Siddiqi, Tanya

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.

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.

Abstract Introduction: Lisocabtagene maraleucel (liso-cel) was approved in the United States for the treatment of CLL in 3/2024 for patients who have received two prior lines of therapy including a covalent BTK inhibitor and a BCL-2 inhibitor. Data regarding outcomes of liso-cel is limited to reports from the registrational TRANSCEND-CLL 004 clinical trial which had strict inclusion and exclusion criteria. This work investigates the real-world efficacy and safety of liso-cel for patients with CLL and its efficacy in specific sub-populations. Methods: This is a multi-institutional retrospective study (Collaborative Assessment of Real-World Evidence of Lisocabtagene Maraleucel in Patients with Relapsed/Refractory CLL/SLL [CARE CAR-T CLL]) of patients with CLL who received commercial liso-cel in the United States. Patients with Richter transformation were excluded. Response was defined by iwCLL criteria. Patients who did not undergo a marrow biopsy but met other criteria for a complete response (CR) were categorized as unconfirmed CR (CRu). CRS and ICANS were graded per ASTCT criteria. Results: A total of 30 patients were identified with a median age of 67 years (range 44 – 80). Twenty of thirty patients (67%) had either del17p and/or mutated TP53, and 8/30 (27%) had complex karyotype (≥ 3 abnormalities) at time of liso-cel infusion. Patients received a median of 6 prior lines of therapy (range 1 - 12), and 24 (80%) were previously treated with chemotherapy. All patients had previous exposure to a covalent BTK inhibitor and a BCL-2 inhibitor. Twenty-seven (90%) of patients had prior exposure to pirtobrutinib. Twenty-nine patients (96.7%) received bridging treatment that was stopped after leukapheresis with 1 patient in CR and 25 patients in PR at time of liso-cel. Eighteen patients (60%) were treated with pirtobrutinib as the last line of treatment prior to liso-cel. Median length of time on pirtobrutinib prior to liso-cel infusion was 4 months (interquartile range [IQR], 2 – 8 months). Twelve (66.7%) patients stopped pirtobrutinib between leukapheresis and lymphodepletion, and 6 continued after liso-cel. Best CR/CRu rate was 60.0% (CR, n = 17/30; CRu, n = 1/30), and best overall response rate (ORR) was 83.3% (25/30) with median time to best response of 30 days (IQR, 28 – 30 days). Of the 18 patients who received pirtobrutinib as their last line of therapy, 13 (72%) achieved a CR/CRu. Meanwhile, of the 12 patients who did not receive pirtobrutinib as their last line of therapy, only 5 (28%) achieved a CR. Measurable residual disease testing (MRD) by flow cytometry was done in 14/30 patients, and 9 patients (64%) had achieved undetectable MRD (uMRD). MRD by next generation sequencing (NGS) was done in 17 patients, and 7 (41%) patients had uMRD. Twenty-seven of 30 patients (90%) were alive at time of data collection. Median follow-up was 3.3 months (IQR, 1.2 – 8.9 months). Twenty-six patients (87%) experienced any grade cytokine release syndrome (CRS), and 3 patients experienced grade 3 CRS (10%). Twelve patients (40%) experienced any grade immune effector cell-associated neurotoxicity syndrome (ICANS), and 4 patients (13%) experienced grade 3 ICANS. There were no grade 4 or 5 CRS or ICANS. One patient experienced grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). At day 30, patients had a median absolute neutrophil count of 1.7K/μL (IQR, 0.8 – 3.6K/μL), hemoglobin of 11.7 g/dL (IQR, 8.6 – 13.1 g/dL), and platelet count of 72K/μL (IQR, 29 – 119K/μL). Conclusion: Real-world analysis of liso-cel for patients with relapsed/refractory CLL showed CR and ORR of 60.0% and 83.3%, respectively. Despite having a heavily pre-treated and chemotherapy-exposed population and with over half the patients having high-risk features, these response rates are higher than what was described in the TRANSCEND-CLL 004 clinical trial. These results are limited by the short follow-up period and the variability in response assessment typical of a retrospective study. As we increase our sample size, we will also be interested if the use of the non-covalent BTK inhibitor pirtobrutinib prior to liso-cel is associated with a higher CR rate, mimicking the findings of the sub-cohort analysis of TRANSCEND-CLL 004 where the concurrent use of ibrutinib led to higher CR rates. Further updates and patients from additional collaborators will be presented at the meeting.

