Dahiya, Saurabh

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (<0.5), standard-low (0.5 to <0.6), standard (0.6 to <0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: <0.5 (n=33), 0.5 to <0.6 (n=131), 0.6 to <0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of <0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.

Abstract Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients < 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients < 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and < 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients < 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the < 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients < 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors associated with DNT and NRM may help with risk mitigation by aiding the development of interventions for potentially modifiable risk factors and also help with clinical decision making. Methods: In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM were evaluated in by univariable and multivariable analysis. Any NRM events occurring after disease progression were censored for NRM evaluation. Results: The median age of the cohort was 65 years old (range: 30-88), median prior lines of therapy (pLoT) were 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLOT) in 16% (n=120) patients. High-risk cytogenetics [del 17p, t(14;16) or t(4;14)] were present in 39%, with extramedullary disease (EMD) in 27% and R-ISS stage III in 18% of patients, respectively. Majority of patients (86%) received bridging therapy with response to bridging (≥ partial response, PR) seen in 33% of patients, respectively. Median follow up was 10.1 months, with response rate of 92% and CR rate of 70%. DNT was seen in 10% (n=75) of patients, with distribution as follows: Parkinsonism in 2.9% (n=22), cranial nerve palsy in 4.6% (n=35) and other DNT in 2.4% (n=18), with some patients manifesting more than one type of DNT. Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, both p<0.05) Of the 22 cases of Parkinsonism, 21 patients (95%) did not respond to bridging, even though they achieved a post CAR-T response with ORR of 91% and ≥ CR in 68%. Absolute lymphocyte count (ALC), a surrogate measure of CAR expansion was higher in patients who developed DNT, particularly Parkinsonism, including ALC at days 7,14,21,28 and as peak ALC in the first month post cilta-cel (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism was: 5.88 vs 1.17/uL (p<0.001). We evaluated risk of Parkinsonism with various thresholds of peak ALC expansion. Amongst patients who developed Parkinsonism vs. not, peak ALC was as follows, > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19% and > 3000/uL: 68% vs 14% (all p<0.001). The absolute risk of Parkinsonism with ALC > 3000 vs ≤ 3000/uL was 12% vs 1%, p<0.001; for ALC 2500 vs ≤ 2500uL was 9% vs 1%, p<0.001. On multivariable analysis, peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) were independent risk factors for developing Parkinsonism after cilta-cel. After cilta-cel, 1 and 2 year NRM estimates were 9% and 10%, respectively. Amongst 63 (8%) patients experiencing NRM events, the most common cause of NRM was infectious complications (35, 56%), followed by acute immune-mediated adverse events (AEs) like CRS, ICANS, IEC-HS in 14 (22%), delayed immune mediated AEs like DNT and colitis in 6 (9.5%), second cancers in 5 (8%) and other causes in 3 (5%) patients, respectively. When evaluating the timing of NRM events, the risk of infection related mortality remained relatively stable in the first year, though immune mediated toxicty deaths were uncommon after 6 months, while SPMs were uncommon within the first 6 months. On multivariable analysis, non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics and age ≥ 70 years were independent predictors for NRM. Conclusion: In a large cohort of over 750 patients receiving cilta-cel, we identified potentially modifiable risk factors for Parkinsonism and NRM. Non-response to bridging therapy and peak ALC > 3000/uL were independent predictors of developing Parkinsonism. Peak ALC of > 2500/uL and > 3000/uL were associated with 9% and 12% absolute risk of Parkinsonism. This indicates that peak ALC of 2500/uL or 3000/uL in the first month after cilta-cel may be a potential biomarker to identify patients for pre-emptive interventions such as steroids that can suppress rapid CAR expansion and perhaps decrease the risk of Parkinsonism. In addition, we need to focus on effective bridging strategies to further decrease the risk of Parkinsonism, as well as NRM with cilta-cel.

