Lisocabtagene Maraleucel Research Articles

A real-world comparison of commercial use axicabtagene ciloleucel and lisocabtagene maraleucel in large B-cell lymphoma.

Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are anti-CD19 CAR-T therapies approved for relapsed and refractory large B cell lymphoma (R/R LBCL); however there is currently no published data on liso-cel outside of clinical trials, nor any data comparing these therapies. In this retrospective analysis, we reviewed patients receiving liso-cel or axi-cel at a single institution in the third-line setting. From June 2021 - September 2022, 50 patients received axi-cel and 37 liso-cel. Baseline patient characteristics were similar aside from older age in liso-cel recipients. Median time from leukapheresis to CAR-T infusion was significantly longer for liso-cel (41 days) than axi-cel (30 days). Complete response rates were not significantly different between axi-cel (72%) and liso-cel (62%). At a median follow-up of 11 months, progression-free survival (PFS) was not significantly different between axi-cel and liso-cel cohorts, with 12-month PFS of 59% and 44% respectively. However, on a propensity score analysis, an inferior PFS was observed with liso-cel (hazard ratio 2.95, 95% CI 1.14 - 7.60). Rates of CRS, ICANS, and prolonged neutropenia were higher with axi-cel than liso-cel. Overall, direct comparison of axi-cel and liso-cel cohorts shows similar key outcomes including response rate and PFS, but prolonged wait times for liso-cel may have resulted in biased selection of patients with more favorable characteristics for liso-cel. When accounting for these higher-risk characteristics, an inferior PFS is observed with liso-cel as compared to axi-cel. These findings warranting further evaluation in a multicenter setting.

Comparative efficacy of lisocabtagene maraleucel in the PILOT study versus second-line chemotherapy regimens in the real world.

This study assessed the comparative efficacy of lisocabtagene maraleucel (liso-cel) in PILOT (NCT03483103), an open-label, phase II study, versus conventional second-line (2L) chemotherapy regimens in the real world administered to patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) who were not intended for hematopoietic stem cell transplantation (HSCT). The liso-cel-treated cohort (n=61) was based on patients who received liso-cel in the PILOT study. The conventional chemotherapy cohort included patients who met PILOT eligibility criteria and received conventional 2L chemotherapy in the real-world clinical setting (n=273). After using the trimmed stabilized inverse probability of treatment weighting method to balance cohorts according to baseline characteristics, there were statistically significant differences in all tested measures of efficacy. Compared with real-world conventional chemotherapy regimens, liso-cel demonstrated higher overall response rates (79.6% with liso-cel vs. 50.5% with conventional chemotherapy; relative risk [RR], 1.6; P.

Comparative Analysis of Bispecific Antibodies and CAR T-Cell Therapy in Follicular Lymphoma.

The treatment landscape for relapsed/refractory follicular lymphoma (RR-FL) is marked by a pivotal debate between chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs). While both CAR-T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA-5 study, underscore axicabtagene ciloleucel (axi-cel)'s efficacy in treating RR-FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso-cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR-FL patients. Thus, CAR-T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost-effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost-effectiveness considerations are essential; while CAR-T therapies incur higher initial costs, their potential for long-term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR-FL management strategies.

Neurotoxicity associated with chimeric antigen receptor T-cell therapy: a real-world study leveraging the FDA Adverse Event Reporting System

