Daratumumab with Dose-Adjusted EPOCH Is Feasible in Newly Diagnosed Plasmablastic Lymphoma: AIDS Malignancy Consortium 105

Background: Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma commonly associated with HIV, immunosuppression, old age, and autoimmune disorders, but can be seen in immunocompetent patients. Intensive regimens, including EPOCH, have only a complete response (CR) rate of 40% to 65% and median overall survival between 9 to 15 months. Patients (pts) with refractory or relapsed disease typically have a dismal prognosis. PBL has morphologic and immunophenotypic characteristics overlapping high-grade B-cell lymphoma and multiple myeloma. It is CD20 negative, MYC + in 50% of cases and expresses plasma cell markers, including CD38, CD138, and MUM-1/IRF-4, with a proliferation index typically > 90%. Daratumumab (DARA) is a human IgG1k anti-CD38 monoclonal antibody (mAb) highly active and FDA approved in multiple myeloma and active in pre-clinical lymphoma models. We hypothesized adding DARA to DA-EPOCH would be safe and feasible and may improve outcomes. We present the feasibility results of the first clinical trial dedicated entirely to pts with PBL. The primary aim was to determine the percentage of newly diagnosed PBL pts completing ≥ 3 cycles of DARA with DA-EPOCH irrespective of HIV status. Given 85% of pts completed ≥ 5 cycles of DA-EPOCH alone in CALGB 50303 study (Bartlett JCO. 2019) and allowing for a lower proportion completing with the addition of DARA, we hypothesized> 75% of pts would complete ≥ 3 cycles of protocol treatment. One prior cycle of anthracycline-containing chemotherapy pre-enrollment was allowed. The planned enrollment was 15 pts.

Study Design and Methods: This is a non-randomized, multicenter study (NCT04139304) conducted by the AIDS Malignancy Consortium. Both HIV negative and HIV positive PBL pts ≥ 18 years old with Stage II to IV PBL or Stage I with elevated LDH and/or bulky tumor, with measurable disease and adequate organ function were eligible. HIV positive pts had a CD4 ≥ 100 cells/μL and were on concurrent combination antiretroviral therapy (cART) or agreed to start cART. Key exclusion criteria included receiving ≥ 1 prior cycle of combination chemotherapy, active hepatitis B seropositivity, and active CNS involvement. DARA was given in conjunction with 21 day cycles of DA-EPOCH for 6 cycles. DARA 16 mg/kg was be administered intravenously weekly for the first 3 cycles on days 1, 8, and 15, then on day 1 for cycles 4-6. DARA was held on day 8 and 15 for ANC <500 or platelets <25K.

Results: Fifteen pts were enrolled as planned. Baseline: male 10. Stage IV 14, LDH elevated 10. HIV+ 8 with median CD4 215 (118-790) and HIV viral load median 728 (20-70K, upper quartile 1600). Pathology: Ki-67 80-100%: 9 EBER +: 7. extra-nodal: 6. MYC +: 4/4 by immunohistochemistry (IHC); 2/3 by FISH one of whom also + by IHC. Three received only one DARA dose. One had a non-infusion related atrial fibrillation and pulmonary embolus 7 days after the first dose of DARA and discontinued all further DARA at the investigator's discretion. Two refused any further therapy within days of first treatment. As of July 14, 2024, the following is the disposition: 11/15 enrolled (73%) and 11/12 (92%) evaluable achieved the primary endpoint: feasibility of receiving ≥3 cycles of therapy with DARA. DARA dose density was 85%. With all 15 pts assessed for toxicity, a total of 36 SAEs occurred. Grade 4 heme toxicity is the expectation of DA-EPOCH which targets an ANC <500 at least once in each treatment cycle. Grade 4 neutropenia was noted in 6 pts, grade 4 thrombocytopenia in 5, grade 4 lymphopenia in 2. The remainder of the SAEs were typical of EPOCH. 10/12 pts (83%) evaluable for disease response achieved and remain in CR including all 4 MYC+ by IHC. With a median follow up of 10 months (95%CI= 6 to 16.1), the 1-yr PFS: 78% (95%CI=45.5 to 92.5) and 1-yr OS: 84.9% (95%CI=51.2 to 96) and 2-yr OS: 63.6% (95%CI=17.4 to 89)

Conclusions: It is feasible to add DARA to EPOCH for the treatment of plasmablastic lymphoma. Preliminary outcomes are promising. We are expanding to a non-randomized phase II to determine the efficacy of this approach. Correlations with clinical outcomes will include predictive biomarkers including MYC over-expression and circulating tumor DNA. (Funding: C01 UM1 PO1568 G TA390)

Noy:NSCI: Honoraria; OncLIve: Honoraria; Medallion Healthcare: Honoraria; health advance: Consultancy; AstraZeneca: Consultancy; ADC therapeutics: Consultancy; Beigene: Consultancy; clearview: Consultancy; janssen Global: Consultancy, Other: drug provided for research; guidepoint global: Consultancy; epizyme: Consultancy; EUSA: Consultancy; PER: Honoraria; Cornerstone Pharma: Honoraria, Research Funding. Barta:Daiichi Sankyo: Consultancy; BMS: Consultancy; Acrotech: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Consultancy. Baiocchi:Viracta Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Other: Advisory Board; ATARABio: Consultancy, Other: Advisory Board; Codiak Biosciences: Research Funding; Prelude Therapeutics: Other: Advisory Board, Research Funding; Agenus: Other: Involved in supply of drug (vaccine) and product development. Ramos:Acrotech Biopharma Inc.: Consultancy.

Daratumumab (DARA) is a human IgG1k anti-CD38 monoclonal antibody (mAb) highly active and FDA approved in multiple myeloma and active in pre-clinical lymphoma models.