 patients remained stable during therapy. The remaining 2 patients (2× SD) experienced an increase of CD4+ T-cells (2%, 43%) with increase of CD4+CD25+ T regulatory cells (50%, 73%). Conclusions: In our study oral lenalidomide demonstrates activity in patients with relapsed/advanced CTCL consistent with activity of other currently available agents, with a manageable toxicity profile. Our data suggest that the immunomodulatory cutaneous effects of lenalidomide could be associated with decreased Treg and correlates with blood CD4+ T-cell number. Skin biopsies from 6 patients are being investigated for cytokine expression before and during therapy. Use as maintenance therapy or in combination with other biologic agents is worth investigating. Disclosures: Off Label Use: Lenalidomide. Rosen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:kyowa: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Consultancy. Kuzel:Celgene: Research Funding, Speakers Bureau.

Abstract 882 Background: PLD is approved for treatment of Kaposi's sarcoma and concentrates highly in the skin. Overall response (ORR: complete response [CR] + partial response [PR] rates) ranging from 56% to 88%, and CRs from 20% to 44% have been reported with PLD in CTCL patients (pts) without strictly defined response criteria (Cancer 2003; 98: 993–1001; Arch Dermatol 2008; 144: 727–33) Bex is a synthetic retinoid with an ORR of approximately 50% in relapsed/refractory CTCL (J Clin Oncol 2001; 19: 2456–71; Arch Dermatol 2001; 137: 581–93). To clarify the true ORR for PLD and to assess whether the ORR and remission durations can be improved by sequential Bex following PLD, a multi-institutional phase II trial was undertaken for pts with advanced stage/refractory CTCL. Methods: Pts were treated with PLD 20mg/m2 IV every 2 weeks for 8 doses (16 weeks) followed by 16 weeks with Bex 300mg/m2 orally. Response assessments were performed after 8 (PLD) and 16 weeks (Bex). The Severity-Weighted Assessment Tool (SWAT) (Arch Dermatol 2002; 138: 42–8) was the primary measure of skin response with the Composite Assessment of Index Lesion Severity (J Clin Oncol 2001; 19: 2456–71) and a self-reported pruritus scale as secondary measures. For stage IV pts with baseline lymphadenopathy, CT of chest, abdomen and pelvis was repeated. Sézary cell count and/or flow cytometry were repeated for patients with Sézary syndrome. Pts with complete disappearance of skin lesions on examination were deemed to have a clinical CR (CCR) in skin. A repeat skin biopsy without evidence of disease changed CCR to full CR. Results: All of the planned 37 pts with stages IV (21 including 7 Sézary syndrome), IIB (10) or refractory earlier stage (6) CTCL have been enrolled and have completed 32 weeks of treatment. Median age was 56 years (27–81). There were 20 males and 17 females. All pts had prior topical treatment with or without irradiation. Fourteen pts had no prior systemic therapy; while23 pts had prior systemic therapies (median 2, range 1–11). Median follow-up for surviving pts is 7.54 months (0.7–41.9). Thirty-four pts were assessable for response (2 withdrew consent, 1 died of disease progression 5 days after initiation of 1st cycle). For 34 assessable pts: ORR 14/34 (41%: PR 12, CCR 2). Maximum responses were all seen after 16 weeks PLD. Median progression free survival (PFS) is 4.82 months. To date, 18 pts have died of disease progression and 1 patient died of CHF which occurred 3 months after last study intervention. That patient had a pretreatment left ventricular ejection fraction of 60%. Treatment-related grade 3/4 serious adverse events occurred in 9 pts: 4 tumor pain, 2 (grade 3) hand-foot syndrome, 1 infection- unknown ANC- skin (cellulitis), 1 infection- normal ANC- skin (cellulitis), 1 neutropenia. Conclusions: With strict criteria, PLD ORR is among the highest reported for single agents in CTCL but lower than previously reported. The population contained a high proportion of patients with advanced disease as reflected in the initial stage and the poor survival. Sequential bexarotene did not increase the response rate or duration. Disclosures: Horwitz: Celgene: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Merck: Honoraria; Millennium: Consultancy; Genzyme: Research Funding.

