Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: A previously unrecognized serious adverse event in a pilot study with romidepsin

Won Seog Kim, J. H. Kim, C. S. Ki, Y. H. Ko, J. S. Kim, W. S. Kim

Research output: Contribution to journalArticle

26 Citations (Scopus)

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). Patients and 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.

Original languageEnglish
Article numbermdv596
Pages (from-to)508-513
Number of pages6
JournalAnnals of Oncology
Volume27
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

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Natural Killer T-Cells
T-Cell Lymphoma
Human Herpesvirus 4
Histone Deacetylase Inhibitors
Peripheral T-Cell Lymphoma
romidepsin
DNA
Therapeutics
Acetylation
Viral Load
Bilirubin
Intravenous Infusions
Histones
Disease Progression
Fever
Prospective Studies
Safety
Cell Line
Liver

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

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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). Patients and 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.",
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Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients : A previously unrecognized serious adverse event in a pilot study with romidepsin. / Kim, Won Seog; Kim, J. H.; Ki, C. S.; Ko, Y. H.; Kim, J. S.; Kim, W. S.

In: Annals of Oncology, Vol. 27, No. 3, mdv596, 01.03.2016, p. 508-513.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients

T2 - A previously unrecognized serious adverse event in a pilot study with romidepsin

AU - Kim, Won Seog

AU - Kim, J. H.

AU - Ki, C. S.

AU - Ko, Y. H.

AU - Kim, J. S.

AU - Kim, W. S.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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). Patients and 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.

AB - 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). Patients and 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.

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