Refractory Large B-cell Lymphoma Research Articles

Chimeric antigen receptor T-cell infusion for large B-cell lymphoma in complete remission: a center for international blood and marrow transplant research analysis.

CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.

Effective bridging strategies prior to infusion with tisagenlecleucel results in high response rates and long-term remission in relapsed/refractory large B-cell lymphoma: findings from a German monocentric study

BackgroundIncorporating chimeric antigen receptor (CAR)-T cell therapy into relapsed or refractory large B-cell lymphoma (rr LBCL) treatment algorithms has yielded remarkable response rates and durable remissions, yet a substantial portion of patients experience progression or relapse. Variations in outcomes across treatment centers may be attributed to different bridging strategies and remission statuses preceding CAR-T cell therapy.PatientsTwenty-nine consecutive adult patients receiving tisagenlecleucel (tisa-cel) for rr LBCL from December 2019 to February 2023 at Jena University Hospital were analyzed.ResultsThe median age was 63, with a median of 3 prior treatments. Twenty patients (69%) were refractory to any systemic therapy before CAR-T cell treatment. Following leukapheresis, 25 patients (86%) received bridging therapy with the majority undergoing chemotherapy (52%) or combined modality therapy (32%). Radiotherapy (RT) was part of the bridging strategy in 44%, with moderately hypofractionated involved site RT (30.0 Gy/2.5 Gy) being applied most frequently (64%). Post-CAR-T infusion, the objective response rate at 30 days was 83%, with 55% achieving complete response. Twelve-month progression-free (PFS) and overall survival (OS) were 60% and 74%, respectively, with a median follow up of 11.1 months for PFS and 17.9 months for OS. Factors significantly associated with PFS were chemotherapy sensitivity pre-leukapheresis and response to bridging.ConclusionThe study underscores the importance of minimal tumor burden at CAR-T initiation, emphasizing the need for suitable bridging regimens. The findings advocate for clinical trials and further real-world analyses to optimize CAR-T cell therapy outcomes by identifying the most effective bridging strategies.

Defining primary refractory large B-cell lymphoma

AbstractPatients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have “primary refractory disease.” However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma

BackgroundApproximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to...

Cost-effectiveness analysis 3L of axicabtagene ciloleucel vs tisagenlecleucel and lisocabtagene maraleucel in Japan.

Aim: Cost-effectiveness analysis (CEA) was performed to compare axicabtagene ciloleucel (axi-cel) with tisagenlecleucel (tisa-cel) and lisocabtagene (liso-cel) for treatment of relapsed or refractory large B-cell lymphoma in adult patients after ≥2 lines of therapy in Japan. Materials & methods: Cost-effectiveness analysis was conducted using the partition survival mixture cure model based on the ZUMA-1 trial and adjusted to the JULIET and TRANSCEND trials using matching-adjusted indirect comparisons. Results & conclusion: Axi-cel was associated with greater incremental life years (3.13 and 2.85) and incremental quality-adjusted life-years (2.65 and 2.24), thus generated lower incremental direct medical costs (-$976.29 [-¥137,657] and -$242.00 [-¥34,122]), compared with tisa-cel and liso-cel. Axi-cel was cost-effective option compared with tisa-cel and liso-cel from a Japanese payer's perspective.

Plain language summary of the TRANSFORM study primary analysis results: lisocabtagene maraleucel as asecond treatment regimen for large B-cell lymphoma following failure of the first treatment regimen.

People diagnosed with a disease called large B-cell lymphoma (LBCL) may experience return, or early relapse, of their disease within the first year after receiving and responding to their first (first-line) treatment regimen. Others may have primary refractory disease, meaning that the disease either did not respond to first-line treatment at all or only responded for a very brief period. Second (second-line) treatment includes immunotherapy followed by high-dose chemotherapy and ASCT, which has the potential to cure LBCL. However, if the disease does not respond to immunotherapy, people cannot receive ASCT, and less than 30% of people are cured. Therefore, new second-line treatment options are required, such as CAR T cell therapy, which uses a person's own genetically engineered lymphocytes, also called T cells, to fight their lymphoma. In this article, we summarize the key results of the phase 3 TRANSFORM clinical study that tested if liso-cel, a CAR T cell treatment, can safely and effectively be used as a second-line treatment for people with early relapsed or primary refractory (relapsed/refractory) LBCL. A total of 184 adults with relapsed/refractory LBCL who were able to receive ASCT were randomly treated with either liso-cel or standard of care (SOC) as second-line treatment. SOC included immunochemotherapy followed by high-dose chemotherapy and ASCT. Almost all (97%) people in the liso-cel group completed treatment, whereas 53% of people in the SOC group did not complete treatment, mostly due to their disease not responding or relapsing, and therefore they were not able to receive ASCT. People who received liso-cel as a second-line treatment lived longer without the occurrence of an unfavorable medical event or worsening of the disease and had a better response to treatment than those who received SOC as second-line treatment. People who received liso-cel reported side effects that researchers considered to be manageable, and that were known to occur with CAR T cell treatment. Results from the TRANSFORM study support the use of liso-cel as a more effective second-line treatment compared with SOC that is safe for people with relapsed/refractory LBCL. Clinical Trial Registration: NCT03575351 (TRANSFORM study) (ClinicalTrials.gov).