7023 Background: Axi-cel is an autologous chimeric antigen receptor (CAR) T-cell therapy approved for adults with R/R LBCL after ≥ 1 prior line of therapy (LoT). Adverse events, such as cytokine release syndrome (CRS) and neurologic events (NEs), may deter centers from using axi-cel in an outpatient (OPT) setting, though individual centers have observed comparable safety and effectiveness in OPT and inpatient (IPT) care (Furqan et al. Blood Adv . 2024). Here, we present safety and effectiveness outcomes of axi-cel by intention to treat in OPT and IPT settings in a multicenter real-world dataset. Methods: Pts receiving axi-cel for R/R LBCL in the US from 01/2021-07/2023 with data in the Center for International Blood and Marrow Transplant Research (CIBMTR) registry were eligible for analysis. Pts with prior allogeneic transplant or unknown intended care setting were excluded. Of potential pts, 119 OPT pts were identified from 29 centers where an increasing trend was seen (9.6% of pts in 2021 were OPT, 13.5% in 2022, 22.8% in 2023). Pts were matched to 119 IPT pts by propensity score matching on age, sex, comorbidities, lactate dehydrogenase (LDH), bulky disease, prior LoT, chemosensitivity, and infusion year (see table). Results: OPT pts had median age of 63 y (25% ≥ 70), 66% were male, and 67% had ≥ 1 comorbidity. Half (50%) had elevated LDH and 73% had 1 prior LoT. Bulky disease was reported in 3%, and 60% had chemo-resistant disease. Outcomes were analyzed at median follow-up of 12 mo. Safety and effectiveness outcomes were similar between OPT and IPT pts (see table). In multivariate analyses, no differences were found between intended care setting and CRS (odds ratio [OR] 1.09 [95% CI 0.51-2.35]), CRS Gr ≥ 3 (OR 0.57 [0.12-2.60]), NEs (OR 1.14 [0.65-2.00]), or NEs Gr ≥ 3 (OR 0.98 [0.48-2.00]). Among OPT pts, 24% and 50% did not require hospital admission within 30 d and 3 d, respectively. In pts aged ≥ 70 y, only any Gr NEs were higher in the OPT group. Conclusions: After matching on key factors that may be used to select pts for OPT infusion, outcomes were comparable between intended care settings. These findings corroborate prior results and support the consideration of axi-cel in appropriate OPT care settings. Outcomes between matched pts with R/R LBCL receiving axi-cel intended for OPT or IPT. OPT (n=119) a IPT (n=119) a CRS any Gr / Gr ≥ 3 83 (75−89) / 3 (<1−7) 83 (74−89) / 4 (1−10) NE any Gr / Gr ≥ 3 47 (38−57) / 19 (12−27) 46 (37−56) / 21 (14−30) Overall / complete response rates 78 (69−85) / 68 (59−76) 76 (67−83) / 62 (52-70) Duration of response @ 12 mo 64 (52−74) 69 (58−78) Progression-free survival @ 12 mo 53 (43−62) 53 (43−61) Overall survival @ 12 mo 71 (61−78) 72 (62−79) Non-relapse mortality @ 12 mo 6 (2−11) 4 (1−8) Hospital admission within 30 days of infusion / median duration (range), d 76 (67−83) / 9 (2−53) Not Applicable a Percent (95% CI) unless otherwise specified.

