A standardized rapid dose escalation of epcoritamab for patients with lymphoid malignancies

Abstract

Abstract Introduction: Cytokine release syndrome (CRS) is a common adverse event associated with the bispecific antibody (BsAb), epcoritamab (epco), occurring in 50% (grade (G) ≥ 3, 2.5%) of patients (pts) with relapsed or refractory large b-cell lymphomas (LBCLs), and in 96% (G ≥ 3 17%) of pts with CLL in previous pivotal trials, respectively. Step-up dosing (SUD) mitigates CRS but delays the first full dose of epco to day (D) 15. In pts with rapidly progressive LBCL, disease progression (PD) can outpace SUD. In the EPCORE NHL-1 trial, PD was the leading cause of death, with 28 pts (18%) experiencing PD within 6 weeks of initiating epco. We developed an internal protocol for a rapid dose escalation of epco completed over 7 days (d). Methods: Between April, 2023 and July, 2025, all pts at the University of Utah (UofU) eligible for epco and willing to receive off-label SUD underwent the rapid dose escalation. Epco was administered subcutaneously on D 1, 4, and 7 in outpatient infusion. Supportive care with 500 ml intravenous fluids, dexamethasone (dex) 16 mg, acetaminophen 650 mg, and diphenhydramine 50 mg was administered 30-120 minutes prior to each epco injection, including through the completion of cycle (C) 1. Dex 16mg was administered orally on D 1-11, during which time pts were instructed to monitor temperature three times per day. Dex 12 mg was given to all pts with instructions to self-administer and call clinic if a fever was recorded at home. A clinic visit was required on D 1, 4 and 7. A nursing visit/phone call for symptom and ICE assessment was optional on D5. Pts were admitted to the hospital for 24 hours (h) after the 1st full dose. If pts experienced CRS or immune effector cell-associated neurotoxicity syndrome (ICANS), the next dose was not given until 24 h after resolution. Epco was resumed per standard of care dosing schedule on D 14. C2 began on D 22. Results: Ten pts have been treated per the rapid SUD schedule. Disease subtypes include LBCL (n=8; HGBCL n=1, T-cell histiocyte rich LBCL n=1, transformed DLBCL from follicular lymphoma n=3) and CLL (n=2). Pts with CLL received epco outside of a clinical trial based on reported data at the time. Among pts with LBCL, median prior lines of therapy (LOT) were 3 (range 1–6). Four pts received prior chimeric antigen receptor t-cell therapy (CART) and 6 were primary refractory (n=3) or early relapse (n=3). Two pts had bulky disease (> 7.5 cm), and 7 had elevated LDH prior to epco. Three pts received epco in combination with gemcitabine and oxalipatin. Five pts received all SUDs in the hospital due to urgent need for treatment. Two pts did not complete SUD due to preference. CRS occurred in 3 pts (37.5%; all G 2) after the intermediate (0.8 mg) dose (n=1) and 1st full dose (n=2). CRS events ≥ G 3 were not observed. CRS was treated with tocilizumab (toci) alone in all 3 pts. CRS resolved in ≤ 2 days in all pts. No ICANS events occurred. The 2 pts with CLL received 6 and 7 prior LOT, respectively. Both pts were double refractory to BTKi and BCL2i and necessitated rapid SUD per treating physician (bridge to CART n=1, rapid PD n=1). Neither pt had bulky disease, however 1 had >95% bone marrow involvement by CLL. CRS was observed in both pts. 1 pt experienced G 2 CRS after the priming (0.16 mg), 1st full, and 2nd full dose. The other pt experienced G 1 CRS after the 1st full dose. CRS was treated with toci and steroids (n=2 episodes; toci alone n=1, steroids alone n=1). CRS resolved in ≤ 2 days in all pts. No ICANS events occurred. UofU is the largest referral center in the Mountain West, United States with a 5-state catchment area. Six pts lived in a different state-Montana, Idaho, Wyoming, Colorado, and Nevada-of whom 4 returned locally for ongoing epco treatment after completion of SUD. Conclusions: We report a standardized process with enhanced supportive care in C1 for a rapid dose escalation of epco, enabling pts to achieve the 1st full therapeutic dose on D 7. This approach has demonstrated feasibility and safety. All CRS events were low grade and resolved quickly. Rapid SUD ensures timely exposure to effective therapy in pts with symptomatic disease and minimizes time away from home for pts traveling to academic centers for C1 epco. We are expanding to an entirely out-pt process with additional nursing support for pts with LBCL. Given higher rates of CRS and evolving optimization of SUD in pts with CLL, we reserve this process for select CLL pts.