Real-world outcomes with bispecific antibody therapies for aggressive B-cell lymphomas in octogenarians

Abstract Background: Bispecific Antibody (BsAb) therapy has improved outcomes in patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL). In pivotal trials, BsAbs demonstrated lower rates of serious adverse events compared to historical trials with CAR T-cell therapy, making it an appealing option in older adults. However, pts who are 80 years (yrs) or older (≥80) were underrepresented in these landmark trials. Hence, we sought to evaluate the safety and efficacy outcomes of BsAbs in pts age ≥80 yrs with R/R LBCL. Methods This is a multicenter retrospective cohort study of adult LBCL pts treated with BsAb between 2018-2024 across 14 academic institutions. Pts were stratified by age (< 80 vs ≥80) at time of first dose of BsAb. Primary endpoints were progression-free survival (PFS) and overall survival (OS) with secondary endpoints of lymphoma-specific survival (LSS), rates of response, cytokine release syndrome (CRS), neurotoxicity (NT), and infection. Cohort characteristics and safety outcomes were compared using descriptive statistics. Time-to-event curves were estimated by Kaplan-Meier method. Cox univariable and multivariable regression analysis (MVA) were used to determine factors that were prognostic of survival. Results In the cohort of 258 pts, 20% (n=51) were in the age ≥80 yrs (older) cohort with a median age of 85 yrs (range: 80-101) and 80% (n=207) were in the age <80 yrs (younger) cohort with a median age of 62 yrs (24-79). Baseline characteristics were similar between the groups except the older cohort had more patients with ECOG 2-4 (36.1% vs 12.3%, p=0.002), a higher median IPI (4 vs. 2), ≤2 lines of therapy (LOT, 47.1% vs. 29.8%, p=0.03), and fewer pts with prior CAR T-cell therapy (17.6% vs 58.0%, p<0.001). While the proportion of pts receiving glofitamab was similar between the older and younger cohorts (45.1% vs 43.6%), a slightly higher proportion of the older cohort received mosunetuzumab (39.2% vs 27.7%) and a lower proportion received epcoritamab (15.7% vs 25.2%) (p=0.2). Altogether, 88 pts received BsAb as part of a clinical trial, and 72 received BsAb in combination with chemotherapy, targeted therapy, or radiation. Among the response evaluable pts (n=205), the older cohort had a numerically lower complete response rate (CRR) (35% vs. 41.2%, p=0.6) and overall response rate (ORR) (57.5% vs. 60.6%, p=0.7) than the younger cohort. With a median follow-up of 9.7 vs 17.0 mos for the older and younger cohorts, the median PFS was not significantly different between the two cohorts (3.4 months [mos] [95% CI: 2.6- 6.4 mos]) vs 4.7 mos [95% CI: 3.4- 6], p=0.22), respectively. With a median follow-up of 12.0 and 18.0 mos, the median OS was numerically shorter for the older cohort (6.5 mos [95% CI: 5.0 - NE]) compared to the younger cohort (13.5 mos [95% CI: 10.4- 25.7]) but did not reach statistical significance (p=0.11). LSS was not statistically different between groups (p=0.45). In the MVA, age was not prognostic for PFS or OS. After controlling for receipt of BsAb in a clinical trial or as a combination therapy, among other covariates, no factors were prognostic of PFS nor OS between older and younger cohorts. CRS rates were numerically higher in the younger cohort (44% vs 39%, p=0.6), but grade ≥3 CRS was more common in the older cohort (25% vs. 12%, p=0.2). The older cohort received more steroids (p=0.6), tocilizumab (p=1.0), and siltuximab (p=0.2) for CRS management. More older pts experienced NT (18% vs. 11%, p=0.3) but had less grade ≥3 NT (17% vs. 23%, p=1.0) despite the younger cohort receiving steroids more frequently for NT management (p=1.0). Rates of infection were similar at 1 (14% vs. 14%, p=1.0) and 6 mos (23% vs. 27%, p=0.8) after start of BsAb. The rate of BsAb discontinuation was higher in the older cohort (62.7% vs. 57.6%, p=0.3), despite both cohorts receiving a median of 4 cycles. Conclusions In pts aged ≥80 years with R/R LBCL treated with BsAb, PFS and LSS were comparable to younger pts. Although OS was numerically shorter in the older cohort, this was not statistically significant, likely due to short follow-up. No factors, including age, were prognostic of PFS or OS. Safety outcomes, including CRS, NT, and infection rates, were similar across age groups, except for a higher incidence of grade ≥3 CRS in the older cohort. Thus, BsAb therapy should be considered for those age ≥80. Longer follow-up and larger pt numbers are needed to confirm these findings.