Reducing and controlling metabolic active tumor volume prior to CAR T-cell infusion can improve survival outcomes in patients with large B-cell lymphoma

Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline (n = 74) and pre-LD (n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV (< 190 cc) had a better time to progression (TTP) and overall survival (OS) compared to high MATV patients (p < 0.001). High MATV patients who remained stable or reduced upon bridging therapy showed a significant improvement in TTP (p = 0.041) and OS (p = 0.015), compared to patients with a high pre-LD MATV (> 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens.

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy

BackgroundOver 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse...

FLT3 Mutated Acute Myeloid Leukemia after CD19 CAR-t Cells.

Chimeric Antigen Receptor T-cells have improved the life expectancy of severely pretreated patients with aggressive hematological cancers; for this reason, therapy-related myeloid leukemias are becoming of great concern in this field, despite their clonal phylogenesis and mutational landscape have not been fully explored yet. This case discusses a 33-year-old man with refractory large B-cell lymphoma, treated with Chimeric Antigen Receptor T-cell (CAR-T) therapy as the 7th line of treatment. Despite a persistent partial response, the patient developed therapy-related acute myeloid leukemia (t-AML) six months post-CAR-T, revealing pre-existing clonal hematopoiesis. The myeloid malignancy exhibited an unusual hypocellular/dysplastic pattern, progressing to an established blast phase with cytopenia. Treatment with demethylating agents and BCL2 inhibitors proved ineffective, leading to t-AML with hyperleukocytosis and FLT3-ITD gain, resulting in the patient's death. This case underscores the impact of severe pretreatment and bone marrow impairment in CAR-T-associated t-AML, emphasizing their role over insertional mutagenesis. Furthermore, it highlights the retention of classic therapy-related leukemia characteristics, including the potential for acquiring FLT3 mutations and displaying dysplastic morphology in these secondary leukemias.

CD19-CAR-DNT cells (RJMty19) in patients with relapsed or refractory large B-cell lymphoma: a phase 1, first-in-human study

Current approved chimeric antigen receptor (CAR) T-cell products are autologous cell therapies that are costly and poorly accessible to patients. We aimed to evaluate the safety and antitumor activity of a novel off-the-shelf anti-CD19 CAR-engineered allogeneic double-negative T cells (RJMty19) in patients with relapsed/refractory large B-cell lymphoma. We report the results from a first-in-human, open-label, single-dose, phase 1 study of allogeneic CD19-specific CAR double-negative T (CAR-DNT) cells. Eligibility criteria included the presence of measurable lesions, at least 2 lines of prior immunochemotherapy, and an ECOG score of 0-1. We evaluated four dose levels (DL) of RJMty19 in a 3+3 dose-escalation scheme: 1×106, 3×106, 9×106 and 2×107 CAR-DNT cells per kilogram of body weight. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The primary endpoints were dose-limiting toxicities (DLTs), incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of standard cellular pharmacokinetic parameters, immunogenicity, objective response rates (ORR), and disease control rate (DCR) per Lugano 2014 criteria. A total of 12 patients were enrolled between 22 July 2022 and 27 July 2023. Among these patients, 66% were classified as stage IV, 75% had an IPI score of 3 or higher, representing an intermediate risk or worse. The maximum tolerated dose was not reached because no DLT was observed. Four patient experienced grade 1 or 2 cytokine release syndrome and dizziness. The most common AEs were hematologic toxicities, including neutropenia (N=12, 100%), leukopenia (N=12, 100%), lymphopenia (N=10, 83%), thrombocytopenia (N=6, 50%), febrile neutropenia (N=3, 25%), and anemia (N=3, 25%). Seven subjects died till the cut-off date, five of them died of disease progression and two of them died of COVID 19. In all patients (N=12), the ORR was 25% and CRR was 8.3%. DL1 and DL2 patients benefited less from the therapy (ORR: 17%, N=1; DCR: 33%, N=2). However, all DL3 patients achieved disease control (N=3, 100%), and all DL4 patients achieved objective response (N=3, 100%). Our results demonstrate that CD19-CAR-DNT cells appear to be well tolerated with promising antitumor activity in LBCL patients. Further study of this product with a larger sample size is warranted. This phase 1 study is registered on clinicaltrials.gov (NCT05453669). Wyze Biotech. Co., Ltd.

Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL)

Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL)

Impact of Complete Response (CR) on Long-Term Survival Among Patients Receiving Axicabtagene Ciloleucel (axi-cel) for Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL)

Impact of Complete Response (CR) on Long-Term Survival Among Patients Receiving Axicabtagene Ciloleucel (axi-cel) for Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL)

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106–4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

Recent advances and future perspectives of T-cell engagers in lymphoid malignancies.

Bispecific antibodies (BsAbs) are monoclonal antibodies that simultaneously bind to a specific antigen on tumors and CD3 on T cells, leading to T cell activation and subsequent tumor cell lysis. Several CD20×CD3 BsAbs are being developed for B-cell lymphomas. Furthermore, multiple clinical trials to evaluate BsAbs for the treatment of multiple myeloma, with targets including BCMA, GPRC5D and FcRH5, are ongoing. Emerging evidence suggests promising efficacy in heavily pretreated patients with relapsed or refractory lymphoid malignancies, showing an overall response rate of 50-60%, with complete response rates of 30-40% for relapsed or refractory large B-cell lymphoma and 60-70% for relapsed or refractory multiple myeloma. Their toxicity profiles are generally consistent with other T-cell redirecting therapies, including cytokine release syndrome, which may be mitigated with several strategies, such as step-up dosing, pre-mediation with glucocorticoids and a subcutaneous route of administration, and very rare neurotoxicity. Several clinical trials evaluated BsAbs in combination with other agents or in earlier lines of treatment, including in front-line settings. BsAbs have the potential to change the treatment paradigm of lymphoid malignancies in the coming years; however, longer follow-ups are required to assess the durability of responses to these agents. We herein provide an overview of the findings of recent clinical trials on BsAbs, including mechanisms of action, safety profiles, and efficacy, and discuss the role of BsAbs in the treatment of B-cell lymphomas and multiple myeloma.

Axicabtagene Ciloleucel versus Tisagenlecleucel for Relapsed or Refractory Large B Cell Lymphoma: A Systematic Review and Meta-Analysis

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory aggressive large B cell lymphoma (LBCL). Significant costs and complex manufacturing underscore the importance of evidence-based counseling regarding the outcomes of these treatments. With the aim of examining the efficacy and safety of axi-cel versus tisa-cel in patients with relapsed/refractory aggressive LBCL, we performed a systematic literature search of comparative studies evaluating outcomes in relapsed/refractory aggressive LBCL after treatment with axi-cel or tisa-cel. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for response, progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity. Meta-analysis and meta-regression were used to generate summary statistics. A total of 2372 participants were included in the 8 studies in our analysis. The dropout rate between apheresis and infusion was 13% for axi-cel versus 18% for tisa-cel, and the median time from apheresis to infusion was 32 days versus 45 days. Axi-cel showed higher odds for a complete response (OR, 1.65; P < .001) and was associated with higher odds for PFS at 1 year after infusion (OR, .60; P < .001). OS appeared to be improved with axi-cel (OR, .84; 95% CI, .68 to 1.02; P = .08), whereas the cumulative incidence of nonrelapse mortality (NRM) was 11.5% for axi-cel versus 3.7% for tisa-cel (P = .002). The main predictors for survival were lactate dehydrogenase level, Eastern Cooperative Oncology Group Performance Status, and response to bridging, and axi-cel maintained superior efficacy even in elderly patients. In terms of safety, axi-cel was associated with significantly higher odds of any-grade CRS (OR, 3.23; P < .001), but not of grade ≥3 CRS (P = .92). Axi-cel was associated with significantly higher odds of severe ICANS grade ≥3 (OR, 4.03; P < .001). In terms of hematotoxicity, axi-cel was significantly associated with higher odds of severe neutropenia at 1 month after infusion (OR, 2.06; P = .003). As a result, axi-cel was associated with significantly greater resource utilization, including prolonged hospital stay, more frequent intensive care admission, and use of agents such as tocilizumab for toxicity management. We provide strong evidence of the greater efficacy of axi-cel versus tisa-cel in relapsed/refractory aggressive LBCL. The higher toxicity and NRM seen with axi-cel might not counterbalance the overall results, highlighting the need for timely intervention and careful selection of patients, balancing resource utilization and clinical benefit.

