Lisocabtagene Maraleucel Research Articles

Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China

BackgroundRelapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready...

FDA-approved CAR T-cell Therapy: A Decade of Progress and Challenges.

CAR T-cell therapy is a promising approach for cancer treatment, utilizing a patient's own T-cells (autologous cell) or T-cells from a healthy donor (allogeneic cell) to target and destroy cancer cells. Over the last decade, significant advancements have been made in this field, including the development of novel CAR constructs, improved understanding of biology and mechanisms of action, and expanded clinical applications for treating a wider range of cancers. In this review, we provide an overview of the steps involved in the production of CAR T-cells and their mechanism of action. We also introduce different CAR T-cell therapies available, including their implementation, dosage, administration, treatment cost, efficacy, and resistance. Common side effects of CAR T-cell therapy are also discussed. The CAR T-cell products highlighted in this review are FDA-approved products, which include Kymriah® (tisagenlecleucel), Tecartus® (brexucabtagene autoleucel), Abecma® (Idecabtagene vicleucel), Breyanzi® (lisocabtagene maraleucel), and Yescarta® (axicabtagene ciloleucel). In conclusion, CAR T-cell therapy has made tremendous progress over the past decade and has the potential to revolutionize cancer treatment. This review paper provides insights into the progress, challenges, and future directions of CAR T-cell therapy, offering valuable information for researchers, clinicians, and patients.

Immunotherapy of Hematological Malignancies of Human B-Cell Origin with CD19 CAR T Lymphocytes.

Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Maraleucel), has provided hope for those with r/r NHL and ALL. These new cell-based immunotherapies use genetically engineered chimeric antigen receptor (CAR) T-cells, whose success can be attributed to CAR's high specificity in recognizing B-cell-specific CD19 surface markers present on various B-cell malignancies and the subsequent initiation of anti-tumor activity. The efficacy of these treatments has led to promising results in many clinical trials, but relapses and adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity (NT) remain pervasive, leaving areas for improvement in current and subsequent trials. In this review, we highlight the current information on traditional treatments of NHL and ALL, the design and manufacturing of various generations of CAR T-cells, the FDA approval of Kymriah, Yescarta Tecartus, and Breyanzi, and a summary of prominent clinical trials and the notable disadvantages of treatments. We further discuss approaches to potentially enhance CAR T-cell therapy for these malignancies, such as the inclusion of a suicide gene and use of FDA-approved drugs.

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CAR-T demonstrates clinical efficacy for patients with RT.

The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of patients with B-cell acute lymphoblastic leukemia (B-ALL). Somewhat uniquely among oncologic clinical trials, early clinical development occurred simultaneously in both children and adults. In subsequent years however, the larger number of adult patients with relapsed/refractory (r/r) malignancies has led to accelerated development of multiple CAR T-cell products that target a variety of malignancies, resulting in six currently FDA-approved for adult patients. By comparison, only a single CAR-T cell therapy is approved by the FDA for pediatric patients: tisagenlecleucel, which is approved for patients ≤ 25 years with refractory B-cell precursor ALL, or B-cell ALL in second or later relapse. Tisagenlecleucel is also under evaluation in pediatric patients with relapsed/refractory B-cell non-Hodgkin lymphoma, but is not yet been approved for this indication. All the other FDA-approved CD19-directed CAR-T cell therapies available for adult patients (axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel) are currently under investigations among children, with preliminary results available in some cases. As the volume and complexity of data continue to grow, so too does the necessity of rapid assimilation and implementation of those data. This is particularly true when considering "atypical" situations, e.g.those arising when patients do not precisely conform to the profile of those included in pivotal clinical trials, or when alternative treatment options (e.g.hematopoietic stem cell transplantation (HSCT) or bispecific T-cell engagers (BITEs)) are also available. We have therefore developed a relevant summary of the currently available literature pertaining to the use of CD19-directed CAR-T cell therapies in pediatric patients, and sought to provide guidance for clinicians seeking additional data about specific clinical situations.

FDA Approval Summary: Lisocabtagene Maraleucel for Second-Line Treatment of Large B-Cell Lymphoma.

