Phase I Study of Lenalidomide Combined with Dose-Adjusted EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma in Participants with or without HIV (NCT02911142)

Abstract

Background: Primary effusion lymphoma (PEL) is a rare, aggressive B-cell neoplasm strongly associated with HIV infection. It generally presents with malignant effusions but may also present with extracavitary (EC) masses. It is caused by the gammaherpesvirus Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8), which is also responsible for the development of Kaposi sarcoma (KS) and a form of multicentric Castleman disease (MCD). There are no prospective studies in PEL and no standard therapy. Prognosis is poor compared to other HIV-associated lymphomas with median survival of 10-22 months when treated with conventional lymphoma chemotherapy regimens. In vitro data demonstrate lenalidomide (LEN), an immunomodulatory agent, downregulates IRF4, a cell activation marker overexpressed in PEL, and can reverse KSHV-induced downregulation of MHC-1 and ICAM-1. Dose-adjusted infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone combined with rituximab (EPOCH-R) has been shown to be safe and effective for CD20+ HIV-associated lymphomas. While PEL is generally CD20 negative, rituximab eradicates the KSHV-infected B-cell reservoir, a source of inflammatory cytokines that drive the natural history of PEL; moreover, many patients have concurrent MCD for which rituximab is a standard treatment. Methods: In a prospective phase 1/2 study conducted in the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI), we are evaluating EPOCH combined with rituximab and LEN (EPOCH-R2) in participants (pts) with untreated PEL. The primary objective was to evaluate safety and tolerability of EPOCH-R2 and determine the recommended phase 2 dose (RP2D) of LEN. PEL was diagnosed/confirmed in the NCI Laboratory of Pathology via cytology and/or flow cytometry of effusions or via biopsy in EC disease. Pts received EPOCH-R days 1-5 and every 21 days for 6 cycles. LEN was administered orally days 1-10 of each cycle starting at 25 mg (with dose de-escalation if toxicity occurred). Dose-limiting toxicities were evaluated during cycles 1-2. Pts with leptomeningeal PEL (CSF-PEL), determined by cytology and/or flow cytometry of cerebrospinal fluid, received intrathecal chemotherapy; intrathecal prophylaxis was given to pts without CSF-PEL. All pts received thromboprophylaxis (aspirin 81 mg daily), opportunistic infection prophylaxis, and antiretroviral therapy (ART). Adverse events (AEs) were evaluated using CTCAEv5 and treatment response was evaluated by Lugano criteria after cycles 2 and 6. Response to treatment, immune reconstitution, and overall survival (OS) were evaluated using descriptive statistics, Wilcoxon signed-rank test and Kaplan-Meier methodology. Results: We are reporting results of the completed Phase I portion of the trial. 6 HIV+ cisgender men (5 Black, 1 White) with stage 4 PEL were enrolled July 2017-August 2019. All received non-boosted integrase inhibitor-based ART. 3 had pleural effusions, 2 had EC disease without effusions, and 1 had both effusions and EC disease. 3 had CSF-PEL and 1 had bone marrow involvement. 4 had concurrent KS; 1 also had concurrent MCD. Median CD4+was 231 cells/µL (IQR: 10, 310) at baseline and 189.5 cell/µL (IQR: 56, 224) at end-of-treatment, which was not a significant decline (p=0.46). The most common AEs were hematologic, including grade (G) 4 neutropenia (100%), leukopenia (100%), thrombocytopenia (67%) and CD4+ lymphopenia (67%). 3 pts (50%) developed G3 pulmonary emboli despite thromboprophylaxis. There were 7 episodes of G3 febrile neutropenia and 2 episodes of sepsis. No pts developed opportunistic infections. There were no dose-limiting toxicities and LEN 25 mg is the RP2D. 4 pts completed all 6 cycles. 2 pts completed 5 cycles: 1 died due to progressive disease and 1 had progressive disease and went on to receive additional therapy. 1 pt who completed all 6 treatment cycles died due to HIV-related complications 5 months after EPOCH-R2 with no evidence of PEL at autopsy. The response rate was 83.3% (95% CI: 36.8-99.6) and 50% (95% CI: 11.8-88.1) after cycles 2 and 6, respectively. 2-year overall survival was 66.7% (95% CI:19.5-90.4). Conclusions: Front-line PEL treatment with EPOCH-R2 is safe, and the most common toxicities were hematologic. This regimen showed preliminary evidence of activity and good OS, which will be further evaluated in the ongoing phase 2. Disclosures Lurain: Celgene: Research Funding; EMD-Serrono: Research Funding; Merck: Research Funding. Ramaswami:Celgene: Research Funding; EMD-Serrono: Research Funding; Merck: Research Funding. Whitby:Patent: Patents & Royalties: Co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers.. Uldrick:Patent: Patents & Royalties: Co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers."; Celgene: Research Funding; Merck: Research Funding; Roche: Research Funding. Yarchoan:Patent: Patents & Royalties: Coinventor on patents on a peptide vaccine for HIV and on the treatment of Kaposi sarcoma with IL12; EMD-Serrono: Patents & Royalties; Patent: Patents & Royalties: Co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers.; Patent: Patents & Royalties: An immediate family member of R. Yarchoan is a co-inventor on patents related to internalization of target receptors, on KSHV viral IL-6, and on the use of calreticulin and calreticulin fragments to inhibit angiogenesis; Celgene: Research Funding; Merck: Research Funding. OffLabel Disclosure: Dose-adjusted infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone combined with rituximab and lenalidomide for the use of primary effusion lymphoma will be discussed.

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

“…Although PEL generally does not express CD20, rituximab has been administered experimentally as part of a multi-drug regimen 7 , 8 , 33 , 34 and we explored whether rituximab can lead to CDC or ADCC of PEL cell lines. We first assayed CD20 levels on the surface of PEL cell lines by flow cytometry and confirmed that they are indeed negative for CD20 ( Figure 5a ).…”

“… 40 It has been used along with other agents in the successful treatment of PEL, although its contribution is unclear. 7 , 8 , 33 , 34 Interestingly, rituximab has been shown to have activity in KSHV-associated MCD even though the KSHV-infected plasmablasts in KSHV-MCD do not express CD20. 41 , 42 Here, we provide evidence that rituximab does not lead to CDC or ADCC in PEL lines.…”

“…Cures are observed in 40% to 50% of patients, but median overall survival is only about 2 years because many patients experience refractory disease or relapse. 7 , 8 Therefore, there is an urgent need to develop new effective therapies for PEL.…”

“…PEL cells are derived from post-germinal center B cells and often express plasma-cell markers including CD38, CD138, CD319, and IRF4. 9 Rituximab, an anti-CD20 monoclonal antibody, has been studied in upfront PEL treatment; 8 , 9 however, because PEL generally does not express CD20, any contribution is likely to be indirect, perhaps from killing of other CD20-expressing KSHV-infected cells.…”

Promising immunotherapeutic approaches for primary effusion lymphoma

“…Rituximab likely kills KSHV-infected CD20-positive B cells in germinal centers that are a source of inflammatory cytokines. Two HIV-infected patients with MCD who received etoposide therapy and four infusions of rituximab developed Kaposi sarcoma with virologic relapses as an increase of blood HHV8 DNA [29]. Nevertheless, considering its effect, rituximab may help to eliminate the KSHV CD20 positive B-cell reservoir that produces inflammatory cytokines and triggers PEL initiation and progression in patients with PEL who have concurrent MCD [12].…”