7037 Background: TRANSCEND CLL 004 (NCT03331198) is a phase 1/2, open-label, nonrandomized, multicohort study in adult patients (pt) with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma with liso-cel mono and liso-cel + ibrutinib combo cohorts. Given the study design, we performed PS matching/weighting to adjust for differences in key covariates between cohorts to compare efficacy and safety. Methods: Here, PS is the probability of receiving combo given the covariates and estimated by logistic regression. Covariates were hemoglobin, LDH, number of prior therapies, platelets, prior BTKi + venetoclax exposure, R/R on prior BTKi, and bulky disease for efficacy; and ALC, bulky disease, CRP, ferritin, and number of prior therapies for safety. PS balancing methods were optimal 1:1 matching, average treatment effect for treated pts (ATT) full matching, and ATT inverse probability of treatment weighting (IPTW). Efficacy endpoints were response (CR rate, ORR) and time to event endpoints (DOR, PFS, OS). Safety endpoints were proportions of pts with any-grade (gr)/gr ≥ 3 cytokine release syndrome (CRS) and investigator-identified neurological events (NE). Results: Fifty-one and 88 efficacy-evaluable pts were treated at dose level 2 (100 × 10 6 CAR + T cells) in the combo and mono cohorts, respectively. Before matching/weighting on PS, odds of achieving CR and overall response were statistically significantly higher for combo (Table). DOR did not differ between cohorts. For PFS and OS, HRs were lower with combo vs mono (not statistically significant [NS]). Odds of gr ≥ 3 CRS/NE were lower with combo vs mono (NS). After matching/weighting, odds of CR (except IPTW ATT) and overall response remained statistically significantly higher in combo. HRs for PFS and OS and ORs for gr ≥ 3 CRS/NE were numerically lower with combo vs mono (NS, except IPTW ATT for PFS). HRs for DOR were less but close to HR of 1. Conclusions: The liso-cel + ibrutinib combo demonstrated a trend for better efficacy and safety vs liso-cel mono, with statistically significant differences for CR rate and ORR. Clinical trial information: NCT03331198 . Efficacy and safety outcomes: combo vs mono. No adjustment ATT optimal 1:1 IPTW - ATT CR rate, OR (95% CI) 2.07* (1.01–4.28) 2.40* (1.05–5.66) 2.00(0.89–4.61) ORR, OR (95% CI) 3.96* (1.68–10.51) 3.43* (1.33–9.71) 4.18* (1.63–11.78) DOR, HR (95% CI) 0.98(0.51–1.87) 0.88(0.43–1.78) 0.96(0.50–1.85) PFS, HR (95% CI) 0.62(0.37–1.02) 0.61(0.35–1.05) 0.59* (0.35–0.98) OS, HR (95% CI) 0.70(0.38–1.28) 0.73(0.37–1.43) 0.66(0.36–1.22) CRS, OR (95% CI) 0.63(0.26–1.56) 0.67(0.24–1.84) 0.69(0.24–1.88) Gr ≥ 3 CRS, OR (95% CI) 0.23(0.01–1.35) 0.49(0.02–5.28) 0.26(0.01–1.94) NE, OR (95% CI) 0.84(0.41–1.68) 0.92(0.40–2.08) 1.10(0.48–2.52) Gr ≥ 3 NE, OR (95% CI) 0.56(0.19–1.45) 0.58(0.16–1.89) 0.68(0.19–2.30) *Statistically significant difference at 5% level.

Abstract Richter transformation (RT) is defined as an aggressive lymphoma emerging in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Despite novel therapeutics developed in CLL, RT is associated with poor outcomes. In light of recent progress regarding the diagnostic procedures and therapeutic concepts of RT, an international group of experts, under the coordination of the European Research Initiative on CLL, has developed consensus recommendations for clinical procedures and future research on this disease. Patients with RT typically present with a rapid clinical decline, worsening B-symptoms, elevated lactate dehydrogenase, and/or rapidly enlarging lymphadenopathy. Workup should include a positron emission tomography–computed tomography scan for patients with suspected RT. An excisional biopsy should be taken from an accessible lesion, preferably with the highest fluorodeoxyglucose avidity, and analyzed for the presence of aggressive lymphoma. The molecular relationship to the original CLL clone(s) should be defined. Because no effective standard treatment for RT exists, patients should be treated in a clinical trial. Response of both RT and CLL should be assessed at an early time point, and survival end points should be prioritized in trial design. We hope that these recommendations can help to harmonize clinical and translational research and improve outcomes for patients with RT.