In June 2022, the FDA extended the indication for lisocabtagene maraleucel (liso-cel) to include adults with large B-cell lymphoma (LBCL) who have refractory disease or relapse within 12 months of first-line chemoimmunotherapy (CIT), as well as transplant-ineligible adults with refractory disease or relapse after first-line CIT. Two clinical trials evaluating a single infusion of liso-cel preceded by lymphodepleting chemotherapy supported the second-line indications. TRANSFORM is a randomized, phase 3, open-label trial comparing liso-cel with standard second-line therapy, including planned autologous hematopoietic stem cell transplantation (HSCT), in 184 transplant-eligible patients. On interim analysis, event-free survival (EFS) by independent review committee (IRC) assessment was statistically significantly improved for the liso-cel arm, with a stratified hazard ratio of 0.34 [95% confidence interval (CI), 0.22-0.51; P < 0.0001]; the estimated median EFS was 10.1 months in the liso-cel arm versus 2.3 months in the control arm. PILOT is a single-arm phase 2 trial of second-line liso-cel in patients who were transplant-ineligible due to age or comorbidities but had adequate organ function for chimeric antigen receptor (CAR) T-cell therapy. Among 61 patients who received liso-cel (median age, 74 years), the IRC-assessed complete response rate was 54% (95% CI, 41-67). Among patients achieving complete response, the estimated 1-year rate of continued response was 68% (95% CI, 45-83). Of the 268 patients combined who received liso-cel as second-line therapy for LBCL, cytokine release syndrome occurred in 45% (Grade 3, 1.3%) and CAR T-cell-associated neurologic toxicities occurred in 27% (Grade 3, 7%), warranting a continued risk evaluation and mitigation strategy.

Lisocabtagene maraleucel for treatment of relapsed and refractory primary mediastinal large B-cell lymphoma in an adolescent patient.

The safety and efficacy of CAR T-cell therapy are unknown in pediatric and adolescent patients with relapsed or refractory primary mediastinal large B-cell lymphoma (R/R PMBCL) which is associated with dismal prognosis. Here, we present a case report of a 16-year-old patient with R/R PMBCL treated with lisocabtagene maraleucel including correlative studies. Patient achieved complete response at 6 months without cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. She only experienced mild cytopenias, requiring filgrastim once. This report highlights the safety and efficacy of lisocabtagene maraleucel in this population, warranting prospective studies to improve clinical outcomes.

Lisocabtagene Maraleucel (liso-cel) in Patients (Pt) with R/R MCL: Subgroup Analyses in Pts with High-Risk Disease Features from the MCL Cohort of the TRANSCEND NHL 001

Lisocabtagene Maraleucel (liso-cel) in Patients (Pt) with R/R MCL: Subgroup Analyses in Pts with High-Risk Disease Features from the MCL Cohort of the TRANSCEND NHL 001

Lisocabtagene Maraleucel (liso-cel) As Second-Line Therapy for R/R Large B-Cell Lymphoma in Patients Not Intended for Hematopoietic Stem Cell Transplantation (HSCT): Final Analysis of the Phase 2 PILOT Study

Lisocabtagene Maraleucel (liso-cel) As Second-Line Therapy for R/R Large B-Cell Lymphoma in Patients Not Intended for Hematopoietic Stem Cell Transplantation (HSCT): Final Analysis of the Phase 2 PILOT Study

Planned Interim Analysis of a Phase 2 Investigator-Initiated Trial of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel

Planned Interim Analysis of a Phase 2 Investigator-Initiated Trial of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel

Outcomes in Patients (pts) with R/R Large B-Cell Lymphoma (LBCL) Who Received Nonconforming Product (NCP) to Commercial Release of Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Outcomes in Patients (pts) with R/R Large B-Cell Lymphoma (LBCL) Who Received Nonconforming Product (NCP) to Commercial Release of Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Comparative Study Evaluating Hospitalizations and Critical Care Stays Among Patients with R/R Large B-Cell Lymphoma (LBCL) Treated with CAR T Cell Therapies Lisocabtagene Maraleucel (liso-cel) and Axicabtagene Ciloleucel (axi-cel) in the Inpatient (IP) and Outpatient (OP) Setting Using United States (US) Claims Data

Comparative Study Evaluating Hospitalizations and Critical Care Stays Among Patients with R/R Large B-Cell Lymphoma (LBCL) Treated with CAR T Cell Therapies Lisocabtagene Maraleucel (liso-cel) and Axicabtagene Ciloleucel (axi-cel) in the Inpatient (IP) and Outpatient (OP) Setting Using United States (US) Claims Data