Abstract 3916 Introduction: Multiple myeloma is clinically and biologically heterogeneous. Certain translocations and chromosomal losses (t{14;16}, t{14;20}, del 17p) and gene expression profiles define high-risk disease. Recently, several groups found microRNAs (miRs) dysregulated in multiple myeloma. A profile composed of 28 miRs was found to define high-risk disease. Among the dysregulated miRs, miR15a, miR16 were down-regulated, miR19b, miR20a, miR181b were increased according to most publications. MiR-21 was generally upregulated in high-risk disease and inducible by interleukin-6. We hypothesized that commonly administered treatments for multiple myeloma would alter the expression pattern of these miRs. Materials and Methods: For these in-vitro experiments, 4 established cell lines were used: RPMI8226, OPM-2 (t4;14), Kas-6 (IL-6-dependent) and MM1-S (t14;16). The cells were treated with ionizing radiation (3- 6 Gy), lenalidomide (10 μM), doxorubicin (50 ng/ml), bortezomib (2- 50 nM), SAHA (1–3x 10−6 M), pegylated interferon α (3–300 ng/ml) and nutlin-3 (10 μM) between 2 and 48 hours. RNA was extracted and quantitative real-time RT-PCR was performed for miR-15a, miR-16, miR19b, miR-20a, miR21, miR-181b and a control gene (U6). The expression was calculated and compared by the ΔΔ CT method. Results: Ionizing radiation increased miR15a in 1/2 cell lines at early time points, increased miR-19b at early time points in 2/2 cell lines (decreased later) and increased MiR20a in 2/2 cell lines at early time points. Lenalidomide induced miR15a in 2/4 cell lines, miR19b in 3/ 4 cell lines and miR-20a in 3/ 4 cell lines. Doxorubicin increased miR-16 in 2/3 cases and miR-20a in 2/3 cases (in 1 cell line decreased). Bortezomib overall induced few changes in miR-expression. SAHA induced miR-15a in 2/3 cell lines and decreased miR-16 in 1/3. MiR-19a was decreased with SAHA in 2/4 and increased in 1/4 cell lines. MiR-20 decreased in 1/4 and increased in 1/4. MiR-21 decreased in 1 and increased in 1/4 SAHA-treated cell lines. MiR-181b increased in 2/4 cell lines. Pegylated interferon decreased MiR-15a in 3/4 cell lines, decreased miR-16a in 3/4 cell lines, increased miR19b in 2/4 cell lines. MiR-20a was increased in 2/4 and decreased in 1/4 cell lines. MiR-181b was decreased in 2/ 4 cell lines. Nutlin-3 increased miR16 in 1/3 cell lines, increased miR-20a in 2/4 cell lines, increased miR-181b in 2/4, decreased miR-181b in 1/4 cell lines. Most changes observed are in the range of −50 – + 200%. Conclusions: Many miRs are induced at early time points under non-cytotoxic conditions. The variability observed in these experiments may be due to the genetic heterogeneity of the cell lines. Interferon mostly down-modulates the expression of the miRs studied. Previous experiments, for example using endothelial cells also showed an induction of certain miRs after cytotoxic or cytostatic treatments. This can be explained as a stress response or protective mechanism enhancing tumor cell survival. However, the functional relevance of our data was not investigated. The downregulation of miRs following interferon treatment is surprising and would argue for a combination of interferon with cytostatic treatments. If confirmed using CD138 selected samples from patients with multiple myeloma, our data may be used to develop a treatment profile which ultimately might prognosticate treatment response. Our results are also relevant for future miR-based treatments for multiple myeloma. Disclosures: Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 444 The CC chemokine receptor 4 (CCR4) is expressed on malignant T-cells in cutaneous T-cell lymphoma (CTCL) and also on the surface of regulatory T cells (T-regs). T-regs also express the transcription factor, foxp3 and suppress effector immune cells, including natural killer (NK) cells. Thus, increased T-regs in the tumor microenvironment is associated with impaired anti-tumor immunity. KW-0761, a defucosylated, humanized monoclonal antibody, binds to CCR4 and induces effective antibody-dependent cellular cytotoxicity (ADCC) against CCR4+ malignant T-cells. The phase I/II clinical trial to determine the safety and efficacy of anti-CCR4 antibody (KW-0761) included a translational component to evaluate its effects on T-regs and NK cells in CTCL patients. Peripheral blood mononuclear cells (PBMCs) were collected from 20 patients [10 with mycosis fungoides (MF) and 10 with Sézary syndrome(SS)] pre- and post-treatment at two centers for flow cytometry analysis of CD3+CD4+CD25+CD127- T-regs, CCR4+ T-regs, and CD3-CD56+CD16+ NK cell subsets. Total RNA was extracted from PBMCs, and foxp3 and CCR4 mRNA were quantified using real-time PCR. The standard 4-hour 51Cr release assay was used to assess the cytotoxicity of NK cells. Fifteen of 20 patients (75.0%) had detectable CD3+CD4+CD25+CD127- T-regs (1.26±1.09 % or 33.79±46.88 /μl) at baseline with 60 –100 % of T-regs positive for CCR4. After 4–6 weeks of treatment with anti-CCR4 antibody (KW-0761), all 15 patients had a decrease in T-reg numbers (0.39±0.49 % or 5.65±8.95 /μl, *p Our results suggest that in addition to ADCC towards malignant T-cells, the anti-neoplastic activity of the anti-CCR4 antibody (KW-0761) may include a reduction in T-regs in most CTCL patients and a subsequent increase in NK numbers and function in some patients. Follow up studies need to be performed to confirm these findings. Disclosures: Ni: KYOWA HAKKO KIRIN CO., LTD: Research Funding. Kim:kyowa: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Consultancy. Duvic:KYOWA HAKKO KIRIN CO., LTD: Research Funding.