Abstract Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Introduction BCL-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome and drug-drug interactions (DDIs) challenge treatment optimization. Lisaftoclax is an investigational, oral BCL-2i with a short half-life, allowing it to be ramped-up on a daily schedule. We present updated results of a phase 1b/2 study of lisaftoclax alone or combined with acalabrutinib or rituximab in pts with treatment-naïve (TN; lisaftoclax-acalabrutinib arm), relapsed/refractory, or prior ven-treated CLL/SLL (NCT04215809). Methods Pts were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity. Intensive blood samples were collected for pharmacokinetic (PK) and exposure-response (E-R) analyses. Results From March 20, 2020, to June 27, 2024, 176 pts were enrolled: 46 in monotherapy and 39 and 91 in rituximab and acalabrutinib combination cohorts, respectively; 154/176 (87.5%) were R/R and 22/176 (12.5%) TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation; and 70.6% had unmutated IGHV. Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) months. In R/R pts, the median (range) number of prior lines of therapy was 2 (1-15), and 14 (9%) pts had been treated with ven. Prior ven pts had a median (range) age of 65 (51-78); 79% were male; of evaluable pts, 50% had del(17p), 36% TP53 mut, 64% del(11q), 38% complex karyotype (≥ 3 abnormalities), and 92% unmutated IGHV; 57% were BTKi naïve; and the median (range) number of prior therapies was 3 (1-6). Incidence and severity of TEAEs were similar across cohorts. Common (>10%) any-grade TEAEs in all cohorts combined were neutropenia (59 [33.5%]), diarrhea (38 [21.6%]), anemia (27 [15.3%]), and thrombocytopenia (26 [14.8%]). Grade ≥ 3 TEAEs were neutropenia in 15 (32.6%), 10 (25.6%), and 22 (24%) pts and anemia in 10 (21.7%), 5 (12.8%), and 12 (13.2%) pts in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively. Comprehensive E-R analyses indicated that lisaftoclax had similar systemic exposure as monotherapy or when combined with acalabrutinib or rituximab; lisaftoclax had no DDI when combined with acalabrutinib or rituximab. No discontinuations were attributed to lisaftoclax TRAEs. Forty-four (95.7%) pts in monotherapy discontinued treatment. Most discontinuations were due to progressive disease (n = 41 [23.3%]) and 13 (7.4%), AEs; 9 (5.1%) pts withdrew consent; 7 (4%) achieved complete response or MRD negativity after ≥ 24 cycles; 5 (2.8%) died; and 18 (10.2%) discontinued for other reasons. Clinical (n = 2) and laboratory (n = 3) TLS was observed in 5 (2.8%) pts on lisaftoclax (by Howard/Cairo-Bishop criteria), with cases rapidly resolving to resume lisaftoclax safely. ORR for lisaftoclax plus acalabrutinib in 87 pts was 96.6%, and the median DOR (95% CI, 23-NR) and median PFS (95% CI, 34-NR) were not reached. The 12- and 18-month PFS rates were 89% and 86%, respectively. Fourteen R/R CLL ven-exposed pts received lisaftoclax plus acalabrutinib, of whom 9 had progressed on ven, 3 relapsed after completing ven, and 2 discontinued due to ven intolerance. Median (range) duration of treatment was 16 (3-25) months. Safety profile was similar to that of other study cohorts. ORR was 85.7% (12/14), 100% (8/8), and 66.7% (4/6) in the ven-exposed, ven-exposed but BTKi-naïve, and ven- and BTKi-exposed pts, respectively. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The 12- and 18-month PFS rates were 84% and 73%, respectively. Conclusions Our data suggest that lisaftoclax combined with acalabrutinib is effective for pts with prior ven exposure, including those with progression on ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL pts treated with lisaftoclax monotherapy/combinations. We continue to accrue pts with prior ven exposure to further evaluate this promising signal. A global registrational phase 3 study GLORA (NCT06104566) is recruiting.

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.