Multicenter, Real-World Study in Patients with R/R Large B-Cell Lymphoma (LBCL) Who Received Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Multicenter, Real-World Study in Patients with R/R Large B-Cell Lymphoma (LBCL) Who Received Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Cost-effectiveness of second-line lisocabtagene maraleucel in relapsed or refractory diffuse large B-cell lymphoma

AbstractLisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T-cell therapy, received the US Food and Drug Administration approval in 2022 for second-line treatment of diffuse large B-cell lymphoma (DLBCL) for patients with refractory disease or early relapse after first-line chemoimmunotherapy. This decision was based on the TRANSFORM study demonstrating improvements in event-free survival with liso-cel compared with standard care. Given the high costs of CAR T-cell therapies, particularly as they transition to second-line treatment, a cost-effectiveness analysis is essential to determine their economic viability. The study used a partitioned survival model with standard parametric functions to evaluate the cost-effectiveness of liso-cel aganist platinum-based chemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation over a lifetime horizon The analysis relied on data from the TRANSFORM and TRANSCEND trials, established literature, and public data sets to calculate the incremental cost-effectiveness ratio (ICER). For a representative cohort of US adults aged 60 years, ICER of liso-cel was $99 669 per quality-adjusted life-year (QALY) from a health care sector perspective and $68 212 per QALY from a societal perspective, confirming its cost-effectiveness at the $100 000 per QALY threshold. Nonetheless, under certain scenarios, liso-cel surpasses this benchmark but remains within the US acceptable range of $150 000 per QALY. A key finding underlines the importance of incorporating productivity losses into such analyses to capture the broader societal values of novel therapies. Although these therapies offer substantial clinical benefits, their high acquisition costs and limited long-term data critically challenge their economic sustainability.

Lisocabtagene Maraleucel in Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis of the Mantle Cell Lymphoma Cohort From TRANSCEND NHL 001, a Phase I Multicenter Seamless Design Study.

To report the primary analysis results from the mantle cell lymphoma (MCL) cohort of the phase I seamless design TRANSCEND NHL 001 (ClinicalTrials.gov identifier: NCT02631044) study. Patients with relapsed/refractory (R/R) MCL after ≥two lines of previous therapy, including a Bruton tyrosine kinase inhibitor (BTKi), an alkylating agent, and a CD20-targeted agent, received lisocabtagene maraleucel (liso-cel) at a target dose level (DL) of 50 × 106 (DL1) or 100 × 106 (DL2) chimeric antigen receptor-positive T cells. Primary end points were adverse events (AEs), dose-limiting toxicities, and objective response rate (ORR) by independent review committee per Lugano criteria. Of 104 leukapheresed patients, liso-cel was infused into 88. Median (range) number of previous lines of therapy was three (1-11) with 30% receiving ≥five previous lines of therapy, 73% of patients were age 65 years and older, 69% had refractory disease, 53% had BTKi refractory disease, 23% had TP53 mutation, and 8% had secondary CNS lymphoma. Median (range) on-study follow-up was 16.1 months (0.4-60.5). In the efficacy set (n = 83; DL1 + DL2), ORR was 83.1% (95% CI, 73.3 to 90.5) and complete response (CR) rate was 72.3% (95% CI, 61.4 to 81.6). Median duration of response was 15.7 months (95% CI, 6.2 to 24.0) and progression-free survival was 15.3 months (95% CI, 6.6 to 24.9). Most common grade ≥3 treatment-emergent AEs were neutropenia (56%), anemia (37.5%), and thrombocytopenia (25%). Cytokine release syndrome (CRS) was reported in 61% of patients (grade 3/4, 1%; grade 5, 0), neurologic events (NEs) in 31% (grade 3/4, 9%; grade 5, 0), grade ≥3 infections in 15%, and prolonged cytopenia in 40%. Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated R/R MCL, including those with high-risk, aggressive disease.

Lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma: feasibility, safety and efficacy in a real-world setting

Lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma: feasibility, safety and efficacy in a real-world setting

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep?