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

PCR76 Generating Health-State Utility Values in Patients Treated with Second-Line Systemic Therapy for Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)

PCR76 Generating Health-State Utility Values in Patients Treated with Second-Line Systemic Therapy for Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Curative Potential of Axicabtagene Ciloleucel (Axi-Cel): An Exploratory Long-Term Survival Assessment in Patients with Refractory Large B-Cell Lymphoma from ZUMA-1

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Long-term results from ZUMA-1, a multicenter, single-arm, Phase 1/2 study of axi-cel in patients with refractory LBCL, demonstrated sustained overall survival (OS), with a median of 25.8 months and a 5-year estimate of 43% (Neelapu SS, et al. Blood. 2023). Initial assessments of disease-specific survival (DSS) in ZUMA-1 suggested axi-cel may be curative for a subset of patients. However, endpoints defining curative potential in patients with LBCL are not yet clearly established. Here, we report exploratory analyses from the Phase 2 portion of ZUMA-1 using proposed endpoints to measure cure along with survival analyses with up to 6 years of follow-up. Methods: Eligible adults in the pivotal Phase 2 Cohorts (1 and 2) of ZUMA-1 had refractory LBCL (diffuse LBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma). Patients were leukapheresed at enrollment, then received lymphodepletion and axi-cel infusion (2×10 6 CAR T cells/kg; Neelapu et al. N Engl J Med. 2017). Exploratory analyses to assess curative potential included lymphoma-related event-free survival (LREFS), duration of complete response (DOCR), and DSS. LREFS was defined as the time from axi-cel infusion until disease progression, initiation of new lymphoma therapy, autologous stem cell transplantation, or death due to progression, whichever was earliest. DSS was defined as time from axi-cel infusion to death due to progression or axi-cel-related adverse events (AEs). Outcomes were analyzed via Kaplan-Meier (KM) estimates and competing risk analyses. Landmark analyses were used to explore prognostic potential of disease status at Week 4 and Months 3, 6, 12 and 24. Results: At a median follow-up of 63.1 months in the 5-year analysis (data cutoff on August 11, 2021), median LREFS was 5.8 months (95% CI, 3.4-13.9) and the 60-month LREFS rate by KM estimate was 33.5%. Among patients who achieved a complete response (CR) as best response (n=59), median DOCR was not reached (95% CI, 12.9 months-not estimable). Median LREFS among those with a CR was not reached (95% CI, 18.4 months-not estimable) and the 60-month LREFS rate was 56.8%. Among those with a CR at Months 12 and 24, 60-month estimated rates of LREFS and ongoing CR were &amp;gt;80% (Table 1). All 3 lymphoma-related events that occurred after Month 24 in those with a CR were disease progression. Among those with a partial response at Week 4 (n=33) and Month 3 (n=10), estimates of 60-month LREFS were 27.3% and 45.0%, respectively. The data cutoff date for the 6-year survival analysis was August 11, 2022. Median OS was 25.8 months (95% CI, 12.8-63.7). In a competing risk assessment of OS, the cumulative incidence of death at 72 months was 61.6%. Between Months 24 and 72, there appeared to be an increase of 6% in the cumulative incidences of death due to progression (40.6% and 46.6%, respectively) and other reasons (5.0% and 11%, respectively), while deaths due to axi-cel-related AEs remained 4.0% at each timepoint. Among patients with a best response of a CR, the cumulative incidence rates of death at Month 24 and Month 72 were 20.3% and 27.2% for progression, 3.4% (both timepoints) for axi-cel-related AEs, and 0% and 10.4% for other reasons, respectively. Those who had a CR at Months 12 and 24 had a 72-month cumulative incidence of death of 18.4% and 14.2%, respectively (Table 2). Additionally, those who had a CR at 12 and 24 months had 72-month KM-estimated DSS of 94.4% and 100%, respectively. Among those with a partial response at Week 4 and Month 3, 72-month cumulative incidences of death were 72.7% and 50.0%, respectively. Conclusion: In this post hoc analysis of ZUMA-1 with up to 6 years of follow-up, axi-cel had long-term LREFS in a substantial proportion of patients, with a 5-year rate of 34% (57% among patients who achieved a CR). Additionally, a CR at 12 and 24 months may be predictive of extended OS. Among patients who achieved a CR, deaths due to axi-cel-related AEs mainly occurred before Month 24. These results demonstrate the curative potential of axi-cel in a subset of patients with R/R LBCL.

Glofitamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma: Extended Follow-Up from a Pivotal Phase II Study and Subgroup Analyses in Patients with Prior Chimeric Antigen Receptor T-Cell Therapy and by Baseline Total Metabolic Tumor Volume

Background: Glofitamab is a CD20xCD3 bispecific antibody with a 2:1 (CD20:CD3) format that engages and redirects T cells to eliminate B cells. In a pivotal Phase II study (NCT03075696), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and had a manageable safety profile in patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL; Dickinson et al. N Engl J Med 2022). Here, we present an extended follow up, as well as subgroup analyses in patients with prior chimeric antigen receptor (CAR) T-cell therapy and by baseline total metabolic tumor volume (TMTV). Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D) 1 of Cycle (C) 1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles; total of 8.3 months). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson et al. J Clin Oncol 2014). Cytokine release syndrome (CRS) events were assessed using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Exploratory analyses were performed to investigate the association between TMTV at baseline and progression-free survival (PFS) and CRS. As there is currently no consensus on the method for standardized uptake value (SUV) thresholding in non-Hodgkin's lymphoma, a variety of methods are used in clinical studies (Keijzer et al. Comput Struct Biotechnol J 2023). Here, we used IRC-assessed TMTV derived from baseline positron emission tomography images using a semi-automatic method with a threshold for TMTV of 2x the SUV mean of the liver. Results: As of May 1, 2023, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics were as previously presented (Dickinson et al. N Engl J Med 2022): median prior therapies received was 3 (range: 2-7); 33% of patients had received prior CAR T-cell therapy, and 85% were refractory to their most recent regimen. Median time on study was 25.8 months (range: 0-35). The IRC-assessed overall response and CR rates were 52% and 40%, respectively. The majority of CRs (40/62; 65%) were ongoing at data cut-off. Median duration of CR (DoCR) was 26.9 months (95% confidence interval [CI]: 18.4-not evaluable [NE]); an estimated 67% of patients with a CR at any time remained in remission at 18 months. PFS and overall survival rates at 12 months in patients with a CR at end of treatment (EOT) were 80% and 90%, respectively. In patients with prior CAR T-cell therapy (n=52), CR rates were consistent with the overall population (N=155; 37% vs 40%, respectively) and median DoCR was 22.0 months (95% CI: 6.7-NE). The safety profile of glofitamab was consistent with what has been described previously, with no new safety signals observed. Baseline TMTV was available for 144 patients and the median was 128.7mL (range: 0-3820; data cut-off: January 16, 2023). Higher TMTV was associated with an increased risk of experiencing a Grade ≥2 CRS event. The proportion of patients with Grade ≥2 CRS events in the first, second, third, and fourth TMTV quartiles was 2.8%, 11.1%, 16.7%, and 38.9%, respectively (Chi-square=16.273; degrees of freedom=1; p&amp;lt;0.0001). Patients with a baseline TMTV above or equal to the median (n=72) had a 12-month PFS rate of 16.8% (95% CI: 9.7-29.1), compared with 50.1% (95% CI: 39.5- 63.7) amongst patients with a baseline TMTV below the median (n=72; hazard ratio: 2.6, 95% CI: 1.7-3.9; Figure). Conclusions: Glofitamab continued to demonstrate durable responses in patients with R/R LBCL, with most patients with CR at EOT still in remission, and no new safety signals observed. These data indicate that there may be potential for favorable long-term outcomes with fixed-duration glofitamab for R/R LBCL. CR rates in patients with prior CAR T-cell therapy were durable and consistent with the overall population. Data from the subgroup analyses showed that higher baseline TMTV was associated with an increased risk of Grade ≥2 CRS and suggested that baseline TMTV may be prognostic for PFS. Updated analyses, with a follow-up of approximately 24 months post EOT, and further TMTV exploratory analyses will be presented.

