Arnason, Jon

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351 ) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD] neg ) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg . Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD neg . ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD neg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Abstract Introduction Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), with axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) both being approved for use. Axi-cel was approved for second-line setting based on studies showing improved outcomes compared to high-dose salvage chemoimmunotherapy followed by autologous hematopoietic stem cell transplantation (HSCT). In contrast, tisa-cel did not demonstrate superiority over traditional salvage therapies in the second-line setting. Although both therapies are currently used in clinical practice, real-world comparative data on the safety of axi-cel versus tisa-cel remain limited. This retrospective study aims to compare the one-year outcomes of axi-cel and tisa-cel in patients with R/R DLBCL, offering practical insights into their outcomes outside of clinical trial settings. Methods A retrospective cohort study was conducted using TriNetX, a global federated health research network that provides access to electronic medical records from approximately 132 million patients, primarily in the United States. Adult patients (≥18 years) diagnosed with R/R DLBCL between January 1, 2022, and January 1, 2024, were identified using ICD-10-CM codes. Patients were categorized into two cohorts: those who received axi-cel and those who received tisa-cel. Propensity score matching (1:1) using nearest neighbor matching with a 0.1 pooled standard deviation caliper was performed for demographics, comorbidities, prior stem cell transplantation, and medications. Study outcomes included 1-year rates of all-cause mortality, all-cause hospitalization, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), anemia, neutropenia, thrombocytopenia, heart failure exacerbation, and acute myocardial infarction. Statistical analyses were conducted on the TriNetX platform, with significance set at P<0.05 (two-sided). TriNetX calculates hazard ratios (HRs) and cumulative incidences (CIs) using R survival package version 3.2-3 with the proportional hazard assumption tested using Schoenfeld residuals. This study does not require Institutional Review Board review or informed consent due to the use of de-identified data. Results Our study identified 1,250 patients with R/R DLBCL, including 1,083 patients who received axi-cel and 167 who received tisa-cel. After propensity score matching (PSM), 160 patients were in the axi-cel group (mean age 61.7 ± 11.8 years; 38.8% female; 73.1% White, 8.1% African American) and 160 patients were in the tisa-cel group (mean age 62.3 ± 16.0 years of age; 39.4% female; 75.0% White, 7.5% African American). Axi-cel group had 45% lower risk of all-cause mortality compared to tisa-cel group (HR: 0.55; 95% CI: 0.34–0.87). However, axi-cel group was associated with higher risks of all-cause hospitalization (HR: 1.33; 95% CI: 1.04–1.70), CRS (HR: 2.19; 95% CI: 1.43–3.36), and ICANS (HR: 2.69; 95% CI: 1.42–5.11) compared to tisa-cell group. No significant differences were observed in anemia (HR: 1.18; 95% CI: 0.82–1.72), neutropenia (HR: 1.30; 95% CI: 0.96–1.77), and thrombocytopenia (HR: 0.96; 95% CI: 0.65–1.43) between these two treatment groups. Additionally, there were no significant differences in terms of septic shock (HR: 0.79; 95% CI: 0.42–1.47), pneumonia (HR: 0.64; 95% CI: 0.34–1.21), and heart failure exacerbation (HR: 1.16; 95% CI: 0.76–1.76) between axi-cel group and tisa-cell group. Conclusion This large and multicenter cohort study provides real-world valuable insights into the one-year comparative outcomes of axi-cel and tisa-cel in patients with R/R DLBCL. Our study suggested axi-cel was associated with lower mortality rate, despites its higher rates of all-cause hospitalization, CRS, and ICANS compared to tisa-cell. These findings highlight the importance of close monitoring and supportive care during the first year following CAR-T therapy to optimize patient outcomes. An important limitation of our study is the lack of data on the number of prior lines of therapy, which may have differed between treatment groups and could have influenced clinical outcomes. Future prospective studies with comprehensive clinical data and inclusion of lisocabtagene maraleucel (liso-cel) would be valuable to provide a more complete comparison across currently available CAR T-cell therapies.

