Abstract
Introduction Bendamustine (benda) has prolonged lymphotoxic effects, and recent benda exposure prior to apheresis negatively impacts CD19 CAR T-cell efficacy and survival outcomes in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL; Iacoboni et al. JCO 2024). Whether this effect applies to bispecific antibodies (BsAb) remains unclear. Prior studies have been limited by small sample size, focus on clinical trial populations, or inclusion of pts treated with combination BsAb therapy. This study evaluates the impact and timing of prior benda exposure on BsAb monotherapy outcomes in real-world pts with R/R LBCL and follicular lymphoma (FL).
Methods This was a retrospective multicenter observational study of pts who received CD3xCD20 BsAb monotherapy between 2017 and 2025 for R/R LBCL or FL from 9 US medical centers who comprise the Collaborative US Bispecific Consortium (CUBIC). We compared response rates and survival outcomes based on prior benda exposure. Separate analyses were performed for LBCL and FL cohorts. Finally, we examined the impact of time from last benda dose on BsAb efficacy outcomes.
Results We included 265 pts (179 with LBCL, 86 with FL). Fifty (28%) of the LBCL cohort and 52 (60%) of the FL cohort had prior benda with median time from benda exposure to BsAb of 16.5 (IQR 6.4-28.7) and 70.5 (IQR 31.3-95.3) months, respectively. Median follow-up was 11 months (range 1-36). Median age was 70 years (IQR 62-78), 161 (61%) were male, and 51 (21%) had ECOG > 1. In the LBCL cohort, median number of prior lines (LOT) was 3 (range 1-11), 136 (80%) were refractory to the last line prior to BsAb, and 100 (56%) had prior CAR T therapy. Benda-exposed pts had more prior lines (median 4 vs. 3, p<0.001) and a higher rate of prior CAR T therapy (69 vs. 51%, p=0.029). In the FL cohort, median prior LOT was 3 (range 1-14), 35 (41%) had POD24, and 15 (17%) had prior CAR T therapy. Baseline characteristics were comparable between benda-exposed and -naïve pts in the FL cohort.
In the LBCL cohort, there were no differences in objective response rate (ORR: 48 vs. 53%, p=0.6) or complete response rate (CRR: 29 vs. 35%, p=0.6) between the benda-exposed and -naïve groups. Among all LBCL pts, median progression-free survival (PFS) was 3.1 months (95% confidence interval [CI]: 2.2-4.3) and median overall survival (OS) was 7.1 months (95% CI: 5.4-10.8). There were no significant differences in PFS or OS between the benda-exposed and -naïve groups, with median PFS 2.3 months (95% CI: 1.6-4.9) vs. 3.6 months (95% CI: 2.4-4.6; p=0.73), and median OS 7.0 months (95% CI: 4.4-21.2) vs. 7.7 months (95% CI: 5.2-12.4; p=0.95), respectively. Finally, benda-exposed and -naïve groups experienced similar rates of CRS (any-grade: 43 vs. 58%, p=0.12; grade 2+: 23 vs. 23%, p>0.9) and ICANS (any-grade: 12 vs. 15%, p=0.7; grade 2+: 4 vs. 8.1%, p=0.5).
In the FL cohort, there were no differences in ORR (88% vs. 88%) or CRR (63 vs. 79%, p=0.2) between the benda-exposed and -naïve groups. Among all FL pts, median PFS was 20 months (95% CI: 13.9-NR) and median OS was not reached (NR). There were no significant differences in PFS between the benda-exposed and -naïve groups (median 20 months (95% CI: 11.3-NR) vs. NR; p=0.12). Finally, pts in the benda-exposed group experienced numerically higher rates of any-grade CRS (42 vs 26%, p=0.2) and ICANS (8.2 vs 0%, p=0.14), but this did not reach statistical significance. Rates of grade 2+ CRS (7.0 vs 2.9%, p=0.6) and ICANS (0 vs 0%) were similar.
We additionally explored the impact of benda timing on survival outcomes by restricting analyses to pts with the shortest quartile (Q1) of time from last benda dose (< 6.4 months for LBCL and < 31.3 months for FL cohorts). Compared to their respective benda-naïve cohorts, there were no differences in ORR, CRR, PFS or OS between the Q1 benda-exposed and benda-naïve groups in either LBCL or FL.
Conclusions Benda exposure prior to BsAb therapy did not appear to negatively impact response rates or survival outcomes in a real-world population of R/R LBCL or FL, even when restricting analyses to pts with more recent benda exposure. These results add to a growing body of evidence suggesting that benda exposure prior to BsAb may not have the same negative impact on clinical outcomes as observed with CAR T therapy. Larger sample size, longer follow-up, and closer evaluation of T cell fitness will be important to better understand the impact of benda on BsAb outcomes.
