Arsenic Trioxide and Lenalidomide: A Promising Combination Therapy for Primary Effusion Lymphoma

Primary Effusion Lymphoma (PEL) is an aggressive malignancy caused by the Kaposi sarcoma associated herpesvirus (KSHV). PEL patients rarely respond to conventional chemotherapy and their prognosis is poor, with a median survival of less than six months. The most promising treatment strategies in these patients combine anti-viral treatments with new agents including chemicals and cytokines. Here, we investigated the efficacy of lenalidomide (Lena), an immune modulator with significant clinical activity in a large number of hematological malignancies, and arsenic trioxide (As), a potent agent in acute promyelocytic leukemia and HTLV-I associated adult T cell leukemia.

We used three PEL cell lines (BC-1, BC-3 and BCBL-1 which are KSHV⁺/EBV^- malignant B cells derived from PEL patients) and one PEL-negative control cell line (RAJI as a KSHV^- malignant B cell line). We demonstrate that the combination of As and Lena resulted in growth inhibition in BC-1 and BC-3 cells and to a lesser degree in BCBL-1 cells while no effect was observed in RAJI cells. This growth arrest was associated with induction of massive apoptosis and a substantial upregulation of phosphorylated and total p53 protein levels. Furthermore, As/Lena inhibited the expression of latent viral transcripts (LANA-1, LANA-2, v-FLIP and v-Cyclin) and proteins (LANA-1/LANA-2) in all tested PEL cells.

Finally, and while Lena alone did not have any inhibitory effect on in vitro treated PEL cells, single agent Lena treatment doubled survival of BC-3 PEL mice and significantly prolonged survival in 75% of BCBL-1 PEL mice and led to cure of the remaining 25%. More importantly, combination of As and Lena was highly synergistic and cured 25% and 75% of BC-3 and BCBL-1 PEL mice respectively. These results provide a rational for the therapeutic use of the combination As/Lena in PEL patients.