ABSTRACT Background CAR-T-associated neurotoxicity is extremely frequent with highly variable clinical presentation. Research design and methods Disproportionality analysis was conducted leveraging the FDA Adverse Event Reporting System (FAERS), covering the period from 1 January 2017, through 31 March 2023. The reporting odds ratio (ROR) and the information component (IC) were utilized to assess the adverse signals in total/individual CAR-T product. The lower limit of the ROR and IC 95% confidence interval (ROR025 and IC025) both exceeding threshold value (1 and 0, respectively) was considered a significant signal. Results Of the 60, 730 records associated with CAR-T, 11, 037 (18.17%) pertained to neurological events. Tisagenlecleucel exhibited the highest percentage of death (38.02%) and life‐threatening (12.90%) outcomes. Notably, it also displayed the broadest distribution of neurotoxicity. Additionally, distinct adverse signals unique to individual CAR-T products were identified. For instance, paraparesis, cerebral hemorrhage, impaired pupillary reflex, Guillain-Barre syndrome, brain death following tisagenlecleucel; dysarthria, orthostatic hypotension, and spinal cord edema after axicabtagene; parkinsonism, Bell’s palsy, and cranial nerve paralysis post ciltacabtagene. Conclusions Axicabtagene ciloleucel, tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel exhibited increased odds of neurotoxicity, with some discrepancies in their characteristics, profiles, and severity.

OUTREACH: phase 2 study of lisocabtagene maraleucel as outpatient or inpatient treatment at community sites for R/R LBCL

AbstractLisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating the safety and efficacy of outpatient monitoring after liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. The primary end points were incidence of grade ≥3 cytokine release syndrome (CRS), neurological events (NEs), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient monitored, 70%; inpatient monitored, 30%). The median follow-up was 10.6 months (range, 1.0-24.5). In outpatients and inpatients, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%, respectively. Among outpatients, 25% were never hospitalized after infusion, and 32% were hospitalized ≤72 hours after the day of infusion; the median time to hospitalization was 5.0 days (range, 2-310). The median initial hospitalization duration after liso-cel was 6.0 days (range, 1-28) for outpatients and 15.0 days (range, 3-31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and the median duration of response was 14.75 months (95% confidence interval, 5.0 to not reached). OUTREACH is, to our knowledge, the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support the feasibility of liso-cel administration at community sites with outpatient monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT03744676.

Efficacy and Effectiveness Outcomes of Treatments forDouble-Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review.

Bruton's tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax-treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double-exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double-exposed CLL patients. PubMed, Embase, and Web of Science databases were searched until December 2023. We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR)T-cell therapy. This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.

ABCL-193 Impact of Bridging Therapy (BT) on Lisocabtagene Maraleucel (liso-cel) as Second-Line (2L) or Later (2L+) Treatment of R/R Follicular Lymphoma (FL) in the Phase 2, Open-Label TRANSCEND FL Study

ABCL-193 Impact of Bridging Therapy (BT) on Lisocabtagene Maraleucel (liso-cel) as Second-Line (2L) or Later (2L+) Treatment of R/R Follicular Lymphoma (FL) in the Phase 2, Open-Label TRANSCEND FL Study

Impact of Bridging Therapy (BT) on Lisocabtagene Maraleucel (liso-cel) as Second-Line (2L) or Later (2L+) Treatment of R/R Follicular Lymphoma (FL) in the Phase 2, Open-Label TRANSCEND FL Study

Impact of Bridging Therapy (BT) on Lisocabtagene Maraleucel (liso-cel) as Second-Line (2L) or Later (2L+) Treatment of R/R Follicular Lymphoma (FL) in the Phase 2, Open-Label TRANSCEND FL Study

Optimizing the post-CAR T monitoring period in recipients of axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel

AbstractCD19–directed chimeric antigen receptor T-cell (CAR T) therapies, including axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), have transformed the treatment landscape for B-cell non-Hodgkin lymphoma, showcasing significant efficacy but also highlighting toxicity risks such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). The US Food and Drug Administration has mandated patients remain close to the treatment center for 4 weeks as part of a Risk Evaluation and Mitigation Strategy to monitor and manage these toxicities, which, although cautious, may add to cost of care, be burdensome for patients and their families, and present challenges related to patient access and socioeconomic disparities. This retrospective study across 9 centers involving 475 patients infused with axi-cel, tisa-cel, and liso-cel from 2018 to 2023 aimed to assess CRS and ICANS onset and duration, as well as causes of nonrelapse mortality (NRM) in real-world CAR T recipients. Although differences were noted in the incidence and duration of CRS and ICANS between CAR T products, new-onset CRS and ICANS are exceedingly rare after 2 weeks after infusion (0% and 0.7% of patients, respectively). No new cases of CRS occurred after 2 weeks and a single case of new-onset ICANS occurred in the third week after infusion. NRM is driven by ICANS in the early follow-up period (1.1% until day 28) and then by infection through 3 months after infusion (1.2%). This study provides valuable insights into optimizing CAR T therapy monitoring, and our findings may provide a framework to reduce physical and financial constraints for patients.

