title: Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin.
abstract: BACKGROUND
  Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL).
  
  
  METHODS
  We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity.
  
  
  RESULTS
  A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study.
  
  
  CONCLUSIONS
  Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul wskimsmc@skku.edu.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Departments of Laboratory Medicine and Genetics.
authors.forename: C S
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
authors.forename: Y H
authors.initials: YH
authors.lastname: Ko
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul.
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: W S
authors.initials: WS
authors.lastname: Kim
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000097:blood; D047630:Depsipeptides / Q000009:adverse effects* / Q000627:therapeutic use*; D020031:Epstein-Barr Virus Infections / Q000473:pathology / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D014775:Virus Activation / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin
keywords: EBV reactivation; extranodal NK/T-cell lymphoma; romidepsin