Abstract Introduction: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. TRANSFORM (NCT03575351) is a global, randomized, open-label, phase 3 study of liso-cel versus SOC as second-line therapy in adults with R/R LBCL. In the TRANSFORM study, liso-cel showed superior, more durable efficacy versus SOC, with a potential long-term survival benefit and a favorable safety profile, highlighting the curative potential of liso-cel for second-line R/R LBCL. Upon completion of TRANSFORM, patients who received liso-cel could enroll into a separate, long-term follow-up (LTFU) study (NCT03435796). Here, we report results after approximately 4 years of follow-up in patients from TRANSFORM who consented to the LTFU study. Methods The TRANSFORM study compared liso-cel versus SOC (chemotherapy [R-DHAP, R-ICE, or R-GDP] followed by high-dose chemotherapy [HDCT] + ASCT) in adults aged ≤ 75 years with LBCL primary refractory to or relapsed within 12 months of first-line therapy and eligible for ASCT. Patients in the liso-cel arm underwent lymphodepletion followed by liso-cel (100 × 106 CAR+ T cells). Crossover to receive liso-cel was allowed for patients in the SOC arm. The LTFU study enrolled patients who received liso-cel and discontinued early or completed TRANSFORM; liso-cel was not administered during the LTFU study and subsequent therapies were administered at investigator discretion. Selected AEs considered related to liso-cel (malignancies, neurologic, hematologic, or rheumatologic/autoimmune disorders) and OS would be assessed at each visit (month 3 and then every 6 months from years 1 to 5, and then annually) for up to 15 years from liso-cel infusion until study withdrawal or death, whichever occurred first. OS for the combined study was defined as the time from randomization to death due to any cause. PFS for the combined TRANSFORM and LTFU studies incorporated data from TRANSFORM, assessed by an independent review committee, and from LTFU, assessed by investigators, and was defined as the time from randomization to disease progression or death from any cause. For LTFU only, OS and PFS were measured from LTFU consent to event or censoring. In cases where the patient was censored at last assessment date (without receiving new therapy) in TRANSFORM and enrolled in LTFU, LTFU data were used. For patients from the liso-cel arm of TRANSFORM who did not enroll in the LTFU study, the data from TRANSFORM were considered (ie, either an event or censored) at their last adequate assessment date or before starting new therapy. Results are reported descriptively. Results In total, 184 patients were randomized in TRANSFORM (92 per arm); key demographics and baseline characteristics were previously reported (Abramson, et al. Blood 2023). The LTFU study enrolled 67 patients who received liso-cel (liso-cel arm, n = 43; crossover from SOC arm, n = 24). The median follow-up (range) for the liso-cel arm was 16.9 months (1.3–29.7) in the LTFU study and 40.1 months (2.2–61.9) combining the TRANSFORM and LTFU studies. The median follow-ups for OS and PFS for the liso-cel arm in the LTFU study were 17.1 (16.1–21.9) and 16.9 months (16.0–21.8), respectively. In patients from the LTFU study in the liso-cel arm (n = 43), median PFS and OS were both not reached (NR) with 95% CIs of NR–NR. The 24-month rates (95% CI) of PFS and OS were 94.7% (87.4–100.0) and 95.1% (88.4–100.0), respectively. In the 92 patients randomized to the liso-cel arm, using combined data from the TRANSFORM and LTFU studies, median (95% CI) PFS was NR (12.6–NR); 48-month PFS rate was 52.2% (41.5–62.8). Median (95% CI) OS was NR (NR–NR); 48-month OS rate was 61.5% (51.2–71.7). Safety results from the LTFU study in the liso-cel arm showed no new signals compared with previous reports from TRANSFORM. AEs of any grade occurred in 2 patients (hypogammaglobulinemia and dyspnea; n = 1 each), with no second primary malignancies or serious infections. AEs of grade 3 or 4 occurred in 1 patient (dyspnea). No AEs led to death.Conclusions: After a median follow-up of approximately 4 years combining data from the TRANSFORM and LTFU studies, liso-cel continued to demonstrate long-term clinical benefit with high PFS and OS rates in patients with second-line R/R LBCL. The safety profile of liso-cel continued to be manageable with no new safety signals observed during LTFU. These results further support liso-cel as an effective second-line treatment with curative potential for R/R LBCL.