Time-dependent cost comparison and health economic impact analysis of second-line interventions for transplant-ineligible patients with relapsed or refractory diffuse large B cell lymphoma.

Novel interventions (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tafasitamab-lenalidomide [Tafa-L], polatuzumab-rituximab-bendamustine [pola-BR]) improve clinical outcomes in second-line (2 L) treatment of transplant-ineligible patients with early relapse or refractory (R/R) diffuse large B cell lymphoma (DLBCL). The costs vary depending on the respective treatment regimen and the treatment duration, difficult comparability in reimbursement decisions. The objective was to analyze the health economic impacts of novel 2 L interventions and conventional immunochemotherapies (bendamustine-rituximab [BR], rituximab-gemcitabine-oxaliplatin [R-GemOx]) from a German healthcare payer's perspective as a function of treatment duration. An economic model was developed to compare treatment costs of 2 L interventions depending on the treatment duration. Treatment duration was measured by progression-free survival (PFS), identified based on a systematic review. Total and average costs were calculated over 5 years to evaluate incremental costs at median PFS for each intervention. Average costs per month at median PFS ranged from €2846 (95% CI: 5067-1641) to €40 535 (95% CI: 91180-N/A) for BR and liso-cel, respectively. Incremental costs at the lowest median PFS (R-GemOx: 5.3 months) revealed -€664, €5560, €11 817, €53 145, and €67 745 for BR, Tafa-L, pola-BR, axi-cel, and liso-cel as compared to R-GemOx, respectively. Analyses uncovered a variation of incremental costs of 2 L transplant-ineligible DLBCL interventions as a function of time leading to amortization of high-priced interventions.

Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d’Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee–assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839.

Second line immune targeted therapies in relapsed or refractory diffuse large B-cell lymphoma: A network meta-analysis.

e19071 Background: Relapsed or refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) patients undergo multiple lines of burdensome therapies. We conducted a network meta-analysis (NMA) of phase 3 randomized control trials (RCTs) to evaluate the effectiveness of second-line (2L) immune targeted treatments (ITTs), including chimeric antigen receptor (CAR)-T cell therapies in R/R DLBCL patients, focusing on overall survival (OS), event-free survival (EFS), progression-free survival (PFS), overall response rate (ORR) and complete response (CR). Methods: In a systematic review, we searched RCTs from PubMed, Embase and Cochrane Library spanning January 2016 to September 2023.We included studies reporting on adults (≥18 years) DLBCL patients experiencing R/R to first-line anti-CD20 antibody and anthracycline-containing regimen. RCTs comparing ITTs with SOC (2L salvage chemoimmunotherapy regimens followed by stem cell transplantation) were included. Frequentist fixed-effect model was utilized to estimate hazard ratios (HRs) for survival outcomes and odds ratios (ORs) for binary outcomes (ORR and CR) with corresponding 95% confidence intervals (CIs). We ranked treatment effectiveness based on the surface under the cumulative ranking curves (SUCRA). Results: Our search identified 539 records; four RCTs contributed to the NMA: three comparing CAR-Ts, axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel) with SOC, and one comparing ofatumumab + cisplatin, cytarabine, dexamethasone (O-DHAP) with SOC. Axi-cel significantly improved OS compared to both tisa-cel (HR, 0.59; 95% CI, 0.36-0.96) and SOC (HR, 0.73; 95% CI, 0.55-0.98). For EFS, axi-cel (HR, 0.38; 95% CI, 0.27-0.53) and liso-cel (HR, 0.32; 95% CI, 0.21-0.51) showed significant improvement compared to ODHAP. Axi-cel and liso-cel improved EFS significantly when individually compared to tisa-cel, and SOC.Axi-cel (HR, 0.51; 95% CI, 0.39-0.67) and liso-cel (HR, 0.4; 95% CI, 0.26-0.61) improved PFS significantly when compared to SOC. Axi-cel and liso-cel also significantly improved PFS when individually compared to ODHAP. In terms of ORR, Axi-cel (OR, 5.93; 95% CI, 3.63- 9.68) and Liso-cel (OR, 6.96; 95% CI, 3.37- 14.37) produced significantly higher ORR compared to SOC. Axi-cel and liso-cel had higher CR significantly when individually compared to ODHAP, tisa-cel, and SOC.In the SUCRA rankings, axi-cel was the most effective for OS, liso-cel ranked the most effective for EFS and PFS. Conclusions: Axi-cel was consistently associated with improved OS and EFS when compared to tisa-cel and SOC while liso-cel improved EFS and PFS over ODHAP and SOC. ORR and CR were higher for axi-cel and liso-cel over tisa-cel, ODHAP and SOC. Results are constrained by lack of multiple studies for each treatment comparison.

Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study.

Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study.

Predictors of severe hematotoxicity after CAR T-cell therapy.

7024 Background: The EHA/EBMT immune effector cell-associated hematotoxicity (ICAHT) grading system characterizes hematotoxicity after CAR T-cell therapy based on depth and duration of neutropenia (Rejeski et al, Blood, 2023). We evaluated pre- and post-infusion factors associated with grade 3-4 ICAHT and developed a predictive model in 602 patients with hematologic malignancies undergoing CAR T-cell therapy at Fred Hutch Cancer Center. Methods: Grading of early hematotoxicity (day-0-30 after CAR T-cell cell infusion) was automated using the heatwaveR package. Associations with 50 patient, disease-related, and laboratory factors, and grade 3-4 ICAHT were modeled using univariate and multivariable logistic regression. Results: The most common disease types were aggressive non-Hodgkin lymphoma (NHL; n = 293; 49%), indolent NHL (n = 150; 25%), and acute lymphoblastic leukemia (ALL; n = 94; 16%). The most common CAR T-cell products were the investigational CD19 CAR T-cell product JCAR014 (n = 197; 33%), axicabtagene ciloleucel (n = 129; 21%), and lisocabtagene maraleucel (n = 73; 12%). Incidences of early ICAHT grades 1, 2, 3, and 4 were 319 (53%), 96 (16%), 60 (10%), and 35 (6%) patients, respectively. Baseline patient factors associated with grade 3-4 ICAHT included ALL (reference: aggressive NHL, OR = 4.18, 95% CI, 2.41-7.26, p < 0.001) , Hispanic or Latino ethnicity (OR = 2.17, 95% CI, 1.07-4.20, p = 0.025), and lower age (OR = 1.03, 95% CI, 1.02-1.05, p < 0.001). Pre-lymphodepletion (LD) laboratory factors associated with grade 3-4 ICAHT in univariate analyses included lower ANC (OR = 6.67 per log10 cells/μL, 95% CI, 4.0-11.1, p < 0.001), LDH (OR = 8.70per log10U/L, 95% CI, 4.03-19.4, p < 0.001), CRP (OR = 3.18 per log10mg/L, 95% CI, 2.06-5.07, p < 0.001), and ferritin (OR = 6.07 per log10mg/L, 95% CI, 3.65-10.6, p < 0.001). Peak CRP (OR = 15.6, 95% CI, 7.27-36.4, p < 0.001), peak ferritin (OR = 7.41, 95% CI, 5.02-11.3, p < 0.001), peak CRS grade (OR = 2.01, 95% CI, 1.59-2.56, p < 0.001), and peak ICANS grade (OR = 1.51, 95% CI, 1.29-1.77, p < 0.001) after CAR T-cell infusion were also strongly associated with grade 3-4 ICAHT. A multivariable model using restricted cubic splines and including disease type, pre-LD ANC, pre-LD LDH, peak CRP, peak ferritin, and CRS grade demonstrated high discrimination to predict grade 3-4 ICAHT (C-index = 0.89). Internal validation using bootstrapping showed near-perfect calibration without overfitting. Sensitivity and specificity based on the Youden criteria was 74% and 90%, respectively. The sensitivity and specificity of the CAR-HEMATOTOX score in predicting grade 3-4 ICAHT was 93% and 30%, respectively. Conclusions: We identified pre- and post-infusion predictors of grade 3-4 ICAHT and internally validated a multivariable logistic regression model including disease-type, pre-LD ANC, pre-LD LDH, peak CRP, peak ferritin, and CRS grade. We plan to further evaluate our model in an external cohort.