Abstract 4158 Background: CTCLs are rare, extranodal non-Hodgkin's lymphomas characterized by the accumulation of malignant T lymphocytes in the skin; mycosis fungoides (MF) and Sézary syndrome (SS) are the most common variants. Their clinical course is typically chronic and progressive, despite multiple therapeutic interventions. Observational studies of patients with CTCL, although limited by rarity, are necessary to improve understanding of prognostic factors. Aims: The goals of this analysis were to describe the initial disease characteristics, prognostic factors, and natural history of disease observed in 44 patients with CD25-positive, recurrent/persistent CTCL included in the placebo arm of Study L4389-11. We were particularly interested to determine if there were any characteristics peculiar to the 16% of patients treated with placebo who were observed to have a response in this study. Methods: This multicenter, randomized, double-blind, placebo-controlled phase III trial compared 2 different doses of denileukin diftitox (9 or 18 μ g/kg/day) with placebo in 144 patients with histopathologically confirmed stage IA to III MF/SS who had received ≤3 previous therapies. Medications essential for patient welfare (cardiac medications, narcotics, anti-nausea agents, vitamins, or laxatives) and transfusions were also allowed. The primary efficacy endpoint was overall response rate (ORR); progression-free survival (PFS) was a secondary endpoint. Relationships between baseline covariates and clinical outcomes were assessed by multivariate regression analyses. Results: Placebo-treated patients had a median age of 59.0 years, and the majority were white (77.3%), had early-stage disease (stage Conclusion: The findings from this study demonstrate that responses can be observed in patients with MF/SS in the absence of anti-tumor treatment. Likely contributing factors to these ‘spontaneous responses' are the use of systemic antibiotics, aggressive ‘rescue medication' use and the waxing and waning nature of skin lesions, particularly in early-stage disease. All future studies should carefully document the use of systemic antibiotics during therapy. These results can serve as standard comparators for other active-treatment studies that lack a placebo control arm. Disclosures: Prince: Eisai: Consultancy, Honoraria. Duvic:Eisai: Consultancy, Research Funding, Speakers Bureau. Assaf:Eisai: Consultancy, Honoraria. Straus:Eisai: Consultancy, Honoraria.

Abstract 2863 Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's lymphomas typically characterized by skin patches, plaques, and tumors. Although CTCL primarily develops in the skin, it may progress to involve lymph nodes, blood, and visceral organs. Denileukin diftitox (DD) is a recombinant fusion protein that targets the interleukin-2 receptor found on malignant T lymphocytes. In a Phase III trial in DD-naïve patients with CD25 assay-positive CTCL (the approved indication for DD), patients treated with DD 9 and 18 μg/kg/day had overall response rates (ORR) of 37% and 46%, respectively, compared with 15% in the placebo arm. Here we analyze results from a multicenter, international, open-label phase 3 study that included a cohort of patients previously treated with DD to determine the benefit of DD retreatment following disease progression. Methods: Study L4389-14 was designed to ascertain the efficacy and safety of DD in patients with stage IA-III CTCL, receipt of ≤3 previous therapies, and life expectancy ≥12 months. The current analysis focuses on the subgroup of CD25-positive patients who experienced response to DD 9 or 18 μg/kg/day in previous clinical trials but who then relapsed. Retreatment consisted of DD 18 μg/kg/day intravenously on Days 1–5 of a 21-day cycle for up to 8 courses. Response assessment was based on the percentage change in tumor burden at each study visit based on a global, weighted score of skin, lymph node, and blood involvement, and responses were confirmed in 3 consecutive DD courses. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), time to treatment failure (TTF), and safety. Results: Twenty patients with CD25-positive CTCL received DD retreatment (4 had complete response to the prior DD treatment, 13 had partial response to prior treatment, 1 had stable disease as prior response, and 2 had unrecorded prior response). At baseline, these patients had a median age of 59.5 years, 70% were male, 80% were white, and 80% had early-stage disease (stage ≤IIA). The 20 patients received a median of 8 courses of DD retreatment. Overall, 40% (8/20) of patients had a secondary response, the majority of which were partial responses (30%; 6/20). Secondary response rates for patients with baseline CTCL stages ≤IIA and ≥IIB were 38% (6/16) and 50% (2/4), respectively. Kaplan-Meier estimated median time to response for the intent-to-treat population was 102 days, and the median duration of response was 274 days. Progression events were observed for 9 patients, all of whom had stage ≤IIA disease at baseline. Kaplan-Meier estimated median PFS for the intent-to-treat population was 205 days (95% CI: 170–429 days), and the median TTF was 189 days (95% CI: 72–429 days). In total, 85% of patients had a treatment-related adverse event (AE), 55% had a treatment-related grade 3/4 AE, and 5% had a treatment-related serious AE. The most common treatment-related AEs were nausea (35%), fatigue (25%), headache (15%), rigors (20%), and pyrexia (10%). The 1 treatment-related serious AE involved pleural effusion. Conclusion: Patients with CD25-positive CTCL who had been treated previously with DD and subsequently relapsed were able to show durable responses upon retreatment. The observed ORR of 40% was similar to that seen with primary treatment with an estimated median duration of response of 9.8 months. Disclosures: Duvic: Eisai: Consultancy, Research Funding, Speakers Bureau. Olsen:Eisai: Research Funding; Merck: Consultancy, Research Funding; Gloucester: Consultancy; Yaupon: Research Funding; Biocryst: Research Funding; Johnson & Johnson : Consultancy, Research Funding. Fivenson:Amgen: Honoraria, Research Funding, Speakers Bureau; Dermik: Research Funding; Centrocor: Honoraria, Research Funding; Abbott: Honoraria, Research Funding, Speakers Bureau; Warner Chilcott: Honoraria, Speakers Bureau; Allergan: Research Funding; Ferndale: Research Funding; Graceway: Research Funding; Biolife: Consultancy, Research Funding; Merck: Honoraria, Research Funding; Pfizer: Research Funding; Galderma: Honoraria, Research Funding; Aspreva: Research Funding; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Perrigo: Research Funding; Organogenesis: Research Funding; Ligand: Research Funding; Connetics: Research Funding; Stiefel/GSK: Honoraria; Clay-Park Labs: Research Funding; Jacobus: Research Funding; Smith and Nephew: Research Funding; Dow Pharma: Research Funding; Therakos: Research Funding; Seragen: Research Funding; Convatec: Research Funding. Prince:Eisai: Consultancy, Honoraria.