Efficacy of Lisocabtagene Maraleucel for Relapsed or Refractory Aggressive B Cell Lymphoma in Our Hospital

[Background] Although the standard treatment for relapsed or refractory large B-cell lymphoma (LBCL) is high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT), the prognosis of relapsed or refractory LBCL is poor. The chimeric antigen receptor (CAR) T-cell therapy showed efficacy against relapsed or refractory LBCL. However, little real-world data on lisocabtagene maraleucel (liso-cel) were reported. Therefore, we report our data on liso-cel for relapsed or refractory LBCL in our institution. [Methods] We retrospectively analyzed clinical characteristics of patients who underwent leukapheresis to manufacture liso-cel between August 2021 and March 2023 at Toranomon Hospital. Overall survival (OS), progression-free survival (PFS), and duration of response (DOR) were calculated using the Kaplan-Meier method. OS was defined as the time from infusion of liso-cel to the date of death or last follow-up. PFS was defined as the time from infusion of liso-cel to progression of disease or death. DOR was defined as the time from first complete response or partial response to disease progression or death. The Cox proportional hazards model was used to determine the significance of multiple variables. [Results] Leukapheresis for the manufacture of liso-cel was performed in 25 cases. Of these 25 cases, liso-cel could not be manufactured in only one patient, and the other 24 patients received liso-cel infusion. Of the 24 patients who received liso-cel, 14 were men and the median age was 64.5 years (range, 29-78). Twenty-one patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; the other 3 had a PS of 2. The other clinical characteristics were as follows: Stage III/IV in 21 (87.5%); Bulky mass in 6 (25%); extranodal involvement &amp;gt; 1 in 9 (38%); international prognostic index (IPI) &amp;gt; 2 in 13 (54%); and elevated LDH in 11 (46％). Histological diagnoses were diffuse large B-cell lymphoma (n=13), transformed follicular lymphoma (n=6), primary mediastinal large B-cell lymphoma (n=3), and high-grade B-cell lymphoma (n=2), respectively. Secondary central nervous system (CNS) involvement was detected in 4 cases. The number of patients with primary refractory disease or relapse within 12 months after first-line chemotherapy is 10 (42%) and 10 (42%), respectively. Since 10 patients with primary refractory disease required immediate chemotherapy until leukapheresis was performed, liso-cel was used as a third-line or later in all cases. Patients had received a median of 4 (range, 2-9) previous lines of chemotherapy. Six patients (25%) had received a previous autologous HSCT, and two (8%) had received a previous allogeneic HSCT, respectively. The median time from leukapheresis to liso-cel arrival at our institution was 42 (range, 37-45) days. Bridging chemotherapy after leukapheresis was performed in all cases, with polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) being the most common with 13 cases (54%). Eight cases (33%) had achieved complete response (CR), and 8 cases (33%) had achieved partial response (PR) before lymphodepleting chemotherapy. The median follow-up of survivors was 7.7 months (range, 2.5-14.5). The median OS, PFS, and DOR were 11.5 months (95% confidence interval [CI]: 8.9 to not applicable, NA), 8.5 months (95% CI: 2.1 to NA), and 8.9 months (95% CI: 3.3 to NA), respectively. The overall response rate was 71%, with 54% achieving CR. Cytokine release syndrome (CRS) and neurological events (NEs) occurred in 21 (88%) and 2 patients (8%); grade 3 or worse CRS and NEs occurred in 1 (4%) and 2 patients (8%). Grade 3 or worse neutropenia, anemia, and thrombocytopenia were occurred in 23 (96%), 14 (50%), and 17 cases (71%), respectively. Prolonged Grade 3 or worse neutropenia was seen in 12 cases (50%) at 28 days after liso-cel infusion. No treatment-related death was not observed. Six patients died, and the causes of death were LBCL (n=3), pneumonia (n=2), and COVID-19 (n=1). In the multivariate analysis, independent risk factors for PFS were PS of 2 (hazard ratio [HR], 56.39; 95% CI, 8.31 to 382.7; p&amp;lt;0.001) and disease status (stable disease/progressive disease) before lymphodepleting chemotherapy (HR, 6.14; 95% CI, 1.07 to 35.06; p=0.04). [Conclusion] In our cohort, liso-cel has shown high response in relapsed or refractory LBCL. Disease status before lymphodepleting chemotherapy is significant for better prognosis.