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known safety concerns following chimeric antigen receptor (CAR) T-cell therapy. Axi-cel, a CAR T-cell therapy approved in the US for adults with R/R LBCL after ≥ 1 line of prior therapy (2L+), has been administered in the outpatient setting, where a common cause for post-infusion hospital admissions were CAR T-cell-related toxicities (Furqan et al., 2024). Due to reimbursement policies in the US, patients at higher risk for safety events requiring inpatient care within 3 days of infusion may not be ideal candidates for outpatient care. We sought to identify what pre-infusion characteristics may put patients more at risk for developing early CRS and ICANS after axi-cel. Methods : Patients receiving axi-cel for R/R LBCL 2L+ between 01/2021−10/2023 registered in the Center for International Blood and Marrow Transplant Research (CIBMTR) observational database were potentially eligible for analysis. Patients with prior non-transplant cellular therapy or missing data for analysis were excluded. Primary endpoints were onset of early CRS and early ICANS, defined as an any grade event within 3 calendar days of axi-cel infusion (date of infusion is defined as Day 0 and onset of CRS/ICANS before the end of Day 3 is an early event). Early Grade ≥ 2 and early Grade ≥ 3 CRS and ICANS (onset of CRS/ICANS before the end of Day 3 and maximum Grade ≥ 2 and ≥ 3 per ASTCT Criteria) were also evaluated. Patient demographics, ECOG PS, comorbidities, disease characteristics at diagnosis and prior to infusion, line of therapy (LoT), lab assessments prior to infusion, and infusion-related attributes were evaluated by univariate screening and multivariable regression for development of early CRS or early ICANS. Results: A total of888 patients from 105 centers were included in the analysis. Median age was 63 years (45% ≥ 65 years) and 66% were male. At LBCL diagnosis, 22% of patients had a histological transformation. Prior to infusion, 5% of patients had ECOG PS ≥ 2 and 70% had at least 1 clinically significant comorbidity. Half (50%) of patients received axi-cel with 1 prior LoT (2L) and 10% of patients underwent a prior autologous hematopoietic cell transplant. Median time from leukapheresis to infusion was 30 days (interquartile range [IQR] 27−34). Bridging therapy of any type was administered in 59%, and systemic bridging therapy in 48%, of patients and 14% of patients were intended to be treated in the outpatient setting. Thirty percent of patients had chemo-sensitive disease prior to infusion. Median follow-up post-infusion was 12.3 months (range 3−38). Median time to onset of CRS was 4 days (IQR 2−6) and 84% of patients experienced CRS at any time. Early any grade (Grade ≥ 3) CRS was observed in 47% (3%) of patients. In the multivariate analysis of early any grade CRS, only prior LoT (≥ 2 vs 1) was associated with lower risk (OR 0.71; 95% CI 0.55−0.94), but this association was not seen in the analyses of early Grade ≥ 2 nor early Grade ≥ 3 CRS. Notably, 47% and 52% of patients with ≥ 2 vs 1 prior LoT, respectively, only experienced early Grade 1 CRS (defined as fever only). In the analysis of early Grade ≥ 3 CRS, only ECOG PS 0−1 was associated with lower risk vs patients with ECOG PS ≥ 2 (OR 0.17; 95% CI 0.06−0.48). Median time to onset of ICANS was 7 days (IQR 5−9) and 47% of patients experienced ICANS at any time. Early any grade (Grade ≥ 3) ICANS occurred in 9% (5%) of patients. After multivariate adjustment, age &lt; 65 vs ≥ 65 (OR 0.38 [95% CI 0.23−0.62]) and 1 vs ≥ 2 prior LoT (OR 0.58 [95% CI 0.36−0.95]) were associated with lower risk of early any grade ICANS. Age &lt; 65 vs ≥ 65 was also associated with lower risk of early Grade ≥ 3 ICANS (OR 0.31 [95% CI 0.15−0.61]), as was ECOG PS 0−1 vs ECOG PS ≥ 2 (OR 0.30 [95% CI 0.11−0.83]). Comorbidities were evaluated and no significant associations with early CRS nor early ICANS were found. Conclusions: This analysis of readily available clinical variables in a real-world contemporary cohort of patients treated with axi-cel demonstrates that younger patients and patients with better ECOG PS have lower risk of early CRS and early ICANS. Axi-cel in 2L setting, vs 3L+, is associated with lower risk of early any grade ICANS and comparable early Grade ≥ 2 CRS, but a higher risk of early fever. These results further enable a more informed decision of patient selection for physicians, which is critical for the success of outpatient administration.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. METHODS We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. RESULTS Among axi-cel–infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse ( P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). CONCLUSION In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

1604 Background: Diversity in clinical studies is essential to address health disparities, but racial and ethnic minorities are often underrepresented in clinical studies, especially in precision medicine studies using genetic data (1). BASECAMP-1 (NCT04981119) is an ongoing prescreening study to identify patients with unresectable advanced or metastatic solid tumors and tumor-associated HLA-A*02 LOH for the EVEREST-1 and -2 Tmod chimeric antigen receptor T-cell therapy trials. When enrollment began in 2021, eligibility for Part 1 was restricted to patients with germline HLA-A*02:01 based on preclinical data. Additional analysis revealed the blocker in the Tmod construct had activity across HLA-A*02 subtypes (Mock, et al. Mol Ther Oncolytics.2022). Eligibility for Part 1 was then expanded to all HLA-A*02 subtypes, allowing enrollment of more diverse patient populations. HLA-A*02 allele subtypes vary by ethnicity and race; the frequency of HLA-A*02:01 is 96% in non-Hispanic Whites, but ranges from 53% to 73% in other ethnicities and races. The frequency of all other HLA-A*02 allele subtypes (HLA-A*02:XX) is <5% in non-Hispanic Whites but up to 66% in other ethnicities and races (2,3). Methods: Patients eligible for BASECAMP-1 were identified at United States study sites. All patients screened before January 16, 2024, for Part 1 were included for demographic and central lab HLA-A typing. The % increase in eligibility and % of heterozygous HLA-A*02 patients with HLA-A*02:XX were calculated by ethnicity and race. Results: A total of 1124 patients were screened for germline HLA-A*02 typing; 431 patients were HLA-A*02:01 heterozygous, of whom 37 (9%) were Hispanic, 14 (3%) African American (AA), 2 (<1%) American Indian or Alaska Native, 17 (4%) Asian or Pacific Islander (API), and 324 (75%) non-Hispanic White (Table). The eligibility expansion identified 62 patients with HLA-A*02:XX heterozygosity, of whom 6 (10%) were Hispanic, 6 (10%) AA, 19 (31%) API, and 25 (40%) non-Hispanic White. Conclusions: By expanding enrollment to include HLA-A*02:XX, 16% more Hispanic, 43% more AA, and 112% more API patients were identified, improving the diversity in this trial compared with that of initial enrollment. 1. Aldrighetti, et al. JAMA Netw Open 2021. 2. Ellis, et al. Human Immunol. 2000. 3. Gragert, et al. Human Immunol.2013. Clinical trial information: NCT04981119 . [Table: see text]