Abstract 3973 Histone deacetylase inhibitors (HDACi), including vorinostat (SAHA), depsipeptide (FK228), panobinostat (LBH589), belinostat (PXD101), and entinostat (SNDX275), show in-vitro and clinical activity against cutaneous T-cell lymphoma (CTCL) cell lines and patients' skin lesions [Zhang & Duvic, Expert Rev Dermatol 5: 393–401, 2010]. Vorinostat and depsipeptide were recently approved [Duvic et al, Blood 109: 31-9, 2007; Olsen et al, J Clin Oncol 25: 3109-15, 2007; Piekarz et al, J Clin Oncol 27: 5410-7, 2009], at response rates of 29% and 42%, respectively, but development of resistance remains an important clinical problem. Because we have shown that curcumin, the active ingredient of turmeric, exhibits anti-cancer activity through selective induction of tumor T-cell apoptosis and inhibition of NF-κB signaling in CTCL [Zhang et al, J Invest Dermatol 130: 2110-9, 2010], we now investigated whether curcumin combined with HDACi has synergistic anti-tumor effects in CTCL. HDACi-resistant MJ, HDACi-sensitive HH and HDACi cross-resistant HH/VOR CTCL cells were treated with HDACi (panobinostat, vorinostat, or enlinostat) plus or minus curcumin for up to 48 hrs. Cell viability was examined by the MTS assay and apoptosis by FACS analysis of annexin V/PI binding populations and/or cell cycle distribution. The NF-κB signaling pathway was analyzed by electrophoretic mobility gel shift assay and Western blotting. In MJ and HH cell lines, 5 nM panobinostat induced 1.4% and 11.4% apoptosis and 10 μM curcumin induced 24.5% and 29% apoptosis compared to vehicle controls. Panobinostat combined with curcumin induced 46.9% and 83.4% apoptosis in MJ and HH cell lines, respectively. Of interest, the HDACi cross-resistant HH/VOR CTCL cells were sensitive to curcumin alone and curcumin further enhanced panobinostat-induced apoptosis by 30% in the HH/VOR CTCL cells. Moreover, panobinostat combined with curcumin synergistically suppressed the DNA binding of NF-κB and decreased protein expression of the NF-κB activator RANK and NF-κBp65. Synergism was associated with down-regulation of NF-κB-regulated anti-apoptotic proteins (bcl-2, bcl-xL, and survivin), anti-proliferative proteins (c-myc and cyclooxygenase-2), and pro-invasive protein matrix metalloproteinase-9. Similar synergism was also seen when vorinostat or entinostat was combined with curcumin. These results suggest that HDACi could be combined with curcumin to enhance apoptosis of malignant T-cells through inhibition of NF-κB signaling in CTCL. Curcumin alone and in combination with HDACi may be an attractive strategy for the treatment of HDACi-refractory CTCL patients. Disclosures: Zhang: Novartis: Research Funding. Duvic:Novartis: Research Funding.

Abstract 2800 Background: Pralatrexate (FOLOTYN®) is an antifolate designed for preferential tumor uptake and accumulation. Pralatrexate was granted accelerated approval by the US Food and Drug Administration at a dose of 30 mg/m2 weekly for 6/7 weeks for relapsed or refractory peripheral T-cell lymphoma. Given that cutaneous T-cell lymphoma (CTCL) is often an indolent disease treated in a maintenance fashion, the goal of this trial was to identify a dose with clinical activity and minimal toxicity to allow continuous or maintenance treatment. In the present study, designated PDX-010, the initial dose of pralatrexate for relapsed or refractory CTCL was based on data showing that 30 mg/m2 demonstrated activity in patients with aggressive lymphoma. A dose de-escalation strategy was used in PDX-010 to identify an optimal dose for CTCL. Methods: Eligibility included CTCL histology of mycosis fungoides, Sézary syndrome, or primary cutaneous anaplastic large-cell lymphoma, with disease progression after at least 1 prior systemic therapy, and written informed consent. The starting dose and schedule was 30 mg/m2 of pralatrexate by intravenous (IV) push weekly for 3/4 weeks. If toxicity as defined per the protocol was observed, subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (weekly for 3/4 or 2/3 weeks). All patients received supplementation with vitamin B12 1 mg intramuscularly every 8 to10 weeks, and folic acid 1 mg orally once daily (QD). Response was evaluated by the modified severity weighted adjustment tool (mSWAT) every 2 cycles for 6 months, and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Fifty-four patients were treated across 2 stages of this study. In the dose-finding phase, 31 patients were sequentially enrolled into 6 cohorts and treated at varying doses and schedules. The optimal dose and schedule, as defined in the protocol, was identified as 15 mg/m2 weekly for 3/4 weeks, based on the tolerability and efficacy (overall response rate [ORR] of 50%) observed in the initial 6 patients in that cohort. Among the 31 patients in the dose-finding stage, the ORR for patients treated at a dose intensity ≥15 mg/m2 weekly for 3/4 weeks was 61% (11/18), and the ORR for those patients treated in lower-dose cohorts was 8% (1/13). The second stage of the study included 23 additional patients treated at 15 mg/m2 weekly for 3/4 weeks, for a total of n = 29 patients treated at this optimal dose. Among