Patients (pts) with R/R large B-cell lymphoma (LBCL) treated with lisocabtagene maraleucel (liso-cel) nonconforming product (NCP) under the Expanded Access Protocol (EAP).

7026 Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product indicated for the treatment of adults with R/R LBCL. Liso-cel NCP is defined as any product wherein one or both of the CD8 or CD4 cell components did not meet ≥ 1 of the commercial release specifications but met EAP release criteria and was considered appropriate for infusion. Methods: This is a prospective, multicenter EAP study of pts with R/R LBCL intended to receive commercial liso-cel but were treated with NCP due to manufacturing outcomes. Data from United States pts are reported here. The study comprised a pretreatment period for pt evaluation, a treatment period, which started at the first dose of lymphodepleting chemotherapy and continued through NCP administration at Day 1, and the posttreatment period, which followed pts up to 3 months after NCP administration for safety and disease status. Study objectives were safety (primary endpoint) and effectiveness by ORR and CR rate assessed by the treating physician per Lugano 2014 criteria (secondary endpoint). Due to the 3-month follow-up, duration of response, PFS, and OS analyses could not be estimated. Results: A total of 167 United States pts (third-line or later, n = 145; second line, n = 22) were included in the analysis set (data cutoff: 11/20/2023), which included pts who were infused and completed 3 months of follow-up (n = 134) or discontinued participation or died before 3 months (n = 33). Median (IQR) time from leukapheresis to NCP infusion was 50 d (44–58). Median age was 69 y (range, 29–87), 57% male, 42% diffuse LBCL (DLBCL) not otherwise specified, and 29% transformed DLBCL. The most frequent types of NCP (≥ 10 cases) were CD4 low T-cell lineage purity (n = 37 [22%]), CD4 low or high vector copy number (n = 31 [19%]), CD4 low transduction frequency (n = 24 [14%]), or CD8 high interferon-γ (n = 12 [7%]). Bridging therapy was reported in 31% of pts. In the total population (N = 167), cytokine release syndrome was reported in 42% of pts (1% grade ≥ 3), neurological events in 8% (4% grade ≥ 3), immune effector cell–associated neurotoxicity in 2% (1% grade ≥ 3), prolonged cytopenia in 40% (grade ≥ 3 on or after Day 29), grade ≥ 3 infections in 14%, infusion-related reactions in 1% (grade ≥ 3), and second primary malignancy in 1% (none grade ≥ 3). Thirteen pts died because of: AEs (n = 6), disease progression (n = 5), or unknown reasons (n = 2). Of 118 efficacy-evaluable pts for best overall response in the first 3 months, ORR was 71% (95% CI, 62–79); 53% had a CR (95% CI, 43–62) and 19% had a PR (95% CI, 12–27). Conclusions: These data add to current clinical experience with liso-cel, show that pts with R/R LBCL can derive clinical benefit from receiving NCP without compromising safety, and provide important evidence to facilitate clinical decision-making. Clinical trial information: NCT04400591 .

Impact of clinical response and AEs on health-related quality of life (HRQoL) in patients (pts) with R/R large B-cell lymphoma (LBCL): Pooled data from 4 lisocabtagene maraleucel (liso-cel) trials.