Background: The primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study with a median follow-up of 21.1 mo showed that a single administration of liso-cel achieved rapid, deep, and durable responses and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL, including those with progression on a previous Bruton tyrosine kinase inhibitor (BTKi) and venetoclax failure (primary efficacy analysis set [PEAS]; Siddiqi T, et al. Lancet 2023). With 5 mo of additional follow-up (median of 23.5 mo), liso-cel continued to demonstrate durable CR/CR with incomplete marrow recovery (CRi) and high undetectable MRD (uMRD; 10−4 by next-generation sequencing) rates with no new safety signals. Median duration of response (DOR) was 35.3 mo (95% CI, 12.4-not reached [NR]), and median OS was 30.3 mo (95% CI, 15.0-NR) (Siddiqi T, et al. Blood 2023). Here, we report updated results from TRANSCEND CLL 004 with 16 mo of additional follow-up since primary analysis and a median on-study follow-up of 23.8 mo (range, 0.4-59.6). Methods: Pts must have received ≥ 2 prior lines of therapy (LOTs), including a BTKi (full population). Eligible pts received liso-cel at a target dose of either 50 × 106 (dose level [DL] 1) or 100 × 106 (DL2) CAR+ T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi per independent review committee in the PEAS at DL2. Key secondary endpoints were ORR and blood uMRD rate. All pts who received liso-cel and completed or discontinued early from the study were asked to enroll in a separate long-term follow-up (LTFU) study (NCT03435796) assessing safety and OS for up to 15 y after liso-cel. Results: As of the data cutoff (01/12/2024), 118 of 137 leukapheresed pts received liso-cel (safety set), 97 (DL1, n = 9; DL2, n = 88) were efficacy evaluable, and 54 (DL1, n = 4; DL2, n = 50) were in the PEAS. A total of 22 pts were ongoing in TRANSCEND CLL 004, and 19 of 60 eligible pts enrolled to the LTFU study. In the safety set, pts had a median age of 65 y (range, 49-82), and 83% had high-risk cytogenetic markers (del[17p], 42%; TP53 mutation, 47%; unmutated immunoglobulin heavy-chain variable gene, 47%). Median prior LOTs was 5 (range, 2-14); 86% of pts had prior chemoimmunotherapy. In the PEAS at DL2, CR/CRi rate remained at 20%, ORR at 44%, blood uMRD rate at 64%, and marrow uMRD rate at 60%. Median DOR was NR (95% CI, 12.4-NR), with a median follow-up of 31.7 mo (95% CI, 21.3-35.5). Estimated 36-mo DOR rate was 61% (95% CI, 30-81). Median (95% CI) DOR was NR in pts with CR/CRi. Median (95% CI) PFS was 11.9 mo (5.7-26.2) overall, 26.2 mo (11.9-NR) in pts with blood uMRD, and 2.8 mo (0.8-3.2) in pts with detectable blood MRD. Median OS, including 19 pts in the LTFU, was 43.2 mo (95% CI, 14.5-NR). Efficacy outcomes were similar in the full population at DL2. A subgroup of 23 pts who had only prior BTKi exposure and were venetoclax naïve was less heavily pretreated, with a median of 3 prior LOTs (range, 2-11); all pts had prior chemoimmunotherapy. In the efficacy-evaluable pts of this subgroup at DL2 (n = 18), the CR/CRi rate was 22%; ORR was 61%; and median (95% CI) DOR was NR (17.1-NR), PFS was NR (18.0-NR), and OS was 52.2 mo (26.9-NR). In the safety set, rates of any-grade/grade ≥ 3 cytokine release syndrome (85%/8%), any-grade/grade ≥ 3 neurological events (45%/19%), prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion [54%]), grade ≥ 3 infections (18%), and second primary malignancy (9%) remained the same as previously reported (Siddiqi T, et al. Blood 2023); most pts with prolonged cytopenia had resolution to grade ≤ 2 by Month 3. Forty-six (34%) of 137 leukapheresed pts died after CAR T cell infusion, including 1 additional pt since the previous report with an unknown cause of death at ~14.5 mo after infusion. Persistence of the liso-cel transgene was detected up to 48 months after liso-cel infusion (2/5 evaluable pts at DL2 at Month 48). Conclusions: In this updated follow-up, liso-cel continued to demonstrate durable responses with an extended median OS of 43.2 mo in pts with R/R CLL/SLL. The safety results were similar to those previously reported with no new safety signals. These data confirm the sustained clinical benefit and favorable benefit-to-risk profile of a single treatment of liso-cel in pts with R/R CLL/SLL.