Abstract During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

Introduction: Axi-cel utilization expanded after demonstration of superior event-free survival in patients (pts) with early relapsed or primary refractory LBCL (Locke, et al. NEJM. 2022) and was reinforced by improved overall survival (OS) among these pts (Westin, et al. NEJM. 2023). Despite increased demand, limited data exist on the impact of bridging therapies (BT) on pt outcomes. Thus, BT use between leukapheresis and lymphodepletion (LD) is largely at the discretion of treating physicians. Here, we assessed the impact of BT on effectiveness and safety outcomes after axi-cel. Methods: Pts receiving axi-cel for 3L+ LBCL in the US between 2017-2020 were prospectively collected through the CIBMTR registry in a post-authorization safety study; data up to May 2023 were included. Effectiveness outcomes were overall response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and OS. Safety outcomes were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT grading, non-relapse mortality (NRM), and other key adverse events. Propensity score-based inverse probability of treatment weighting (IPTW) was used in logistic and Cox regressions to account for potential confounding in BT use. For pts who had BT, effects of BT types and responses on outcomes were evaluated using conventional logistic and Cox regressions. Results: Of 1497 pts registered, 1307 had BT data available and were included (median follow-up, 36 mo). Overall, 430 pts (33%) received BT (median time from leukapheresis to LD, 23 days [IQR, 21-28]). Systemic therapy was used in 403 pts (31%), including 305 (23%) with chemotherapy (CT)-based BT (19% treated with CT + anti-CD20 monoclonal antibody [mAb; mainly rituximab] and 4% with CT only), and 98 (7%) with non-CT systemic therapy (Table). Radiotherapy (± systemic therapy) was used in 44 pts (3%). Pts with ≥3 lines of prior therapy (odds ratio [OR], 10.67 [95% CI, 7.17−15.87]) or mild hepatic impairment prior to infusion (OR, 1.64 [1.06−2.55]) were more likely to receive BT, while those with histologic transformation (OR, 0.69 [0.51−0.92]) or longer time from diagnosis to leukapheresis were less likely to receive BT. ORRs to axi-cel were 70% and 79% (CR rates 51% and 64%) for pts with or without BT, respectively. Unadjusted DOR, PFS, and OS at 3 years were 40%, 28%, and 37%, respectively, in pts with BT vs 49%, 39%, and 49%, respectively, in those without BT. After multivariate adjustment, no statistical significance was found between BT and any effectiveness outcome. Adjusted hazard ratios (HRs) for BT were 1.13 (95% CI, 0.94-1.36) for PFS and 1.11 (95% CI, 0.92-1.34) for OS, respectively (Figure). Most safety endpoints were consistent regardless of BT. Grade ≥3 CRS and ICANS occurred in 12% and 30% of pts, respectively, who received BT vs 10% and 24% of pts who did not. Use of BT was associated with more frequent prolonged neutropenia (OR, 2.24 [1.44-3.50]) and thrombocytopenia (OR, 2.33 [1.67-3.24]), but not associated with a higher rate of infections or NRM (Table). Among pts receiving BT, 74 (17%) had a CR or partial response to BT. Of them, median PFS and median OS post infusion were 12.7 mo (3.8-not estimable [NE]) and 48.7 mo (18.6-NE), respectively. Response to BT was associated with increased CR rate (OR, 2.00 [1.07-3.75]), PFS (HR, 0.69 [0.49-0.99]), and OS (HR, 0.59 [0.40-0.88]) and decreased any-grade ICANS (OR, 0.51 [0.29-0.92]). When different BT strategies were considered, effectiveness and most safety outcomes for CT + anti-CD20 mAb vs non-CT treatment were comparable without significant difference. CT + anti-CD20 mAb was associated with improved ORR (OR, 1.90 [1.00-3.60]), PFS (HR, 0.69 [0.49-0.98]), and OS (HR, 0.66 [0.46-0.95]) but increased any-grade CRS (OR, 2.16 [1.02-4.57]) vs CT only. CT use was associated with an increased risk of prolonged thrombocytopenia (41% vs 24% for pts receiving non-CT treatment; OR, 2.37 [1.39-4.02]). No significant association was found between use of radiotherapy as BT and any outcome. Conclusion: These US real-world findings suggest that the addition of BT prior to axi-cel is associated with more frequent prolonged cytopenias but does not impact effectiveness or other critical safety outcomes. Response to BT may prognosticate more favorable outcomes after axi-cel infusion. Further study is warranted to identify the optimal bridging regimen.