11105 Background: Four liso-cel clinical trials in R/R LBCL (TRANSCEND NHL 001, PILOT, OUTREACH, and TRANSFORM) demonstrated a favorable clinical profile with high response rates (73%–80%) and positive changes in HRQoL after treatment. This analysis pooled data across 4 trials to assess the impact of clinical response and AEs on HRQoL. Methods: The EORTC QLQ-C30 and EQ-5D-5L were used to assess HRQoL repeatedly at prespecified time points up to Day 730. Six clinically relevant domains (EORTC QLQ-C30 global health status/quality of life [GHS/QoL], physical functioning, cognitive functioning, fatigue, pain, and the EQ-5D-5L visual analog scale [VAS]) were analyzed in liso-cel–treated pts pooled across trials with HRQoL scores at baseline and postbaseline visits. Linear mixed-effects regression models examined changes in HRQoL over time, with clinical response status and AEs as time-varying covariates, adjusting for relevant baseline and other time-varying factors. Trends in HRQoL change up to Day 730 over time were examined by cytokine release syndrome (CRS) and neurological events (NE) occurring ≤ 30 days after infusion. Results: The analysis included 368 and 372 pts for EORTC QLQ-C30 and EQ-5D-5L VAS, respectively. Achieving a clinical response (CR or PR) was associated with significant HRQoL improvement versus stable disease (SD) or PD in all 6 domains (Table). Meaningful improvement occurred ≤ 30 days after achieving CR or PR for all domains except cognitive functioning, where improvement occurred ≤ 90 days, and was sustained across remaining follow-up visits. CRS and NEs were associated with HRQoL worsening in selected domains; however, pts who experienced CRS or NEs ≤ 30 days after infusion recovered to levels of pts without the AE by Day 60 and maintained thereafter. Conclusions: Among liso-cel–treated pts with R/R LBCL, positive clinical response was associated with meaningful and sustained improvement in nearly all HRQoL domains. CRS and NEs may negatively impact certain HRQoL domains but are temporary. As liso-cel has demonstrated high response rates and a manageable safety profile across studies, these findings further support the pt-reported benefits of liso-cel for R/R LBCL. [Table: see text]

Efficacy outcomes of treatments for double exposed chronic lymphocytic leukemia/small lymphocytic lymphoma: A systematic literature review.

e19019 Background: Bruton's tyrosine kinase inhibitors (BTKis) and the B-cell lymphoma 2 inhibitor (BCL2i) venetoclax have improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) in both first-line and relapsed/refractory settings. Despite advances in treatment with these targeted agents, some CLL/SLL patients remain incurable. Notably, patients who fail to respond to both BTKis and venetoclax, termed 'double-exposed,' often exhibit poor outcomes. Data on treatment efficacy for this subgroup is limited. This study systematically reviews treatments and their efficacy outcomes in double-exposed CLL/SLL patients. Methods: A comprehensive search was conducted across MEDLINE/PubMed, Embase, and Web of Science databases from inception to November 2023, using relevant keywords and MeSH terms. The search focused on identifying studies reporting treatments and efficacy outcomes in double-exposed CLL/SLL patients, irrespective of discontinuation reasons. Key efficacy outcomes included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Results: From 3942 retrieved articles, 12 publications covering 8 unique studies (4 clinical trials and 4 observational studies) were included. The median patient age ranged from 60-69 years in clinical trials to 56-76 years in observational studies. Two clinical trials reported PFS, with pirtobrutinib-treated patients showing a median PFS of 16.8 months (95% CI, 13.2-18.7) and lisocabtagene maraleucel-treated patients demonstrating a median PFS of 13 months (95% CI,2.8-not reached). BELLWAVE-001 was the sole study reporting a median OS of 10.1 months (95%CI, 7.4-15.9) in nemtabrutinib-treated patients. ORR varied, with 58% in nemtabrutinib-treated patients and 80% in those receiving lisocabtagene maraleucel. In the four observational studies, PFS ranged from 3 months (chemoimmunotherapy) to 12 months (BTKis), and ORR ranged from 31.8% (chemoimmunotherapy) to 85.7% (CAR T-cell therapy). Conclusions: This study underscores the scarcity of clinical data addressing efficacy outcomes in double-exposed CLL/SLL patients. Treatments like pirtobrutinib and CAR-T cell therapy show promise for this group. However, the limited treatment options and efficacy data following failure on BTKis and venetoclax highlight a significant unmet medical need. Further research is necessary to comprehensively understand efficacy outcomes in the double-exposed CLL/SLL population.

