Lenalidomide (LEN) and Epstein-Barr Virus (EBV) Reactivation
Authors: Mezo Melinda , Bjorklund Chad C. , Weiss Lilia , Minton Neil , Freeman John 
Published: October 2019

Abstract
Background: EBV is a common infection that can be reactivated from latency by exposure to chemotherapy and immunosuppressants. The EBV-positive prevalence rate in the adult population is ≈ 80% to > 90% (Serraino et al, J Biol Regul Homeost Agents, 2005). A recent report suggested that Ikaros is an indirect repressor of the immediate-early EBV genes, BZLF1 and BRLF1 (Iempridee et al, J Virol, 2014). Ikaros has also been demonstrated as a LEN-inducible substrate of the cereblon-dependent E3-ubiquitin ligase complex CRL4ACRBN, therefore targeting it for degradation (Chamberlain et al, Nat Struct Mol Biol,2014). These data suggest that both BZLF1 and BRLF1 could be activated by LEN. However, no data suggest that LEN treatment (Tx) leads to activation of EBV lytic replication in patients (pts). In contrast, the downregulation of c-Myc and IRF4, which is facilitated by LEN-induced degradation of Ikaros, may disrupt the c-Myc/IRF4-dependent EBV transcriptional program (Bjorklund et al, Blood, 2014). Thus, LEN could possibly suppress EBV reactivation. Several observations have linked the presence of viral activation and/or the presence of EBV during multiple myeloma (MM) Tx regardless of therapy, suggesting that EBV reactivation could be from a therapy-induced stress response and not from any particular Tx. Additionally, many commonly used therapies in MM have also been shown to reactivate EBV, including glucocorticoids and melphalan (Yang et al, Brain Behav Immun, 2010).
Objective: Our study investigated the impact, if any, of LEN on EBV reactivation in LEN-treated pts by identifying and analyzing all EBV reactivation/infection reports in the Celgene global safety database.
Methods: The overall occurrence of EBV infection during LEN Tx was determined by searching for the MedDRA High-Level Term of "Epstein-Barr viral infection" and Preferred Terms of "Epstein-Barr virus antibody positive," "Epstein-Barr virus antigen positive," and "Epstein-Barr virus test positive" from all sources in the Celgene global safety database. The occurrence of EBV reactivation was derived from all EBV infections and laboratory findings of EBV positivity identified in the database.
Results: Overall, the review of the Celgene global safety database identified 42 pts with EBV infection during LEN Tx, of whom 8 pts were considered to have EBV reactivation. Thirty-four pts were identified with EBV infection that lacked any information regarding preexisting EBV infection. Therefore, the occurrence of EBV reactivation and impact of LEN could not be ascertained. Of the 42 pts, 14 reported EBV infection with B-cell malignancies (Hodgkin disease [9 pts] and 1 pt each with B-cell lymphoma, diffuse large B-cell lymphoma, lymphomatoid granulomatosis, lymphoma, and post-transplant lymphoproliferative disorder), of which one (Hodgkin lymphoma) was in a pt with EBV reactivation. With a cumulative LEN pt exposure of 428,373, the reporting rate for EBV infection was 0.01% (42/428,373) and for EBV reactivation was 0.002% (8/428,373). Most (73.8%; 31/42) of the reports were identified in the clinical trial setting, and over half (54.8%; 23/42) of the pts received LEN in the MM indication. Approximately half (52.4%; 22/42) of all pts with EBV infection/reactivation were aged < 65 yrs and 71.4% (30/42) were male. There were 5 reports with a fatal outcome, of which 4 were EBV-associated lymphomas. The median time to onset of all EBV infection/reactivation was 318.5 days (range, 3-1670 days), and median time to onset of EBV infection with B-cell malignancies was 791.5 days (range, 128-1430 days) from start of LEN therapy. The event seriousness, outcome, causality, and action taken with LEN were not available for > 50% of the reports. Review of the 42 pts with EBV infection/reactivation revealed confounding factors that may have contributed to or predisposed pts to develop EBV infection, including immunosuppression, multiple chemotherapies, concomitant use of dexamethasone, and stem cell transplantation.
Conclusions: Immunomodulatory agents have been reported to potentially reactivate the lytic cycle in B cells latently infected with EBV due to effects on Ikaros. However, observations suggesting that EBV reactivation is the result of a therapy-induced stress response, as well as the very low reporting rates of EBV infection/reactivation, do not substantiate an increased risk of EBV infection/reactivation in LEN-treated pts.

Disclosures
Mezo: Celgene Corporation: Employment, Equity Ownership. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Weiss:Celgene Corporation: Employment, Equity Ownership. Minton:Celgene Corporation: Employment, Equity Ownership. Freeman:Celgene Corporation: Employment, Equity Ownership.