We report 3-year follow-up results from TRANSFORM comparing lisocabtagene maraleucel (liso-cel) versus standard of care (SOC) for second-line primary refractory/early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (N = 184) were randomly assigned 1:1 to liso-cel (100 × 10 6 chimeric antigen receptor–positive T cells) or SOC. Results are reported descriptively. With a median follow-up of 33.9 months, median (95% CI) event-free survival was 29.5 months (9.5 to not reached [NR]) for liso-cel versus 2.4 months (2.2 to 4.9) for SOC (hazard ratio [HR], 0.375; 95% CI, 0.259 to 0.542). Median progression-free survival was NR (12.6-NR) for liso-cel versus 6.2 months (4.3-8.6) for SOC (HR, 0.422; 95% CI, 0.279 to 0.639) with 36-month rates of 51% versus 26.5%. Median overall survival (OS) was NR for both arms (HR, 0.757; 95% CI, 0.481 to 1.191), with 66% of patients crossing over to receive liso-cel; 36-month OS rate was 63% for liso-cel versus 52% for SOC. OS HR (0.566 [95% CI, 0.359 to 0.895]) favored liso-cel when accounting for the treatment effect of crossover. Safety results were consistent with previous reports. At 3-year follow-up, liso-cel confirmed superior, more durable efficacy versus SOC with a favorable safety profile and no new safety signals. These data support liso-cel as an effective second-line treatment with curative potential for relapsed/refractory LBCL.

Abstract Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post–CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell–associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

Introduction CD19-directed CAR T-cell therapies are an important option for the management of relapsed/refractory (R/R) DLBCL. Studies suggest that ~50% of pts receiving CAR T-cell therapies will relapse within 6 months, with an estimated overall survival (OS) of only 5 months. Additionally, 25-35% of pts do not receive subsequent treatment, indicating a high unmet need. CD19 loss is a potential mechanism of resistance to CAR T-cell therapies; thus, treatments that target alternate B-cell antigens are an attractive option. Here, we report for the first time the primary analysis of the ELM-1 expansion cohort investigating the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in pts with R/R DLBCL progressing after CAR T-cell therapy (NCT02290951). Methods Pts aged ≥18 with DLBCL and disease progression after CAR T-cell therapy received intravenous odronextamab weekly in 21-day (D) cycles during Cycles (C) 1-4, with steroid prophylaxis and step-up dosing in C1 (described previously), followed by 160 mg on D 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg Q2W until disease progression or unacceptable toxicity. Pts with complete response (CR) for ≥9 months transitioned to Q4W dosing. All pts received infection prophylaxis. The primary analysis was conducted when all pts had completed ≥9 months of follow-up. Primary endpoint was objective response rate (ORR), as assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and OS. Exploratory endpoints included immune biomarker assessment. Results As of January 22, 2024, 60 pts were treated and evaluable for efficacy and safety, with median follow-up of 16.2 months. Prior CAR T-cell therapies were axi-cel (50%), tisa-cel (12%), liso-cel (10%), and not specified (28%). Median time since prior CAR T-cell therapy was 6.5 months (range 1.2-46.2). Median age was 63 years (range 27-82; aged ≥75 years: 10%), and 65% were male. Pts had received a median of 3 prior lines of therapies (range 2-9); 77% of pts were refractory to their last therapy, 77% were double refractory, and 72% were refractory to prior CAR T-cell therapy. 