these 29 patients, the median number of prior systemic therapies was 4.5 (range 1 to 11), and patients received pralatrexate for a median of 4 cycles (range 1 to 23). Patients enrolled in this cohort could be dose-escalated at investigator discretion if there was an absence of toxicity and a response < CR. At this time 53/54 patients treated in this study are evaluable for efficacy, including 28/29 patients treated at 15 mg/m2 for 3/4 weeks. At the optimal dose, the ORR was 43% (12/28) and 50% (20/40) in patients treated at a dose intensity ≥15 mg/m2 weekly for 3/4 weeks. At the optimal dose/schedule, grade 1–2 adverse events (AEs) occurring in >10% were fatigue (34%), mucositis (28%), nausea (24%), edema (24%), epistaxis (21%), pyrexia (17%), constipation (14%), and vomiting (14%). The only grade 3 AE in >10% was mucositis (17%). Hematologic toxicities were limited to grade 3 neutropenia (3%), grade 1–2 anemia (14%), grade 3 anemia (3%), grade 1–2 thrombocytopenia (7%), grade 3 thrombocytopenia (3%), grade 1–2 leukopenia (3%), and grade 4 leukopenia (3%). No grade 4 nonhematological toxicities were observed. Conclusions: Pralatrexate shows high activity with acceptable toxicity in patients with relapsed or refractory CTCL at the identified optimal dose and schedule of 15 mg/m2 weekly for 3/4 weeks. The lack of significant hematologic toxicity or cumulative toxicity seen in this study suggests that pralatrexate should be further evaluated as continuous or maintenance therapy for patients with CTCL. Final efficacy and tolerability data will be reported. Disclosures: Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Lechowicz:Allos Therapeutics, Inc.: Consultancy; Celgene Corporation : Consultancy. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding.

Abstract 962 Introduction: KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is over expressed in PTCL and CTCL, and is a potential target for anti-neoplastic therapy in these disorders. Study Design: This multicenter, open-label, dose escalation phase 1/2 study is in patients with previously treated PTCL and CTCL (including MF and SS). The study is composed of a dose escalation phase (Phase 1) and preliminary assessment of safety and efficacy (Phase 2). The phase 1 portion is a standard 3+3 design at doses of 0.1, 0.3, and 1 mg/kg. In the first treatment course, KW-0761 is administered i.v. once a week for four weeks, followed by a 2-week observation period. Subjects demonstrating a response or maintaining stable disease may receive additional infusions of KW-0761 every other week until progression or withdrawal from study. For CTCL patients, the overall global response score is a composite of response in all compartments (skin, lymph nodes, viscera). For subjects with Sezary Syndrome (SS), response in blood is also considered for overall response. For PTCL patients, the response is based on criteria defined by the International Working Group (IWG). Results: Forty-two patients who had received at least one prior systemic therapy (median 5; range 1–17) are enrolled. The median age is 67 (range: 35–85) years with more males (57%) than females (43%). A total of 40 patients received at least four doses of KW-0761 at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3) and 1 mg/kg (n=34). There are no dose limiting toxicities (DLT) or drug-related serious adverse events (SAEs) reported in the dose escalation portion of the study. Most observed adverse events (AEs) are mild to moderate in severity. There does not appear to be any dose relationship with the incidence or severity of the AEs. The most frequent AEs are chills, headache, nausea, pyrexia, infusion related reactions and back pain. There does not seem to be an increase in the rate of infections associated with the use of this drug. Six of 42 patients who received at least one dose of KW-0761 developed a new skin eruption not consistent with the patients' underlying disease, including one grade 3 hypersensitivity rash with eosinophils. No significant hematologic AEs have been observed except for lymphopenia which is due to the pharmacologic effect of the drug. A total of 38 patients (23 with MF; 15 with SS) are evaluable for efficacy (only one subject with PTCL was enrolled and is not included in this analysis). A summary of all patients evaluable for efficacy to date is presented in the table belowa: Conclusions: KW-0761 is well tolerated at doses of 0.1–1.0 mg/kg. The MTD has not been reached in this study. The overall response rate is 39% for all patients in the phase 1/2 trial with a higher rate in SS patients (47%) versus MF patients (35%). Additionally, 12 of 15 SS patients had a response in the blood, including 7 CRs. These promising results warrant further clinical studies using KW-0761 in refractory or relapsed CTCL patients. Disclosures: Duvic: Kyowa-kirin-pharma.com: Consultancy, Research Funding. Pinter-Brown:Kyowa-Kirin: Consultancy, Research Funding. Foss:Kyowa-Kirin: Consultancy, Research Funding. Sokol:Kyowa-Kirin: Research Funding. Jorgensen:Kyowa Hakko Kirin Co, Ltd.: Research Funding. Spitalny:Kyowa-Kirin: Employment. Kim:Kyowa-Kirin: Consultancy, Research Funding.

