Daratumumab induces cell-mediated cytotoxicity of primary effusion lymphoma and is active against refractory disease

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara's effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.

Automated summary

Primary effusion lymphoma (PEL), caused by Kaposi sarcoma-associated herpesvirus (KSHV), is an aggressive non-Hodgkin lymphoma with no standard therapy. CD38 is highly expressed in PEL cells, and daratumumab (Dara) shows significant antibody-dependent cell-mediated cytotoxicity (ADCC) against PEL cells with high CD38 levels. Two FDA-approved drugs, all-trans-retinoic acid (ATRA) and pomalidomide (Pom), increase CD38 expression in low-CD38 expressing PEL cells, enhancing Dara-induced ADCC.