48% of pts relapsed within 90 D of CAR T-cell therapy, and 67% relapsed within 180 D. Of the 20 pts with available tumor biopsies at baseline, 10 were CD19(-) and only 2 were CD20(-). 92% of pts completed C1 and 52% completed ≥4 C of treatment. The median duration of treatment was 12 weeks (range 0.7-154.1). The ORR and CR rate by ICR were 48% and 32%, respectively, and were consistent across pts with high-risk features and across prior CAR T products. ORR in pts relapsing in ≤90 D was 21% (6/29) and in pts relapsing in ≤180 D was 33% (13/40). ORR was observed even in pts with low CD20. Median DOR was 14.8 months (95% CI 2.8-not estimable [NE]) and median duration of CR was not reached (NR) (95% CI 3.3-NE); the probability of maintaining CR for 24 months was 68%. Median PFS was 4.8 months (95% CI 2.6-5.4) and median OS was 10.2 months (95% CI 4.6-15.8). Median PFS and OS in complete responders was NR. T-cell counts increased at Week 14 and demonstrated a functional phenotype (CD69 expression and TEMRA count), which was confirmed by ex vivo stimulation. T-cell expansion was observed regardless of CAR T product or time from CAR T administration. The most common TEAE was CRS (any grade [G]: 48%; G1: 25%; G2: 23%; G≥3: 0%). G≥3 TEAEs occurred in 77% of pts (most common: neutropenia 17%, anemia 13%, and neutrophil and white blood cell count decrease 10% each). Five pts (8%) permanently discontinued odronextamab due to AEs (COVID-19, pneumonia, encephalopathy, epilepsy, and gait disturbance [n=1 each]). There was one treatment-related death (COVID-19 pneumonia). No cases of ICANS were reported. G≥3 infections occurred in 12 pts (20%); 2 were due to COVID-19. No cases of tumor flare or TLS were reported. Conclusions ELM-1 is the only study to prospectively evaluate efficacy and safety of a CD20×CD3 bispecific antibody in pts with R/R DLBCL progressing after CAR T-cell therapy. Odronextamab monotherapy was associated with encouraging efficacy and generally manageable safety in a setting with limited treatment options and historically dismal outcomes. Efficacy was observed even in pts relapsing in ≤90 D, supporting the potential of odronextamab as an accessible, off-the-shelf option in the post-CAR T setting.

Background: ctDNA clearance after frontline DLBCL tx has shown strong prognostic value for favorable outcomes, with the potential to improve MRD-driven therapeutic strategies and establish MRD as a surrogate endpoint in future studies (Roschewski M, et al. Blood 2022; Goldstein J, et al. Blood 2023). However, further study is needed to evaluate the association of this noninvasive approach with efficacy outcomes after 2L LBCL tx. We previously reported ctDNA analysis after liso-cel infusion in TRANSFORM (NCT03575351; Stepan L, et al. Blood 2023;142[suppl 1]). Here, we describe the predictive value of pre-tx and on-tx ctDNA levels for durable clinical benefit (CR and event-free survival [EFS]) in both liso-cel and SOC arms from TRANSFORM (Kamdar M, et al. J Clin Oncol 2024), evaluating ctDNA as an earlier surrogate for conventional clinical outcomes. Methods: Baseline (prerandomization) and longitudinal ctDNA levels were assessed in randomized pts treated with liso-cel or SOC in TRANSFORM using the phased variant enrichment and detection sequencing assay (PhasED-Seq; Foresight Diagnostics). Phased variants were identified from baseline plasma samples for longitudinal ctDNA monitoring at multiple on-tx time points, as previously described (Stepan L, et al. Blood 2023;142[suppl 1]). Randomization was defined as study Day 1. Association of ctDNA levels with response per independent review committee using Lugano 2014 criteria and EFS was investigated at various predefined time points, including