Real-world outcomes of lisocabtagene maraleucel (liso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR).

7010 Background: Pts with RT have poor prognosis and no standard treatment options with median OS of 3–12 mo (Eyre TA. Hematology Am Soc Hematol Educ Program 2023), indicating an unmet need. We report the largest cohort of real-world pts with RT treated with commercial liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product. Methods: This analysis included US pts with RT from the CIBMTR who received commercial liso-cel between 02/2021 and 02/2023. Primary outcomes included ORR, CR rate, duration of response (DOR), PFS, OS, and safety (including cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] based on Lee 2018 criteria, and prolonged cytopenia defined as grade [gr] 4 thrombocytopenia and/or neutropenia persistent at 30 d after infusion). Results: At data cutoff (08/04/2023), 30 pts with RT were included. Demographics and baseline characteristics at liso-cel infusion are shown in the Table; additional data regarding the pts’ indolent disease and treatment history will be provided in the presentation. Median time from leukapheresis to liso-cel infusion was 35 d (range, 28–63). At median follow-up of 12.3 mo, ORR was 76% among evaluable pts (n = 29) with 66% in CR. Median time to first response was 1.1 mo (range, 0–3.1). Median DOR was not reached (NR); 12-mo DOR rate was 77% (95% CI, 49.5–91). Median PFS (n = 29) and median OS (n = 30) were NR; estimated 12-mo PFS was 54% (95% CI, 33–72) and 12-mo OS was 67% (95% CI, 44–83). Overall, 70% of pts had CRS (gr 3, 0; gr 4, 3%; gr 5, 3% [this pt also had hemophagocytic lymphohistiocytosis]); most common CRS treatments were corticosteroids and tocilizumab (23%) and tocilizumab (20%). ICANS was seen in 47% of pts (gr 3, 17%; gr 4, 10%; gr 5, 0) and most commonly treated with corticosteroids (23%), antiepileptics and corticosteroids (7%), and antiepileptics (7%). Prolonged cytopenia occurred in 17% of pts. One pt had a second primary malignancy (gastrointestinal). Eight (27%) pts died, including 7 because of progression. Conclusions: Pts with RT have poor prognosis with a high unmet need. Here, we show that liso-cel provided meaningful clinical benefit with low incidences of gr ≥ 3 CRS and ICANS observed. The high CR rate is promising in this difficult-to-treat population, and longer follow-up in a larger cohort is needed. [Table: see text]

Estimating the health care costs associated with receipt of lisocabtagene maraleucel: Insights from adults with mantle cell lymphoma (TRANSCEND NHL 001).

