Background: Prognosis of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) is particularly poor upon relapse after treatment with targeted agents and, in particular, following transformation to Richter's syndrome (RS). RS is characterized by transformation of CLL to an aggressive lymphoma, most commonly CD20+ large B-cell lymphoma (LBCL). Because no established standard of care exists, a major unmet medical need remains for patients with RS. Epcoritamab is a novel, subcutaneously administered (SC) CD3xCD20 bispecific antibody that has shown substantial clinical efficacy in R/R LBCL (Thieblemont et al, EHA 2022, abstract LB2364). Encouraging early results were also observed in patients with R/R CLL from the dose-escalation phase of the EPCORE CLL-1 trial, which is currently assessing the safety and efficacy of epcoritamab in multiple expansion cohorts. Here we present initial data from the RS-LBCL cohort in the ongoing phase 1b/2 EPCORE CLL-1 trial (NCT04623541).

Methods: Eligible adults had biopsy-proven transformation to CD20+ RS-LBCL with a clinical history of CLL or small lymphocytic lymphoma (SLL) disease (PET and/or CT/MRI) and no more than 1 prior line of therapy for RS. SC epcoritamab was administered QW in cycles 1-3, Q2W in cycles 4-9, and Q4W in cycles ≥10 (28 d/cycle) until disease progression or unacceptable toxicity. In cycle 1, step-up dosing and corticosteroid prophylaxis were required to mitigate CRS. Response assessment was performed according to Lugano 2014 criteria using PET-CT.

Results: As of the data cutoff on July 15, 2022, 10 patients with RS (median age, 70.5 y; range, 53-80) had received epcoritamab 48 mg with a follow-up of ≥12 wk. The median time from RS diagnosis to first dose of epcoritamab was 2 mo (range, 0.5-11). Prior therapies for RS included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP), and 6 patients received epcoritamab as first-line therapy for RS. Median treatment duration was 2.5 mo (range, 0.5-6.5), with 5 (50%) patients receiving ongoing treatment. The most common related treatment-emergent AEs (TEAEs) of any grade were CRS (90%; 40% grade 1, 50% grade 2), anemia (40%), diarrhea (40%), hypophosphatemia (30%), injection-site reaction (30%), and thrombocytopenia (30%). Notable grade 3-4 TEAEs included neutropenia (n=4; 2 patients grade 3, 2 patients grade 4), anemia (n=2), and COVID-19 (n=2). Most CRS events were associated with the first full dose of epcoritamab. All CRS events resolved (median time to resolution, 3 d), no patients discontinued treatment due to CRS, and 6 patients received tocilizumab. No cases of ICANS were observed. Clinical tumor lysis syndrome (grade 2) occurred in 1 patient and resolved within 3 d. No patients discontinued treatment due to AEs. Two patients died due to disease progression. Antitumor activity was observed early (majority of responses seen at the first [wk 6] assessment), with an overall response rate of 60% and a complete response rate of 50%.

Conclusions: In patients with RS, SC epcoritamab demonstrated a manageable safety profile with only low-grade CRS events, mostly associated with the first full dose and all of which resolved. This safety profile was consistent with previous reports of epcoritamab monotherapy, and no new safety signals were reported. Preliminary efficacy findings show that SC epcoritamab has encouraging single-agent activity in RS-LBCL, with high overall and complete response rates observed and the majority of responses seen at the first (wk 6) assessment. This is the first report of epcoritamab in patients with RS-LBCL. The study is ongoing, and updated data with longer-term follow-up and additional treated patients will be presented.

Kater:Abbvie, Astra Zeneca, BMS, Janssen, Roche/Genentech: Research Funding; Abbvie, Astra Zeneca, Janssen: Other: Speakers fee; Janssen, LAVA: Patents & Royalties: Pending; Astra Zeneca, BMS, Roche/Gennetech, Janssen, Abbvie, LAVA: Membership on an entity's Board of Directors or advisory committees; Amsterdam UMC, University of Amsterdam: Current Employment. Ye:BMS: Consultancy; Ascentage: Research Funding; sanofi: Research Funding; Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Nektar: Research Funding; Janssen: Consultancy, Research Funding; GSK: Research Funding; Regeneron: Research Funding; Genmab: Research Funding. Mato:PER: Honoraria; Genentech: Honoraria, Research Funding; Johnson & Johnson: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; LOXO: Honoraria, Research Funding; Pharmacyclics, LLC: Honoraria, Research Funding; TG Therapeutics, Inc: Honoraria, Research Funding; PerView: Honoraria; Nurix: Research Funding; BMS: Honoraria; Dava: Honoraria; Curio: Honoraria; Pfizer: Research Funding; Octopharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; DTRM Biopharma: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Medscape: Honoraria; Acerta: Research Funding. Janssens:Genmab: Current Employment; Abbvie: Consultancy, Other: Travel Grants, Speakers Bureau; Amgen: Consultancy, Other: travel grants, Speakers Bureau; Astra-Zeneca: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene: Other: travel grants. Oki:AbbVie: Current Employment. Hoehn:Genmab: Current Employment. Rios:Genmab: Current Employment. Kuznetsova:Genmab: Current Employment. Valentin:Genmab: Current Employment. Eradat:Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Morphosys: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Juno: Research Funding; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding; Kite: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; BMS: Research Funding; ATARA: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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