LYMPHOID NEOPLASIA CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma

Primary effusion lymphoma (PEL) is an aggressive and rare malignancy predominantly occurring in patients with HIV infection and severe immunodeficiency. PEL has also been reported in recipients of solid organ transplants and in elderly patients in the absence of immunodeficiencies. PEL is a distinct subtype of B-cell non-Hodgkin lymphoma (NHL) characterized by lymphomatous effusions within major body cavities (pleural, peritoneal, and pericardial); extracavitary tumors are rare but have been reported and have similar morphologic and phenotypic characteristics. Morphologically, PEL cells range in appearance from large immunoblastic or plasmablastic cells to cells with a more anaplastic morphology. PEL cells may usually express CD45 but lack pan-B–cellmarkers, including surface and cytoplasmic immunoglobulin (Ig), and frequently harbor clonal Ig rearrangements. In addition, PEL cells frequently express activation and terminally differentiated B-cell/plasma cell-related markers (eg, HLA-DR, CD30, CD38, IRF4, and CD138). Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is uniformly detected in PELcells. Although KSHV is the main causative agent for PEL, almost 80% of the cases are also co-infected with Epstein-Barr virus (EBV), which may contribute to cell transformation. The majority of PEL cells are latently infected with KSHV and express latency-associated viral proteins, including viral cyclin, viral FADD-like interleukin-1b-converting enzyme inhibitory protein, latency-associated nuclear antigen (LANA), kaposin, and a group of viral microRNAs. In a very small fraction of infected cells, the virus undergoes lytic replication producingmature virions and cell lysis. The lytic replication occurs in a coordinated cascade of immediate early (IE), early, and late genes. IE genes transactivate and promote the expression of early lytic genes, which in turn participate in viral DNA replication. Late lytic genes are expressed after viral DNA replication, allowing mature virion formation and egress from the cells. PEL displays an aggressive clinical course with a median survival timeof only 6months fromdiagnosis. Current therapeutic approaches, including combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone-like regimens, highly active antiretroviral therapy, and other antiviral approaches lead to only transient responses and do not cure these patients. Recently, treatment with bortezomib (a proteasome inhibitor) alone or in combination with vorinostat (a histone deacetylase inhibitor, also know as a suberoylanilide hydroxamic acid) has been found to prolong the survival of mice bearing PEL tumors. But the systemic efficacy of these drugs is yet to be evaluated in PEL patients. Overall, there is an urgent need to develop more effective therapeutic approaches to PEL. Antibody-based therapies have shown remarkable therapeutic activities in various tumors, including rituximab in B-cell lymphoma, trastuzumab in breast cancer, and cetuximab in colorectal cancer. These approaches target specific antigens expressed on the cancerous