2683 Poster Board II-659 Background: Responses to romidepsin, a novel pan-HDAC inhibitor, have been observed in patients (pts) with cutaneous T-cell lymphoma (CTCL) in 2 phase 2 studies. One of these studies, the pivotal study was a phase 2, single-arm, open-label study that enrolled 96 pts with CTCL (Stages IB–IVA) at 33 European and US sites. The objective response rate (ORR) was 34% including 6 complete clinical responses (CCR) in all treated pts. Responses (including CCRs) were seen across all stages of disease with a 42% ORR in stage ≥IIB. The median duration of response (DOR) was 14.9 months (mo). The safety profile was characterized principally by mild (grade 1 and 2) gastrointestinal disturbances, hematologic toxicities, clinical chemistry abnormalities and asthenic conditions [Kim, et al. Blood (ASH Abstracts), Nov 2008; 112: 263]. This report summarizes the analysis of 37 pts in the study with blood involvement (Sezary cells >5% circulating lymphocytes at baseline). Methods: Pts who failed ≥1 prior systemic therapy, had adequate organ function, and ECOG PS 0 or 1 were eligible. Exclusions included significant cardiovascular abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. Pts received romidepsin 14 mg/m2 as a 4-hr IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles (extended for stable disease [SD] or response). Response was measured with a quantitative composite which included skin involvement [severity-weighted assessment tool (SWAT) or erythroderma scale], lymph node involvement (CT or MRI scans), and blood involvement (circulating Sezary cells assessed by flow cytometry). Pruritus was assessed by visual analog scale (VAS). Pts with baseline VAS ≥30mm were included in pruritus analysis. Results: Of the 37 pts with >5% circulating Sezary cells, 27 (73%) met the definition of evaluable (received ≥2 cycles of romidepsin) for efficacy. 8 of these 27 pts with blood involvement had a greater blood tumor burden (Sezary cell counts >1000 cells/mm3 and/or Sezary cells >20% of lymphocytes). Mean age was 57±13 yrs and median number of prior systemic therapies was 6 (range 1–14) for all pts. 17 (46%) pts received prior bexarotene and 5 (14%) received prior denileukin diftitox. Response (by composite assessment) and pruritus relief data for the evaluable pts are included in the [table][1]. Pts who achieved a response had a rapid, dramatic and durable reduction in Sezary cell counts. ORR was 32% by composite assessment in all pts including 2 CCRs. 5 pts who responded had received bexarotene (including 1 CCR) and 2 had received both denileukin diftitox and bexarotene. The median DOR (for pts with a response by composite assessment) has not been reached; the maximum DOR was 19.8 months. 12 of 27 evaluable pts had erythroderma; 5 of these pts had ≥50% response in skin (4=partial response [PR], 1=SD by composite assessment). 16 of the 37 as-treated pts had erythroderma; 6 of these pts had '50% response in skin (4=PR, 2=SD by composite assessment). | | Evaluable Pts Lower blood tumor burden N=27 | Evaluable Pts Higher blood tumor burden N=8 | |:---------------------------------------------------------------- | ------------------------------------------- | ------------------------------------------- | | Confirmed ORR | 41% | 50% | | CCR, n (%) | 2 (7%) | | | PR, n (%) | 9 (33%) | 4 (50%) | | Median DOR (months) (range) | NE (1.6+-19.8+ months) | NE (5.6+ - 8.5+ months) | | Relief of pruritus[a][2], n (%) Relief of severe pruritus, n (%) | 9/19 (47%) 4/9 (44%) | 3/6 (50%) 3/5 (60%) | * NE, not estimable * [↵][3] a relief = ≥ 30mm decrease on 100mm VAS or score of 0 for 2 consecutive cycles The safety profile in this subset of 37 pts is similar to the overall safety profile of romidepsin in this study and the overall safety profile of romidepsin. No unusual drug-related adverse events were observed. Conclusions: This study shows clinical benefit associated with romidepsin treatment in a heavily pre-treated group of pts with CTCL with blood involvement. Additional treatment options are needed for these pts. The ORR (32%) in all pts in this group was comparable with the ORR in the entire study (34%). Toxicities associated with romidepsin were tolerable and manageable. The new drug application for the use of romidepsin in CTCL is under review at the FDA. Disclosures: Robak: F Hoffmann-La Roche: Honoraria. McCulloch: Gloucester Pharmaceuticals: Consultancy. Whittaker: Gloucester Pharmaceuticals: Research Funding. [1]: #T1 [2]: #fn-2 [3]: #xref-fn-2-1

