Outcomes of bispecific antibody therapy after CAR T-cell failure in relapsed/refractory large B-cell lymphoma

• Early relapse post-CAR-T (≤3 mo) is associated with poor outcome of subsequent BsAb therapy

• LDH, higher IPI, refractoriness to the last therapy predict poor outcome of BsAb following CAR-T failure

Patients with large B-cell lymphoma (LBCL) who experience relapsed disease after CD19-directed CAR T-cell therapy (CAR-T) have a poor prognosis. Bispecific antibodies (BsAbs) induce complete remissions in approximately 35% of these cases. Hypothesizing overlapping LBCL-intrinsic resistance mechanisms as well as common poor prognosis predictors to CAR-T and BsAb therapy, we conducted a multicenter retrospective analysis including 92 relapsed/refractory (r/r) LBCL patients treated with BsAb after CAR-T failure. Overall response rate (ORR) was 43% with a progression-free survival (PFS) of 2.8 months (mo). BsAb patients in early relapse (≤3 mo) achieved a significantly worse outcome (ORR of 29%, PFS 2.2 mo) compared to patients with an intermediate (4-6 mo, ORR 54%, PFS 3.7 mo) or a late relapse (>6 mo, ORR 60%, PFS 10.5 mo). The benefit of later relapse was particularly notable in patients receiving BsAb as first salvage therapy compared to those receiving BsAb in subsequent lines (PFS not reached vs. 2.7 mo; overall survival not reached vs. 9.1 mo). In addition to early relapse/refractory state prior to BsAb, elevated LDH and higher IPI were significant predictors of poor outcomes to BsAb in multivariate Cox-regression analyses. That patients with early relapse following CAR-T respond particularly poorly to BsAb highlights the necessity for alternative treatment options in this high-risk patient cohort.