Sequencing CD20-directed bispecific antibody and CD19-directed CAR T cell therapy in large B cell lymphoma: A multicenter real-world study

Abstract Introduction Multiple T-cell engaging therapies, including CD20-directed bispecific antibodies (BsAb) and CD19-directed chimeric antigen receptor T cell therapy (CAR T), are approved for use in relapsed and refractory (R/R) large B cell lymphoma (LBCL). However, there are few data on the outcomes of these therapies in patients (pts) who had already received another T cell-directed treatment. Methods We performed a retrospective study evaluating outcomes of pts who received both standard-of-care BsAb and CAR T for LBCL across 9 centers (CUBIC consortium). Pts were assigned to 1 of 2 cohorts: those who received CAR T before BsAb, and those who received BsAb before CAR T. The primary outcome was progression-free survival (PFS) following CAR T therapy in the CB cohort, and complete response rate (CRR) in the BC cohort. Other outcomes of interest included overall response rate (ORR), overall survival (OS), cytokine release syndrome (CRS), and immune effector cell associated neurologic toxicity (ICANS) rates. Results A total of 160 pts were included in the study: 144 with CAR T before BsAb, and 16 with BsAb before CAR T. CAR T before BsAb At BsAb initiation, median age was 68 (IQR 57-75) and 65% were male; 86% were white, and 13% Hispanic. Pts had a median of 3 prior lines of treatment (LOT) and median IPI at BsAb initiation of 3. Best ORR to prior CAR T was 70%, and CRR 39%. Median time from CAR T to BsAb was 5.6 months (mo) (IQR 3.1-11.6). BsAb was epcoritamab in 71 (49%), glofitamab in 68 (47%), and mosunetuzumab in 5 (4%); 21 (15%) received additional systemic therapy or radiation with bispecific treatment. Best ORR to BsAb was 51% (95% CI 42-60), and CRR 34% (95% CI 26-43). At a median follow-up of 11.4 mo, median PFS was 3.6 mo (95% CI 2.1-4.6) and median OS 10.5 mo (95% CI 6 – NR). On multivariate analysis, a shorter interval between CAR T and BsAb was independently associated with higher risk of progression (0-3 mo vs >12 mo, HR 2.8, 95% CI 1.2 – 6.4; 3-6 mo vs >12 mo, HR 2.2, 95% CI 1.01 – 4.8; 6-12 mo vs > 12 mo, HR 0.7, 95% CI 0.3 – 1.6). Other factors independently associated with progression included more prior lines of treatment (2 vs ≥ 4, HR 0.37, 95% CI 0.2 – 0.7; 3 vs ≥ 4, HR 0.54, 95% CI 0.3 – 0.96); and albumin below median (HR 1.85, 95% CI 1.1-3.3). CRS occurred after BsAb in 49 pts (35%) with Grade (G)≥3 in 4 (3%). ICANS was reported in 11 (7.8%), G≥3 in 1 (0.7%). Post-BsAb CRS was not more frequent with prior CAR T CRS history (35% with CRS history vs 37% without), nor was ICANS in those with CAR T ICANS history (10% with ICANS history vs 8.6% without). BsAb before CAR T A total of 16 pts received BsAb prior to CAR T (axi-cel, n = 7; liso-cel, n = 6; tisa-cel, n = 3). Median age was 66 and 75% were male. At BsAb initiation, median IPI was 4 and median prior LOT 3. Median time from BsAb initiation to CAR T was 72 days (IQR 48-140); 10 pts began BsAb therapy prior to apheresis for CAR T (6 as standalone therapy and 4 as bridging therapy to CAR T), while 6 pts received bridging BsAb therapy only after completing apheresis. In 12 pts assessed for BsAb response, ORR was 67% and CRR 33%. Disease progression to BsAb was present in 9 pts at time of CAR T initiation, while 7 proceeded to CAR T without documented progression to BsAb. In 15 evaluable pts, the ORR to CAR T after BsAb was 73% (95% CI 45-92%), and CRR 47% (95% CI 21-73%). Median follow-up after CAR T was 3.6 mo; 3-mo PFS was 57% and 3-mo OS 72%. In 9 evaluable pts who received BsAb prior to apheresis, ORR to CAR T was 78% (95% CI 40-97), with CRR 56% (95% CI 21-86%). In 9 pts with evidence of progression to BsAb prior to CAR T, response rates to CAR appeared to be lower (ORR 66%, CRR 23%). In 6 pts without progression to BsAb before CAR T initiation, ORR and CRR were both 83%. After CAR T, CRS was seen in 75% of pts (all G1-2) and ICANS in 44% (including G3-4 in 19%). Discussion In this real-world study, PFS with BsAb therapy after CAR T was comparable to reported outcomes in pts without prior CAR T, though longer time from CAR T to BsAb was strongly associated with BsAb efficacy. To our knowledge, this is also the first study evaluating real-world BsAb use prior to CAR T. Despite high-risk disease features, the observed efficacy of CAR T after BsAb was not markedly different than that reported in the literature without prior BsAb treatment. Given this is a relatively small and heterogenous cohort, larger studies with longer follow-up are needed.