Daratumumab for relapsed/refractory primary effusion lymphoma, plasmablastic lymphoma and multicentric castleman disease.

Abstract Background and Significance Primary effusion lymphoma (PEL), an aggressive B-cell non-Hodgkin lymphoma (NHL), and a plasmablastic form of multicentric Castleman disease (MCD) are both caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8. Plasmablastic lymphoma (PBL) is an NHL frequently caused by Epstein-Barr virus infection and involves extranodal or osseous manifestations. PEL, PBL and MCD occur at higher rates among people with HIV (PWH). Both PEL and PBL are post-germinal center B cell neoplasms that express immune surface markers consistent with plasmacytic differentiation such as CD45, CD38, CD138, MUM-1 and IRF4. The pathologic hallmark of MCD is the presence of KSHV-infected l-restricted plasmablasts in the mantle zones of lymph nodes that are CD38 and CD45 positive but CD20 negative. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody, which is FDA approved for the treatment of multiple myeloma. In preclinical studies, Dara induced significant and dose-dependent increases in antibody-dependent cell-mediated cytotoxicity of PEL cell lines (Shrestha P, et al., Oncoimmunology 2023). Several case series have demonstrated the activity of Dara in patients with refractory PEL (Shah NN, et al. NEJM 2018). Dara has also been evaluated using combination strategies in newly diagnosed and relapsed PBL (Noy A, et al., Blood 2024 and Dittus C, et al., Br. Journal Haematology 2022). Although Dara has not been evaluated in patients with MCD, the immunophenotype of KSHV-infected MCD plasmablasts and the effect of Dara on PEL cell lines suggest that it may be of therapeutic benefit. Study Design and Methods This is a single-center Phase 2 study evaluating the response rate to subcutaneous Dara in participants (pts) with relapsed or refractory PEL, PBL or newly diagnosed or recurrent MCD (NCT05907759). The primary objective is to assess the combined partial response (PR) and complete response (CR) rate to Dara in pts with relapsed/refractory PEL or PBL, and separately, in those with symptomatic KSHV-MCD. Secondary objectives include evaluating the safety of Dara in these populations. Exploratory objectives correlating longitudinal T-cell, B-cell, and NK cell populations with outcomes. We will evaluate CD38 expression by flow cytometry and/or cytology/immunohistochemistry to assess its association with treatment response. In PWH, we will investigate the impact of Dara on HIV latency reversal and the size of HIV reservoirs in pts receiving effective antiretroviral therapy (ART). The study plans to enroll 12 pts with PEL or PBL and 12 pts with MCD. Eligible PEL/PBL pts must be ineligible for front-line therapy. For those with MCD, pts are required to have at least one clinical symptom and one laboratory abnormality attributed to an active MCD flare. PWH must be receiving or initiating a fully suppressive ART regimen. There is no exclusion criterion based on CD4+ T-cell counts. So far, 6 pts (1 in PBL/PEL cohort and 5 in MCD cohort) have been enrolled. For pts with PEL or PBL, Dara will be administered at 1800 mg weekly for 8 weeks (8 doses), then every 2 weeks for 16 weeks (8 doses), and subsequently every 4 weeks for up to 96 weeks (24 doses). For pts with MCD, Dara is given weekly at the same dose for 8 weeks. If a response assessment indicates a CR, no additional treatment will be given; if PR or stable disease is noted, Dara will be continued every 2 weeks for an additional 8 doses, for a total of up to 24 weeks. To avoid systemic injection-related reactions, acetaminophen, diphenhydramine premedication will be administered before every Dara dose. Corticosteroids will be administered mandatorily in the first three doses prior to and after Dara. Responses for PEL and PBL will be assessed using a modified version of the International Working Group Response Criteria for Malignant Lymphoma (Cheson BD et al., J Clin Oncol 2007). MCD response will be evaluated using a modified Clinical Benefit Response Criteria (Uldrick TS et al., Blood 2011). The proportion of pts achieving PR or CR will be reported separately for PEL/PBL cohort and MCD cohort, along with 95% confidence intervals. A similar subgroup analysis will be performed for MCD. Progression-free survival and overall survival will be estimated separately by disease type using the Kaplan-Meier method, with 95% confidence intervals calculated for median PFS.