title: Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma.
abstract: The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to "not reached"). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692).
authors.affiliation: Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Sarit E
authors.initials: SE
authors.lastname: Assouline
authors.affiliation: Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Torsten Holm
authors.initials: TH
authors.lastname: Nielsen
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Stephen
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Miguel
authors.initials: M
authors.lastname: Alcaide
authors.affiliation: Centre for Lymphoid Cancer, Department of Experimental Therapeutics, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Lauren
authors.initials: L
authors.lastname: Chong
authors.affiliation: Hematology, QEII Health Sciences Centre, Halifax, NS, Canada;
authors.forename: David
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Departement d'oncologie et hematologie, Hopital Sacre-Coeur, Montreal, QC, Canada;
authors.forename: Axel
authors.initials: A
authors.lastname: Tosikyan
authors.affiliation: Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada;
authors.forename: Vishal
authors.initials: V
authors.lastname: Kukreti
authors.affiliation: Department of Oncology and Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada;
authors.forename: Abbas
authors.initials: A
authors.lastname: Kezouh
authors.affiliation: Department of Pathology, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Tina
authors.initials: T
authors.lastname: Petrogiannis-Haliotis
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Marco
authors.initials: M
authors.lastname: Albuquerque
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Daniel
authors.initials: D
authors.lastname: Fornika
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Sepideh
authors.initials: S
authors.lastname: Alamouti
authors.affiliation: Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Remi
authors.initials: R
authors.lastname: Froment
authors.affiliation: Lady Davis Institute, Department of Oncology and Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada;
authors.forename: Celia M T
authors.initials: CM
authors.lastname: Greenwood
authors.affiliation: Lady Davis Institute, Department of Oncology and Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada;
authors.forename: Kathleen Klein
authors.initials: KK
authors.lastname: Oros
authors.affiliation: Department of Radiology, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Errol
authors.initials: E
authors.lastname: Camglioglu
authors.affiliation: Ozmosis Research, Toronto, ON, Canada;
authors.forename: Ayushi
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Rosa
authors.initials: R
authors.lastname: Christodoulopoulos
authors.affiliation: Quebec Clinical Research Organization in Cancer, Montreal, QC, Canada; and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rousseau
authors.affiliation: Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: Crump
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada;
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
mesh_terms: D000328:Adult; D000368:Aged; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics; D000077767:Panobinostat; D012008:Recurrence; D000069283:Rituximab / Q000008:administration & dosage*
chemical_list: D004273:DNA, Neoplasm; D006877:Hydroxamic Acids; D007211:Indoles; D064326:MEF2 Transcription Factors; C578038:MEF2B protein, human; D009363:Neoplasm Proteins; D000069283:Rituximab; D000077767:Panobinostat