Abstract Background: Glofitamab, a bispecific CD20xCD3 T-cell engager, is FDA-approved for R/R DLBCL after ≥2 prior lines of therapies (LOT) using a standard step-up dosing (SUD) regimen. The BiCAR trial demonstrated high efficacy (ORR 76%) and acceptable safety profile (CRS ≥Gr2: 8%, ICANS ≥Gr2: 2.2%, no Gr 3) with a 1-week accelerated (a) SUD in post-CAR-T DLBCL (NCT04703686). The aSUD, however, is needed for patients (pts) with rapidly progressive disease or impending risk of disability, a population often excluded from clinical trials. We present preliminary safety and efficacy of an aSUD glofitamab in high-risk pts in the real-world settings for whom the standard SUD may not be appropriate due to disease kinetics. Methods: In this single-center study, we evaluated outcomes of all adult pts (18 yrs) with R/R DLBCL treated with aSUD glofitamab (Feb 2024–Apr 2025). Dosing was as follows: Cycle (C) 1—obinutuzumab 1000 mg (Day D 1), glofitamab 2.5 mg (D4), 10 mg (D6), 30 mg (D11). Subsequent dosing was at 30 mg starting on D18 (C2) and continued every 3 weeks up to total 12 cycles. Before Oct 2024, patients received 20 mg IV dexamethasone (dex) as premedication (premed group); thereafter prophylactic dex 10 mg PO (D5, 7–9, 12–14) was added (prophy group). A minimum of 24-hr inpatient observation was mandated for D4 and D6. SUD completion was defined as receiving the 30 mg dose (C1D11). OS and PFS were measured from the first dose of glofitamab, and censoring at the time of CAR T or allogeneic stem cell transplant (alloHCT). Results: Out of 29 pts planned for aSUD glofitamab, 26 received at least one glofitamab dose; 2 died before treatment, and 1 was found to have a different diagnosis. Of 26 pts included in this study,13 received SUD with an intent to bridge either to CAR-T (n=10) or alloHCT (n=3). Median age was 58 yrs (range 22–82) and 54% were female. B-symptoms were present in 13 (50%), high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements in 10 (38%), GCB subtype in 12 (46%), Stage IV in 21 (81%), bulky disease (≥10 cm) in 7 (27%), 2 extranodal sites in 11 (42%) pts, CAR-HEMATOTOX score 2 in 16 (62%) pts. Median prior LOT was 2 (range 0–5); 46% had a history of primary refractory disease and 9 patients (35%) had prior CAR-T. Notably, 69% (n=18) would have been ineligible from BiCAR trial due to ECOG ≥2 (n=13), platelets 50 × 10⁹/L (n=3), neutrophil count 1000/µL (n=3), hemoglobin 8 g/dL (n=5), CNS involvement (n=6), recent CAR T within 30 days (n=2). The aSUD glofitamab was completed in 23/26 pts (88%) with. median number of glofitamab cycles 2 (range: 1–8).; 20 (77%) completed without delays while 3 were delayed due to CRS. Three pts did not complete aSUD- 1 died from gastrointestinal bleeding due to disease, 1 discontinued due to recurrent Gr2-3 CRS and 1 discontinued due to G3 CRS with no intention to be re-challenged. Of the pts who completed aSUD, 6 bridged to CAR T, 2 bridged to alloHCT, 9 discontinued due to progression, 3 died from other causes (renal cell carcinoma, bowel perforation, COVID-19), 2 remain on therapy and 1 was lost to follow-up. Overall, CRS occurred in 61% (≥Gr3 in 15%), most often after the first dose (50%), declining thereafter: dose 2 (17%), dose 3 (13%). ICANS occurred in 12% (≥Gr3: 7%), all within D4 and D6. CRS rates and severity were similar in the prophy dex (n=14) vs. the premed dex (n=12) group (any CRS 71.4 vs. 41.7% p=0.2; Gr2 40% vs. 60%; p=0.6). Median duration of hospitalization after receiving dose 1 is 5 days (range 1-21). Overall, infections occurred in 6 pts (23%): 2 bloodstream, 2 urinary tract, and 2 respiratory (3 were Gr 3). Among 26 evaluable pts, the best ORR was 42% with 15% CR. At a median follow-up of 4.27 months, median OS was 3.65 months (95% CI: 1.97–NA) and median PFS was 1.9 months (95% CI: 1.18–NA). Conclusions: In a real-world study of glofitamab aSUD in high-risk R/R DLBCL, most pts completed Cycle 1, and some pts could be successfully bridged to CAR T or alloHCT. However, CRS/ICANS incidence was higher, and efficacy outcomes were lower than reported in clinical trials, consistent with their high-risk profile. Dex prophylaxis did not significantly reduce CRS incidence or severity over a small sample size of treated pts. Pts most in need of aSUD often exhibit high risk features associated with increased toxicity and reduced therapeutic efficacy, and further work is needed to identify patients who would benefit from accelerated dosing.
Biwei Cao (Mon,) studied this question.