The clinical development of chimeric antigen receptor (CAR) T-cell therapy has been more challenging for chronic lymphocytic leukemia (CLL) compared to other settings. One of the main reasons is the CLL-associated state of immune dysfunction that specifically involves patient-derived T cells. Here, we provide an overview of the clinical results obtained with CAR T-cell therapy in CLL, describing the identified immunologic reasons for the inferior efficacy. Novel CAR T-cell formulations, such as lisocabtagene maraleucel, administered alone or in combination with the Bruton tyrosine kinase inhibitor ibrutinib, are currently under investigation. These approaches are based on the rationale that improving the quality of the T-cell source and of the CAR T-cell product may deliver a more functional therapeutic weapon. Further strategies to boost the efficacy of CAR T cells should rely not only on the production of CAR T cells with an improved cellular composition but also on additional changes. Such alterations could include (1) the coadministration of immunomodulatory agents capable of counteracting CLL-related immunological alterations, (2) the design of improved CAR constructs (such as third- and fourth-generation CARs), (3) the incorporation into the manufacturing process of immunomodulatory compounds overcoming the T-cell defects, and (4) the use of allogeneic CAR T cells or alternative CAR-modified cellular vectors. These strategies may allow to develop more effective CAR-modified cellular therapies capable of counteracting the more aggressive and still incurable forms of CLL.

Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma : A Cost-Effectiveness Analysis.

First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. State-transition microsimulation model. ZUMA-7, TRANSFORM, other trials, and observational data. "High-risk" patients with DLBCL. Lifetime. Health care sector. Axi-cel or liso-cel versus ASCT. Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was -$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was -$102 477. To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Differences in preinfusion bridging therapies precluded cross-trial comparisons. Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. No research-specific funding.

Phase 2 Study of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel: Planned Interim Analysis

BACKGROUND CD19 chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape for patients (pts) with relapsed/refractory B-cell malignancies, but they remain limited by significant toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While a more favorable toxicity profile had been reported with lisocabtagene maraleucel (liso-cel), based on our real-world experience CRS and ICANS are still observed in 70% and 30% of pts, respectively (Portuguese et al., ASH abstract #172978). Data from our group (Gazeau, TCT, 2023) and others (Strati, Blood, 2023; Park, Nat Med, 2023) suggested the recombinant interleukin-1 receptor antagonist anakinra may successfully prevent and treat CRS and ICANS. Thus, we conducted a phase 2 investigator-initiated clinical trial of anakinra to prevent CRS and ICANS after liso-cel (NCT04359784). We report here our planned interim analysis (n = 15). METHODS Adults ≥18 years of age with Karnofsky performance status ≥60% and B-cell non-Hodgkin lymphoma receiving liso-cel per the FDA label were eligible for this study. Anakinra was administered at 200 mg/day SC from day 0 through day +13 after liso-cel infusion, with the first dose administered approximately 2-4 hours prior to liso-cel infusion. CRS and ICANS severity were assessed per 2019 ASTCT criteria. The primary endpoint was the absence of any grade CRS assessed using the Bayesian optimal phase 2 design.The primary endpoint was not met if ≥6 of the first 15 pts developed any grade CRS. RESULTS Nineteen pts were screened for the study and 15 pts were enrolled. All 15 pts received liso-cel and all doses of SC anakinra. All pts were evaluable for toxicity assessment; 12 pts were evaluable for disease response assessment at day +28 (n = 3, no measurable disease prior to lymphodepletion [LD]). Pt and disease characteristics are shown in Table 1. Eleven pts (73%) had diffuse large B-cell lymphoma, 3 (20%) had active CNS involvement, and 5 (33%) had bulky disease (≥5 cm). Median pre-LD serum ferritin and C-reactive protein (CRP) were 153 ng/mL (IQR, 129-231) and 6.8 (IQR, 1.5-17.2), respectively. All 15 pts received anakinra as planned without dose adjustment or interruption. There were no injection-site reactions or AEs attributed to anakinra. Two pts developed infections during anakinra treatment and were both due to mild Clostridium difficile colitis requiring oral antibiotics. Eight pts (53%) developed any grade CRS, including 1 (7%) case of grade 3 CRS. Four pts (27%) developed any grade ICANS, including 3 (20%) with grade 3 (Figure 1). Median CRS onset and duration were 2 and 2.5 days, respectively, and median ICANS onset and duration were 6 and 9 days, respectively. Three pts (20%) required tocilizumab (range, 0-1 doses), 4 (50%) required dexamethasone (median total dose, 5 mg; range, 0-200 mg), and 1 (12%) required high-dose methylprednisolone. The best overall response rate (ORR) by Lugano criteria was 67% (complete response, n = 5 [42%]). Study pts were retrospectively compared to pts who received liso-cel per standard of care off trial without prophylactic anakinra at our center (n = 42). Despite higher median pre-LD CRP and IL-6 levels, the incidence of CRS was lower in anakinra-treated compared to anakinra-untreated pts (53% vs. 69%, respectively) with comparable median duration of CRS (2.5 vs. 3 days, respectively). The incidence and duration of ICANS were similar (27% vs. 28%; median 9 vs. 8 days, respectively), as was the incidence and duration of hospitalization (67% vs. 74%, median 9.5 vs. 10 days, respectively). Based on Locally Estimated Scatterplot Smoothing (LOESS) estimates, time from liso-cel infusion to CRP normalization was faster in patients receiving anakinra (9 days) compared to those receiving liso-cel alone (14 days). CONCLUSION Low-dose SC anakinra prophylaxis during liso-cel treatment was very well tolerated with preserved anti-tumor efficacy. While our primary endpoint was not reached at our planned interim analysis, we observed lower CRS rates and faster resolution of CRS in comparison to a real-world cohort of pts receiving liso-cel without prophylactic anakinra. To further enhance the preventative effects of anakinra, we plan to change the administration route from SC to intravenous, and to allow anakinra dose uptitration for the last 10 participants in the study.

