Lenalidomide in Combination with Arsenic Trioxide: an Effective Therapy for Primary Effusion Lymphoma

Abstract

Primary effusion lymphoma (PEL) is a rare aggressive subset of non-Hodgkin B cell lymphoma. PEL is secondary to Kaposi sarcoma herpes virus (KSHV) and predominantly develops in serous cavities. Conventional chemotherapy remains the treatment of choice for PEL and yields high response rates with no significant comorbidities. Yet, chemotherapy often fails in achieving or maintaining long-term remission. Lenalidomide (Lena), an immunomodulatory drug, displayed some efficacy in the treatment of PEL. On the other hand, arsenic trioxide (ATO) in combination with other agents effectively treated a number of blood malignancies, including PEL. In this study, we present evidence that the combination of ATO/Lena significantly enhanced survival of PEL mice, decreased the volume of exacerbated ascites in the peritoneum, and reduced tumor infiltration in organs of treated animals. In ex vivo treated PEL cells, ATO/Lena decreased the proliferation and downregulated the expression of KSHV latent viral proteins. This was associated with decreased NF-κB activation, resulting in reactivation of viral replication, downregulation of interleukin-6 (IL-6) and IL-10, inhibition of vascular endothelial growth factor, and apoptosis. Our results elucidate the mechanism of action of ATO/Lena and present it as a promising targeted therapeutic modality in PEL management, which warrants further clinical investigation.

A Set of 17 microRNAs Common for Brain and Cerebrospinal Fluid Differentiates Primary Central Nervous System Lymphoma from Non-Malignant Brain Tumors

“…Moreover, we revealed that the expression of miRs of the identified CNS DLBCL-specific profiles may be affected by a group of small molecules/drugs and bioactive substances, including arsenic trioxide and epigenetic drugs (histone deacetylase inhibitors (HDACis), LAQ824 (dacinostat), ITF2357 (givinostat), Vorinostat, DNA methyltransferase inhibitors (DNMTis), Decitabine, Azacitidine, and Temozolomide). The combination of arsenic trioxide with other compounds proved efficient in various hematological and lymphoid malignancies, including acute promyelocytic leukemia [ 75 ], primary effusion lymphoma [ 76 ], and adult T-cell leukemia/lymphoma [ 77 ]. HDACis and DNMTis demonstrated promising anticancer activities in both hematological and lymphoid malignancies and solid tumors [ 78 , 79 ] and Vorinostat (SAHA) has been approved for treating primary cutaneous T-cell lymphoma [ 80 ].…”

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

“…In this study, lenalidomide/ATO treatment decreased the proliferation of PEL cells and downregulated the expression of KSHV latent viral proteins. This was associated with less NF-kB expression and downregulation of IL-6 and IL-10 as well as the inhibition of VEGF and the induction of apoptosis [163].…”

HHV-8 associated lymphoma

“…Drugs belonging to the IMiDs family, such as thalidomide, lenalidomide, and pomalidomide, are recognized as promising drugs in terms of their antiproliferative effects against the majority of PEL cell lines and in murine models [33,34,35 ▪▪ ]. Actually, a clinical trial investigating the efficacy of chemotherapy (EPOCH-R2) combined with lenalidomide is being conducted at the national cancer Institute (NCT02911142).…”