title: Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients.
abstract: BACKGROUND
  Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients.
  
  
  RESULTS
  Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone.
  
  
  CONCLUSIONS
  Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes.
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.|National Cancer Center Singapore, Singapore, 169610 Singapore.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tang
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Rossella
authors.initials: R
authors.lastname: Marullo
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Shao-Ning
authors.initials: SN
authors.lastname: Yang
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Haelee
authors.initials: H
authors.lastname: Ahn
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Jayeshkumar
authors.initials: J
authors.lastname: Patel
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.|Present address: Genentech, Inc., 1 DNA Way, 444B, San Francisco, CA 94080 USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elstrom
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Furman
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.
authors.forename: John
authors.initials: J
authors.lastname: Leonard
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.|Hematology and Oncology Division, Weill Cornell Medical College, Cornell University, 1305 York Ave, New York, NY 10065 USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065 USA.|Hematology and Oncology Division, Weill Cornell Medical College, Cornell University, 1305 York Ave, New York, NY 10065 USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine
keywords: Chemosensitization; Demethylating agents; Histone deacetylase inhibitors; Lymphoma; Phase Ib