Abstract 3745 Poster Board III-681 Cutaneous T-cell lymphoma (CTCL) is a disorder of CD4+ helper T-cells with manifestations in the skin, nodes, and, in advanced stages, blood and visceral sites. For many patients, the clinical course of the disease is chronic and progressive, despite multiple therapeutic interventions. To date, are few controlled clinical trials which demonstrate durable complete responses (CR) in advanced stage patients. Denileukin diftitox (DD) is a recombinant fusion protein targeting interleukin-2 receptor which has demonstrated efficacy in early and advanced stage CTCL with response rates of 30% and 44% in two clinical trials of CTCL pts with Stage Ib-IVA relapsed and refractory CTCL or Stage I-III disease, ≤3 prior therapies respectively. In these trials, patients (pts) were randomized to receive DD at a dose of either 9 or 18 ug/kg/d daily x 5 every 21 days. Another rollover trial enrolled pts who had progressed after prior response with DD (N=29) or were CD25- (N=36); all pts in the rollover trial were treated with DD at 18ug/kg dose. Of 263 intent-to-treat pts in these trials, 227 had CD25+ skin infiltrates by immunohistochemistry (IHC) confirmed by a reference pathologist and 36 were CD25-. Overall, 24 (9.1%) pts attained durable complete response (CR). The median age of the responders was 59, and 12 CR pts were over age 60. Of the CR group, 15 pts had early stage (I-IIa) disease and 9 had advanced stage (IIb-IV) CTCL. The mean prior therapies was 3.6 with 37% of patients having received >3 therapies. Of the 24 CR pts, 21 were CD25+ and 3 were CD25-. Two CR were pts who had previously responded to DD in an earlier clinical trial. Of all pts receiving 9 ug/kg dose (N=80), there were 6 (7.5%) CR; for all pts receiving 18 ug/kg dose (N=183), there were 18 (9.8%) CR. There was no significant difference frequency of CR between the 9 and 18 ug/kg groups (P=0.56) or between the CD25+ (N=118) and CD25- (N=36) pts treated at 18 ug/kg dose (P=0.64). CR rate was similar between the early and advanced stage patients (10.7% vs 8.9% respectively). The median time to response was 53.5 vs 41days for CD25+ pts treated in the 9 and 18 ug/kg groups respectively, and 43 days for the CD25- group. The response durations ranged from 57 days to >1325 days in the CD25+ and 190-400 days in the CD25- groups. Of the 24 CR, 7 have progressed as of the time of the analysis and 17 remain in CR. The overall median PFS at the time of analysis has not been reached (range 169-1388+ days). Of the 24 CR, 3 pts had hypersensitivity reactions and 3 had capillary leak syndrome associated with DD treatment. In summary, these studies demonstrate clinical benefit of DD with CR in both early and advanced CTCL at both 9 and 18 ug/kg doses and with durable responses in a small number of pts whose malignant lymphocytes were CD25- by ICH. Disclosures: Foss: Eisai : Speakers Bureau. Olsen:Eisai: Research Funding. Kozlovski:Eisai Pharm: Employment.

Abstract 1732 Poster Board I-758 Vorinostat (suberoylanilide hydroxamic acid, SAHA), a pan-histone deacetylase (HDAC) inhibitor, has an overall response rate of 24-30% in two phase II studies of patients with cutaneous T cell lymphoma (CTCL). Since a considerable proportion of CTCL patients did not reach a partial response and loss of response could occur after only a few months, development of resistance became an important clinical problem. Although we have shown that constitutive activation of STAT signaling may be involved in resistance to vorinostat, the other mechanisms of resistance to vorinostat in CTCL are largely unknown. To further investigate mechanisms of vorinostat resistance, we have generated a vorinostat-resistant CTCL cell line (HH/VOR) from a parent vorinostat-sensitive HH CTCL cell line by long term exposure to stepwise increasing concentrations of vorinostat. The HH parental cells were cultured in increasing concentrations of vorinostat starting at 10 nM. Viable cells were then passaged into a higher concentration of vorinostat in 10 nM increments until a concentration of 1 μM vorinostat was reached. The HH/VOR cells were then maintained in complete RPMI1640 medium containing 1 μM vorinostat. We studied the molecular and biological characteristics of the vorinostat-resistant CTCL cells. Compared with the parental vorinostat-sensitive HH cells, the vorinostat-resistant HH/VOR cells were highly resistant to vorinostat-mediated growth inhibition and apoptosis. Of interest, the HH/VOR also exhibited cross resistance to another pan-HDAC inhibitor panobinostat and a class I HDAC inhibitor SNDX-275. The vorinostat-resistant HH/VOR cells had reduced accumulation of acetylated histones (H3 & H4) and decreased expression of class I and class II HDACs (1-11), and no expression of multi-drug resistant (MDR) efflux transporters. Moreover, the vorinostat-resistant HH/VOR cells had elevated DNA binding of NF-κB and increased expression of phospho-NF-κB p65 and phospho-STAT-1 compared with the parent sensitive HH cells. Co-treatment with the RXR-selective retinoid bexarotene selectively enhanced vorinostat-induced apoptosis in the vorinostat-sensitive HH and -resistant HH/VOR CTCL cell lines as well as in patients' Sézary cells compared to normal CD4+ T-cells. Taken together, our findings provide further evidence for the potential of vorinostat to cause acquisition of HDAC inhibitor resistance in CTCL. This acquired HDAC inhibitor resistance neither correlates with over-expression of HDACs nor with expression of MDR but correlates with abnormal activation of the NF-κB and STAT-1. Bexarotene may override this acquired resistance of CTCL cells to vorinostat and other HDAC inhibitors. Disclosures Zhang: Merck: Research Funding. Duvic:Merck: Honoraria, Research Funding, Speakers Bureau.