Day 43 (after 2 cycles of salvage immunochemotherapy for SOC; Day 15 after liso-cel infusion), Day 64 (after 3 cycles of salvage immunochemotherapy for SOC; 1 month after liso-cel infusion), and Day 126 (within 2 months after ASCT; 3 months after liso-cel infusion). To assess the surrogacy value of ctDNA, ctDNA-MRD dynamics and ctDNA clearance were investigated within both arms. Results: In pooled analyses combining the liso-cel and SOC arms, higher baseline ctDNA levels (above the median) were associated with shorter EFS (P = 0.05). Pts achieving Day 126 CR had substantial reductions in ctDNA burden vs baseline, while pts with PD or stable disease had persistently high ctDNA levels vs baseline. Achieving undetectable ctDNA at different time points was associated with significantly longer EFS in pooled analyses, observed as early as study visit Day 43, with the strongest association at Day 126. HR (95% CI) for inferior EFS was 3.0 (1.6-5.7) at Day 43, 3.8 (2.1-7.0) at Day 64, and 4.2 (2.3-7.7) at Day 126 in pts with detectable vs undetectable ctDNA. In the analysis by tx arm, consistent with the pooled analyses, ctDNA clearance was associated with EFS benefit at all measured time points with either liso-cel or SOC. Significantly more pts achieved undetectable ctDNA with liso-cel vs SOC during the study (39/63 [62%] vs 25/65 [38%], respectively; P = 0.013), consistent with superior EFS (primary endpoint) with liso-cel in TRANSFORM. All pts in the SOC arm with evaluable ctDNA at Day 126 (n = 28) had received high-dose chemotherapy (HDCT)/ASCT. However, pts with undetectable ctDNA in the liso-cel vs SOC arm had longer EFS at all predefined time points and had statistically longer EFS at Day 126 (SOC vs liso-cel: HR, 3.9 [95% CI, 1.4-10.6]), indicating a deeper and more durable response with liso-cel vs SOC. In pts with CR, ctDNA showed significant predictive value beyond the response assessment at all time points in the liso-cel arm with a HR (95% CI) of 3.8 (1.3-11.0) at Day 64 and 7.0 (2.0-24.3) at Day 126 for EFS in pts with detectable ctDNA vs undetectable ctDNA. Among pts in the SOC arm who experienced subsequent PD despite achieving CR (all received HDCT/ASCT) and undetectable ctDNA at Day 126, serial ctDNA assessment showed consistent reversion to detectable ctDNA at later time points. Conclusions: ctDNA data from TRANSFORM confirm the value of ctDNA as a biomarker for disease burden monitoring and early prediction of durable clinical benefit after 2L LBCL treatment. Furthermore, longitudinal ctDNA molecular response results agree with previously reported clinical efficacy data and confirm the superiority of liso-cel with deeper responses over the historical SOC in 2L LBCL. ctDNA may have a key role as a surrogate endpoint in future LBCL studies, including after CAR T cell therapies.

Background: In TRANSCEND CLL 004 (NCT03331198),monotherapy with liso-cel, an autologous, CD19-directed CAR T cell product (100 × 106 CAR+ T cells [dose level (DL) 2]), resulted in 43% ORR and 18% CR/CR with incomplete marrow recovery (CRi) rate per IRC in pts with third-line or later R/R CLL/SLL who had PD on Bruton tyrosine kinase inhibitor (BTKi) and failed venetoclax (Siddiqi T, et al. Lancet 2023). Ibr + other CAR T cell therapies has shown high ORR and reduced cytokine release syndrome (CRS) severity in pts with R/R CLL/SLL. In the phase 1 dose-escalation ibr combination cohort, DL2 was the recommended dose of liso-cel for expansion (Wierda WG, et al. Blood 2020). Here, we report results of liso-cel + ibr in pts with R/R CLL/SLL from TRANSCEND CLL 004. Methods: Eligible pts ≥ 18 y of age with CLL/SLL had ≥ 1 of the following: 1) receiving BTKi with PD at entry, 