Outcomes of CD20xCD3 bispecific antibody therapy in adult patients with Relapsed/Refractory transformed indolent lymphoma

Abstract Introduction Though transformed indolent lymphomas (tiNHL) have historically been associated with poor outcomes in the relapsed or refractory (R/R) setting, novel treatments e.g. chimeric antigen receptor (CAR) T-cells offer some improvement. Bispecific antibodies (BsAbs) are effective in R/R large B-cell lymphoma (LBCL), but their activity in tiNHL is not well characterized. The goal of our study is to explore the clinical efficacy and safety of BsAbs delivered outside of clinical trials in R/R tiNHL, compared to de novo diffuse LBCL not otherwise specified (NOS) (dnDLBCL) using an adapted propensity score matching (PSM) analysis. Methods We conducted a multicenter retrospective study across 9 centers that are part of the Collaborative US Bispecifics Consortium (CUBIC). The study included adults (≥18 years old) with R/R tiNHL or dnDLBCLtreated with CD20xCD3 BsAbs (epcoritamab or glofitamab), outside of clinical trials from May 2023 to May 2025. We defined tiNHL as LBCL transformed from follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL), or low-grade B-cell lymphoma NOS. Patients (pts) with Richter's syndrome were excluded. To balance covariate distribution between the tiNHL and dnDLBCLcohort, an exhaustive list of covariates was used for PSM: age, sex, race, ethnicity, number of prior lines of treatment before BsAb, prior treatment line by CAR T-cells therapy, prior autologous stem cell transplantation (ASCT), performance status (PS), B symptoms, Ann Arbor stage, central nervous system involvement, >1 extranodal site of involvement, LDH, specific BsAb and year of BsAb initiation. PSM was performed considering a 1:1 matching. The primary outcomes were the overall response rate (ORR) and complete response rate (CRR), assessed by local investigators using the Lugano 2014 criteria. Secondary outcomes included progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The study was approved by the Institutional Review Board at each site. Results 61 pts with R/R tiNHL and 157 pts with dnDLBCL were included in the study. Among the tiNHLs, 80% arose from FL, 10% from MZL, 4% from WM/LPL and 5% from a low-grade B-cell lymphoma NOS. At treatment initiation, 69% of tiNHL had DLBCL NOS, 23% high-grade B-cell lymphoma, 3% T-cell/histiocyte-rich LBCL and 3% LBCL without further specification. Following the 1:1 matching process, the study included a total of 122 pts (61 tiNHL and 61 dnDLBCL). At the time of BsAb treatment, among the tiNHL and dnDLBCL cohorts, respectively, 43%/48% received epcoritamab while 57%/52% received glofitamab; the median age was 72 years (range: 38-91)/71 years (23-89), 41%/44% were female, the median number of prior lines received was 3 (range: 1-9)/ 3 (1-7), 52%/51% had previously received CAR T-cells, 8%/5% had a prior ASCT, 15%/33% had ECOG ≥2, 79%/79% had advanced-stage disease (III-IV), 46%/52% had >1 extranodal involvement and 61%/57% had LDH above the upper normal limit. With a median follow-up of 8.9 months, efficacy outcomes were comparable. The best ORR/CRR was 51% (95% CI, 38-64)/33% (95% CI, 21-46) for the tiNHL cohort and 49% (95% CI, 36-62)/33% (95% CI, 21-46) for the dnDLBCL. 56 pts died, 28 in each cohort. No significant differences were observed between the two cohorts (tiNHL vs dnDLBCL respectively) for the 6-month PFS (34%, [95% CI,23-50] vs 34%, [95% CI, 23-48], p=0.78), 6-month OS (56%, [95% CI,43-72] vs 56%, [95% CI, 44-71], p>0.99), and 6-month DOR (49%, [95% CI,32-76] vs 52%, [95% CI, 34-78], p=0.71). Among tiNHL pts, no differences were observed for response rate, OS and PFS, based on the type of BsAb. Similar toxicities were observed in both cohorts. In tiNHL and dnDLBCL cohort, respectively, any grade CRS were observed in 41% and 36% pts (p=0.84) and any grade ICANS in 11% and 15% pts (p=0.58). In tiNHL cohort 25 pts experienced CRS (grade 1: 16, grade 2: 7 and grade 3: 2) and 7 experienced ICANS (grade 1: 3, grade 2: 3 and grade 3: 1). Conclusions This is the first large multicenter study to specifically report the effectiveness of BsAbs in real-world for R/R tiNHL and shows that the results are in keeping with clinical trial data. Acknowledging the limited sample size and follow-up, the effectiveness of this treatment in R/R tiNHL appears comparable to that in dnDLBCL and suggests that BsAbs provide an important salvage option in this challenging-to-treat population.