7028 Background: Anti-CD19 CAR T cell therapy is a major advancement for treating R/R B-cell malignancies such as mantle cell lymphoma (MCL). While effective disease management with CAR T cell therapy is expected to reduce patients’ health care resource utilization (HCRU) over the long-term, few studies have examined the short-term impacts of this treatment on HCRU and associated health care costs. Here, we used data from the TRANSCEND NHL 001 (NCT02631044) clinical trial to estimate the HCRU-related costs incurred by patients with R/R MCL over the first 12 months after receipt of lisocabtagene maraleucel (liso-cel). Methods: A retrospective analysis of clinical trial data was conducted to calculate the frequency of HCRU (medications [excluding liso-cel], diagnostics, procedures, ICU and non-ICU hospitalizations) observed over the 12 months immediately after administration of liso-cel. Costs for each HCRU event were derived from public databases and literature, adjusted to 2023 United States (US) dollars, and used to estimate patient-level health care costs. Results: Of the patients treated (N = 88), 76.1% were male, 87.5% were White, and mean ± standard deviation (SD) age was 67.5 ± 9 years. All patients were treated in the US and completed a median (range) of 3 (1–11) prior lines of therapy before receiving liso-cel. Most patients (93.2%) received the recommended dose of 100 × 106 CAR+ T cells. The total mean ± SD per-patient cost (excluding liso-cel) was estimated at $138,413 ± $58,555 over 12 months. Facility use accounted for 77.7% of all costs, primarily owing to non-ICU hospitalizations (98.9%), which had a mean ± SD length of stay of 19.5 ± 16.7 days per eligible patient. Half of all health care costs were incurred within the first month of infusion (53.2%), with each subsequent month contributing a fraction (1.5%–6.3%) of total costs. A total of 13 out of 88 patients received their initial infusion in an outpatient setting and incurred 23% fewer costs compared with those who received their infusion in an inpatient setting ($110,050 vs $143,418), primarily as a function of reduced first-month facility use. Total costs for patients receiving liso-cel in outpatient settings were further reduced to $72,771 upon exclusion of 3 outliers. Conclusions: Non-ICU hospitalizations were the largest driver of liso-cel–related costs in this R/R MCL cohort of clinical trial participants. Most of the cost burden was incurred within 1 month of treatment, with dramatic reductions in HCRU and health care costs observed thereafter. Results suggest that treatment in the outpatient setting, even in part (eg, at initial infusion only), may confer substantial cost savings to the health care system.

Factors associated with manufacturing failure of commercial CD19 CAR-T cell products for large b cell lymphoma (LBCL).

7044 Background: As CD19 chimeric antigen receptor T-cell (CAR-T) therapy has shown curative potential in patients (pts) with relapsed/refractory (R/R) LBCL, indications for treatment are expanding. The reported manufacturing failure rate was 1-13% in clinical trials, but there is poor understanding of out-of-specification (OOS) products and CAR-T products on 2nd apheresis. This study aims to characterize factors associated with successful manufacturing. Methods: This study includes pts with R/R LBCL who underwent apheresis for CAR-T product between 12/2017 and 2/2023. Baseline variables were obtained at time of apheresis. OOS product is defined as not meeting eligibility for a commercial product but suitable for infusion on expanded access protocol. 2nd apheresis was performed due to initial manufacture failure. Progression-free survival (PFS) is the time from CAR-T conditioning to disease progression or death, whichever occurs first. Overall survival (OS) is defined as time from conditioning to death or last follow-up. A chi-square test or Fisher’s exact test was used for comparison of 2 categorical variables. Results: 319 pts underwent apheresis; 261(78%) were axicabtagene ciloleucel, 26(8%) were tisagenlecleucel and 47(14%) were lisocabtagene maraleucel 284(85%); products were in-specification (in-spec) on 1st apheresis, 8(2%) in-spec on 2nd apheresis, 27(8%) OOS, and 15(4%) manufacturing failures. Comparison of variables are in the table. OOS rates were 10/250(4%) for axicabtagene, 4/23(17.4%) for tisagenlecleucel and 13/46(28.3%) for lisocabtagene. Reason for OOS product were low viability:14, high interferon:4, internal manufacturing issue:2, CD4 lineage purity:2, high transduction:1, low transduction:2, and low vector copies:2. No association was found with clinical factors and OOS. Factors associated with OOS were advanced stage (P=0.012), IPI score >3 (p=0.001), extranodal involvement (P=0.012) and older age (p= 0.002). In-spec product on 1st apheresis had greater OS (p= 0.011) and PFS (p=0.043) than 2nd apheresis. Conclusions: Factors predictive of OOS product include older age, advanced disease, extranodal involvement and high IPI. Pts requiring 2nd apheresis had worse survival. Lisocabtagene had higher likelihood for OOS product. Outcomes for OOS products are not well described. Failure to manufacture an eligible product is a barrier for LBCL pts to receive CAR-T therapy. [Table: see text]