Background: Plasmablastic lymphoma (PBL) is commonly associated with HIV, immunosuppression, old age, and autoimmune disorders, but can be seen in immunocompetence. Intensive regimens, including EPOCH, have a complete response (CR) rate of 40% to 65% and median overall survival 9-15 months. Patients (pts) with refractory or relapsed disease have a dismal prognosis. PBL has morphologic and immunophenotypic characteristics overlapping high-grade B-cell lymphoma and multiple myeloma (MM). 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 MM 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 and early efficacy results of the first clinical trial dedicated entirely to 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. Planned enrollment 15 pts. Up to 3 replaced if they did not complete cycle 1 for reasons unrelated to DARA toxicity. 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. 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: 18 pts were enrolled with 3 pts inevaluable having only received 1 dose of DARA, removed from study unrelated to DARA toxicity and replaced as pre-specified. 1 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. 2 refused any further lymphoma therapy within days of first treatment. 15 evaluable pts, baseline: male 10. Stage IV 14, LDH elevated 10. HIV+ 7 with median CD4 203 (range=118-790) and HIV viral load median 1330 (range=20-70K, upper quartile 1600). Pathology: Ki-67 80-100%: 10 EBER +: 9. extra-nodal: 6. MYC +: 5/5 by immunohistochemistry (IHC); 3/4 by FISH one of whom also + by IHC. As of June 30th, 2025, the following is the disposition: 13/18 enrolled (69%) and 13/15 (87%) evaluable achieved the primary endpoint: feasibility of receiving ≥3 cycles of therapy with DARA. DARA dose density was 81% including a dose missed for a hurricane. With all 18 pts assessed for toxicity, a total of 48 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 10 pts, grade 4 thrombocytopenia in 5, grade 4 lymphopenia in 3. The remainder of the SAEs were typical of EPOCH . 11/15 (73%) evaluable for response achieved a CR with 2 relapses. 4 MYC + by IHC achieved a CR far. With a median follow up of 21.3 months (95%CI= 14 to 28.5), the 1-yr PFS: 71.5% (95%CI=40.4 to 88.3) and 1-yr OS: 78.8% (95%CI=47.3 to 92.7) and 2-yr OS: 70 (95%CI=37.9 to 87.8)Conclusions: It is feasible to add DARA to EPOCH for the treatment of plasmablastic lymphoma. Preliminary outcomes are promising. A non-randomized phase II is activated to determine the efficacy of this approach. Correlations with clinical outcomes will include predictive biomarkers including MYC over-expression and circulating tumor DNA. (Funding: UM1 CA121947 P30 CA008748)

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2025
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