Reactivation of DNA viruses in association with histone deacetylase inhibitor therapy: a case series report

Abstract

Histone deacetylase inhibitors are a class of anti-neoplastic agents that induce growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. A phase II study exploring the efficacy of romidepsin, an histone deacetylase inhibitor, in patients with cutaneous or peripheral T-cell lymphomas was initiated at the National Cancer Institute. To date, over 120 patients with T-cell lymphoma have been treated on a multi-institutional phase II trial of romidepsin. Reactivation of latent DNA viruses including EBV, HBV, and VZV is well described as a consequence of the immune suppression associated with systemic chemotherapy. The incidence of viral reactivation in patients treated with histone deacetylase inhibitors is not yet known. We report the observation of EBV-associated illnesses in 2 patients and the reactivation of HBV in an additional patient treated with romidepsin. These cases may represent reactivation of DNA viruses due to histone deacetylase inhibitor induced immunosuppression, or direct promotion of viral replication via histone deacetylase inhibitor induced chromatin remodeling, or, alternatively, may be related to the underlying disease process. These observations suggest that vigilance for DNA virus reactivation is needed to quantify the risk in patients treated with histone deacetylase inhibitors.

Figures

Figure 1.

Tissue biopsies from Case 1 taken at first presentation (A–C), at first progression post-CHOP+R (D–F), at time of diagnosis of peripheral T-cell lymphoma in 2004 (G–I) and at disease progression in 2006 with NK/T-cell lymphoma from lymph node (D–F) or liver (G–I) biopsies. (A) H & E stain and high power view of lymph node shows atypical lymphoid infiltrate with prominent immunoblastic reaction. (B) CD20 immunostaining reveals numerous B cells including immunoblasts. (C) In situ hybridization studies for Epstein-Barr virus using the EBER probe show scattered positive cells. (D) H&E stain showing atypical lymphoid cells of varied size. Eosinophils are frequent in the background. (E) Tumor cell, some with mitotic figures, are positive for T-cell marker CD3. (F) In situ hybridization studies for Epstein-Barr virus using the EBER probe show no cells positive for EBV. (G) H&E stained section shows highly atypical cells with hyperchromatic, enlarged nuclei with irregular nuclear contours. (H) Tumor cells are positive for T-cell marker CD3 only occasional B cells were identified with the CD20 immunostain (data not shown). (I) In situ hybridization studies for the EBER probe staining the majority of the tumor cells. (J) H&E stained section shows atypical lymphoid infiltrate involving a portal tract. (K) The infiltrate is mainly composed of T cells highlighted by the CD3 immunostain. CD20 stain (data not shown) did not identify B cells at the same area. (L) In situ hybridization with the EBER probe proved to be positive in the tumor cells.