Abstract 3369 Poster Board III-257 Introduction: Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma (CTCL), is defined as erythroderma and >1000 abnormal T-cells per mm3 in the peripheral blood, and is currently incurable. A recent study of erythrodermic CTCL conducted at our center reported a median overall survival of 5.1 years which is twice that in the literature [Vidulich K, et al. Int. J of Dermatol. 2009; 48: 243-252]. Although complete remissions (CR) may be achieved in earlier stages of CTCL, they are rarely achieved in SS patients. Patients and Methods: A retrospective analysis of a prospective database of 1550 CTCL patients seen at the MD Anderson Cancer Center since 1984 identified a subset of 145 SS patients (9%) whose long-term complete responses (>2 years) to various therapies is reported. The most commonly used combination therapies were topical steroids, psoralen with ultraviolet A (PUVA), oral retinoids (isotretinoin, acetretin, or bexarotene), alpha-interferon, and extracorporeal photopheresis (ECP). A combination of total skin electron beam radiation (TSEB) followed by induction chemotherapy and allogeneic stem-cell transplant was given to 23 CTCL patients. Chronic Staphylococcus aureus carriers identified by cultures were treated with antibiotics and preventive skin care. Results: Of the 145 Sézary Syndrome patients, 13 (8.96%) achieved CRs, including 6 females and 7 males. Their median age was 48 (20 to 85 years) at diagnosis. Nine were Caucasian, 3 were African American, and 1 was Hispanic. At initial diagnosis their stages were IB (n=1), stage III (n=3), stage IVA (n=4), and stage IVB (n=5). Six achieved a CR on front-line combination immunomodulatory therapy consisting of ECP with alpha-interferon and/or oral retinoids, antibiotics, and topical steroids. Seven SS patients failed therapy but were able to obtain CRs after TSEB and allogeneic peripheral blood stem cell transplantation (SCT) from matched related donors (n=6) or unrelated (n=1) donors. The conditioning regimen for SCT was fludarabine and melphalan. The median time between diagnosis and CR was 4.07 years (range 1 to 20 years). The median duration of CR is 5 years (mean 5.15 years, range 2 to 13 years). Conclusion: Sézary Syndrome is extremely symptomatic and usually refractory to current therapies. CRs may be achieved using immunomodulatory therapy with biological response modifiers and photopheresis or with total skin electron beam followed by non-ablative allogeneic stem cell transplant in appropriate patients and may have an impact on overall survival. Disclosures: No relevant conflicts of interest to declare.

Abstract 920 Background: Belinostat is a pan-HDAC inhibitor of the hydroxamate chemical class that is well-tolerated and has shown clinical activity. Methods: Open label, multicenter trial enrolling patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Pts received 1000 mg/m2 IV belinostat over 30 min on days 1 to 5 of a 3-wk cycle. Primary endpoint was objective response (OR) assessed by IWG criteria for PTCL and by SWAT (cutaneous lesions) and IWG criteria (non-cutaneous lesions) for CTCL. Pruritus in pts with CTCL was assessed using a 10-point scale; relief defined as reduction of pruritus score of ≥ 3 points in pts with baseline score ≥ 3. ECGs were monitored and reviewed centrally (pre-/ post-infusion ECGs on all treatment days in cycle 1, and pre-/ post-infusion ECGs on day 1 of subsequent cycles) to evaluate potential cardiac toxicity. Results: The study enrolled a total of 53 treated pts, including 20 and 29 evaluable pts with a diagnosis of PTCL and CTCL, respectively. The 20 pts with PTCL [10 PTCL-unspecified (PTCL-U), 3 anaplastic large cell lymphoma (ALCL), 3 angioimmunoblastic TCL (AITL), 3 NK/T-cell lymphoma, and 1 subcutaneous panniculitis-like TCL (SPTCL)] had received a median of 3 prior systemic therapies (range 1 – 10), and 40 % of them had stage IV disease. 5/20 (25%) PTCL pts responded with 2 CR (both in patients with PTCL-U) and 3 PR (PTCL-U, AITL, ALCL). The 5 responding pts had a median duration of response of 159+ days (range 1 – 504+). Additionally, SD was observed in 5 pts (2 PTCL-U, 2 NK/T-cell, and 1 ALCL) with median duration of SD of 109+ days (range 80 -185+). The 29 pts with CTCL [15 mycosis fungoides (MF), 7 Sezary syndrome (SS), 5 non MF/SS, 2 unclassified] had received a median of 1 prior skin directed therapies (range 0 – 4) and 3 prior systemic therapies (range 1 – 9), and 55 % of them had stage IV disease. 4/29 (14%) CTCL pts responded with 2 CR (ALCL, MF) and 2 PR (MF, SS). The 4 responding pts had a median duration of response of 273 days (range 48 - 469+). Importantly, time to response was short with a median of 16 days (range 14-35). In addition, SD was observed in 17 pts (10 MF, 3 SS, 2 non MF/SS, 2 unclassified) with current duration of up to 127 days. Pruritus relief (score reduction ≥ 3) was seen in 7 of 14 pts with significant baseline pruritis. Median time to pruritus relief was also short, 16 days (range 7-45). Hematological toxicity was minimal without any grade 4 events (shift from baseline) and only one pt each experiencing grade 3 neutropenia and grade 3 thrombocytopenia, respectively. No grade 3 QTcF prolongation was detected in more than 700 ECGs. Four grade 3/4 drug-related AEs were reported: pruritis, rash/erythema, edema, and adynamic ileus. Conclusions: Belinostat monotherapy is safe, well tolerated, and efficacious in pts with recurrent/refractory T-cell lymphoma with durable remissions in both CTCL and PTCL. These results are the basis for a pivotal study with belinostat monotherapy in pts with PTCL. Disclosures: Advani: Seattle Genetics, Inc.: Research Funding. Duvic:Topotarget: research support for conduct of clinical trial. Fagerberg:TopoTarget A/S: Employment, Equity Ownership. Foss:Eisai : Speakers Bureau.