2) high-risk disease and < CR after ≥ 6 mo on BTKi, 3) BTK/PLCγ2 mutation ± ibr PD, 4) prior BTKi with no contraindications to ibr, and 5) (per amendment) PD on BTKi and received prior venetoclax. At enrollment, pts started or continued ibr (420 mg daily or less for toxicity) through leukapheresis and for up to 90 d (or longer per investigator [inv]) after liso-cel (target dose of 50 × 106 CAR+ T cells [DL1] or DL2). Response was per inv by 2018 iwCLL criteria. Primary endpoint was CR/CRi rate at DL2; secondary endpoints included safety, ORR, duration of response (DOR), duration of CR/CRi (DOCR), time to response, time to CR/CRi, PFS, OS, and undetectable MRD (uMRD) rate in blood. Cellular kinetics was exploratory. Efficacy analyses were at DL2 and safety at DL1 + DL2. Treatment-emergent AEs (TEAE) occurred the latter of ≤ 90 days after liso-cel or ≤ 30 days of ibr completion. Liso-cel-treated pts who completed or withdrew from study could enroll in a separate long-term follow-up (LTFU) study (NCT03435796) for safety and OS ≤ 15 y after liso-cel. Results: A total of 65 pts underwent leukapheresis; 56 received ibr + liso-cel (DL1, n = 5; DL2, n = 51). At data cutoff (01/12/2024), 28 of 56 (50%) pts had discontinued the study, 11 (20%) completed the study, and 17 (30%) were ongoing; 5 of 28 (18%) eligible pts enrolled in LTFU. Median (IQR) on-study follow-up (including LTFU) was 24.8 mo (14.2-34.6). Median (range) age was 65 y (44-77); 55 (98%) pts had high-risk cytogenetics, such as del(17p) (n = 25), TP53 mutation (n = 24), and unmutated IGHV (n = 39); 43% had LDH ≥ ULN; and median (range) SPD was 27 cm2 (1-218). Pts had a median (range) of 5 (1-13) prior therapies (≤ 2, n = 13 [23%]). Median (range) time from leukapheresis to liso-cel availability was 25 d (17-79). Median (range) ibr exposure was 34 d (15-188) before and 94.5 d (6-1517) after liso-cel. At DL2, ORR (95% CI) was 86% (73.7-94.3), median (range) time to first response was 1.0 mo (0.9-6.0), and median (95% CI) DOR was 41.4 mo (23.3-not reached [NR]). CR/CRi rate (95% CI; primary endpoint) was 45% (31.1-59.7), median (range) time to first CR/CRi was 3.1 mo (0.9-12.1), and median (95% CI) DOCR was NR (26.6-NR). Median (95% CI) PFS and OS was 31.4 mo (20.1-NR) and NR (27.5-NR), respectively. uMRD rate (95% CI) in blood and marrow was 86% (73.7-94.3) and 84% (71.4-93.0), respectively. Grade (gr) ≥ 3 TEAEs occurred in 48 (86%) pts (most commonly neutropenia [52%] and anemia [41%]) with no gr 5 TEAEs. Liso-cel-related gr ≥ 3 TEAEs occurred in 32 (57%) pts and ibr-related gr ≥ 3 TEAEs in 24 (43%) pts including cardiovascular events of hypertension (7%) and atrial fibrillation (2%). Any-gr CRS occurred in 45 (80%) pts (gr ≥ 3, n = 2 [4%]) and any-gr neurological events (NE) in 23 (41%) pts (gr ≥ 3, n = 6 [11%]). Eight (14%) pts had gr ≥ 3 infections and 5 (9%) had second primary malignancies. Twenty-five (45%) pts had prolonged cytopenias (gr ≥ 3 at D30); most recovered to gr ≤ 2 by D90. Sixteen pts died after infusion (PD, n = 6; unknown, n = 6; COVID-19, n = 3; mixed septic/cardiogenic shock, n = 1). Liso-cel showed rapid expansion (median tmax, 10 d) and was detected up to 42 mo after infusion. Conclusions: Combined liso-cel + ibr demonstrated substantial efficacy with deep remissions (86% ORR, 45% CR rate, and 86% blood uMRD rate) and manageable safety in pts with R/R CLL/SLL. Though comparisons should be made with caution and there were differences in disease characteristics between cohorts, liso-cel + ibr showed a numerically higher ORR/CR rate and lower gr ≥ 3 CRS/NE rates vs liso-cel monotherapy, supporting the combination as a promising new therapeutic strategy for pts with R/R CLL/SLL.