Impact of bridging therapies prior to CAR T cell therapy for large B-cell lymphoma: Real-world analysis from the cell therapy consortium

Abstract

Abstract Introduction Treatment with anti-CD19 CAR T cell therapy for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) often requires bridging therapy (BT) to stabilize disease while awaiting CAR T cell infusion. There are varying BT approaches with limited real-world data available regarding its effect on outcomes. We performed a retrospective multicenter study to assess the impact of BT on outcomes in R/R LBCL pts treated with CAR T. Methods Pts aged ≥ 18 years (yrs) with LBCL who received commercial CAR T at 9 academic US medical centers from 4/2016-7/2024 were identified in the Cell Therapy Consortium registry. BT initiated prior to leukapheresis and continued until lymphodepleting chemotherapy (LDc) was subclassified as holding therapy (HT). CRS and ICANS were graded per ASTCT consensus criteria. Tumor response was assessed per Lugano criteria. Results Among 714 total pts, 429 (60%) received BT, of whom 66 (15%) received HT. Median age at leukapheresis for pts receiving BT was 64yrs with 27% >70yrs, 63% were male, 15% had an ECOG performance status (PS) ≥ 2, and 18% were non-Caucasian. Median prior lines of therapy received was 3, with 48% of pts receiving axi-cel, 36% tisa-cel, and 16% liso-cel. Flu/Cy LDc was used in 78% of pts and bendamustine in 21%; 46% of pts had elevated LDH pre-LDc, and 50% achieved an objective response to BT. Among pts receiving BT, 42% received systemic chemotherapy (chemo) while 58% received non-chemo-based BT. Median follow-up for all pts was 12.4mo (range: 0.1-67 mo). PFS at 12 mo for all pts was 46% (95%CI: 43-50%). Pts receiving BT had a 12mo PFS of 40% (95%CI: 36-45%) vs 55% (95%CI: 50-61%) for no BT (p<0.01). OS at 12 mo was 65% (95%CI: 61-69%) for all pts. Pts receiving BT had a 12 mo OS of 58% (95%CI: 53-63%) vs 76% (95%CI: 71-81%) for no BT (p<0.01). Non-relapse mortality (NRM) at 12mo for all pts was 5% (95%CI: 4-7%); 12mo NRM for those receiving BT was 7% (95%CI: 4-10%) vs 3% (95%CI: 1-4%) (p=0.03). Any grade CRS occurred in 66% of all pts receiving BT (4% grade 3-4). Any grade ICANS occurred in 36% of pts (7% grade 3-4). There were no differences in rates of CRS or ICANS by receipt of BT. Among pts receiving BT, 37% died related to lymphoma at a median 4.2 months post-infusion, 6 (1%) pts died due to CRS and/or ICANS, while the most common other cause of death was infection (5%). Among pts receiving BT, 404 (94%) pts were evaluable at 90 days post-infusion; objective response rate (ORR) was 49% and complete response (CR) rate was 40%. BT was started at a median 4 days (IQR 1-9) after leukapheresis, while in 66 (15%) pts HT was employed at a median 19 days (IQR 10-30) before leukapheresis. There was no difference in PFS (p=0.34) or OS (0.49) among pts receiving HT vs BT. Pts receiving chemo as BT had inferior 12mo PFS (34%, 95%CI: 28-42%) compared to those who received non-chemo BT (44%, 95%CI: 38-51%). Among pts who received pola-based BT, 12mo PFS and OS did not differ based on addition of bendamustine to pola (p=0.43). Factors associated with PFS on multivariable analysis (MVA) were elevated LDH pre-LDc (HR 2.3, p<0.01) and receipt of BT (HR 1.5, p<0.01). Factors associated with OS on MVA were ECOG PS (HR 1.7, p<0.01), elevated LDH pre-LDc (HR 2.0, p<0.01), primary refractory disease (HR 1.3, p=0.03), and history of CNS disease (HR 1.6, p<0.01). On MVA, after correcting for time-dependency, receipt of BT did not have a significant impact on OS. Propensity-score matching (PSM) by baseline patient characteristics showed that pts receiving BT (n=223) had an inferior 12mo PFS of 39% (95%CI: 33-46%) compared to 55% (95%CI: 49-62) (p<0.01) in pts (n=223) not receiving BT. Matched pts receiving BT also had an inferior 12mo OS of 58% (95%CI: 52-65%) compared to 75% (95%CI: 69-81%) (p<0.01) in pts not receiving BT. Conclusions In this large real-world analysis of BT practices and outcomes, pts receiving BT experienced inferior outcomes, even after PSM by baseline characteristics. Our analysis suggests that while receiving BT is an adverse prognostic factor, this is time-dependent at earlier times after CAR T cell therapy and may be a surrogate for more aggressive disease. In our subgroup analyses, non-chemo BT was associated with superior efficacy compared to chemo-based BT, and early institution of HT did not compromise CAR T efficacy. Exploration of novel BT modalities such as bispecific antibodies are warranted to further augment CAR T outcomes in pts receiving BT.