CAR-T Cell Therapy Vs. Standard of Care for B-Cell Lymphoma: A Systematic Review and Meta- Analysis of Updated Results of Clinical Trials

Background: For many years, platinum based immunochemotherapy followed by high dose chemotherapy and stem cell transplantation remained standard of care for relapsed/refractory large B-cell lymphoma. About half of the patients do not undergo transplantation due to disease insensitivity to 2 nd line therapy and cured in &amp;lt;30%. In recent years, feasibility of chimeric antigen receptor (CAR) t-cell therapies is tested as 2 nd line of treatment. In this meta-analysis, we will assess the efficacy and safety of CAR-T cell therapy as 2 nd line therapy as compared to standard therapy in large B cell lymphoma based on updated clinical trial results. Methods: A literature search was performed on PubMed and Embase with keywords for “CAR-T cell therapy” and “B-cell lymphoma” from the inception of data till 07/01/2023. PRISMA guidelines were followed while conducting this meta-analysis. A total of 3091 articles were screened and 3 randomized clinical trials (RCTs, N=865) were included based on inclusion criteria. “R” software was used to conduct this meta-analysis. Results: In 3 RCTs (N=865), 180 patients were treated with axicabtagene ciloleucel, 92 patients with lisocabtagene maraleucel, 162 patients with tisagenlecleucel, and 431 patients with standard therapy. Based on updated results of 2 trials (N=543), pooled hazard ratios (HRs) of progression free survival (PFS) was 0.47 (95% CI= 0.37-0.60, I 2=0), overall survival (OS) was 0.73 (95% CI=0.56-0.94, I 2=0), and event free survival (EFS) was 0.4 (95% CI=0.32-0.49, I 2=0) in favor of CAR-T cell therapy as compared to standard therapy. Pooled relative risk (RR) of complete response (CR) and overall response (ORR) were 1.88 (95% CI=1.57-2.25, I 2=2%), and 1.69 (95% CI=1.48-1.92, I 2=0%), respectively, in favor of CAR-T cell therapy. The Belinda RCT on tisagenlecleucel by Bishop et al. was the outlier. HR of EFS, RR of CR, and RR of ORR were 1.07 (95% CI= 0.82-1.4), 1.03 (0.73-1.47), and 1.09 (95% CI= 0.85-1.39), respectively, similar in the two groups. In 3 RCTs, RR of ≥ grade 3 any adverse effects were 1.02 (95% CI=0.92-1.12, I 2=72%), neurotoxicity was 7.35 (95% CI=0.97-55, I 2=64%), and neutropenia was 1.41 (95% CI=1.04-1.91, I 2=78%). Pooled incidence of ≥ grade cytokine release syndrome (CRS) was 5% (CI=0.03-0.08) and was 0 with standard therapy. Fig 1. Conclusion: Based on updated results, CAR-T cell therapies, axicabtagene ciloleucel and lisocabtagene maraleucel, were significantly more effective in terms of response and survival rates. ≥Grade 3 side effects were similar with CAR-T cell and standard therapy. CRS, neurotoxicity, and hematological side effects were higher with CAR-T cells. Tisagenlecleucel was found as an outlier and the efficacy was similar to standard care. More randomized double-blind large-scale phase III clinical trials are needed to confirm these results.