Refractory Large B-cell Lymphoma Research Articles

PET-based radiomics signature can predict durable responses to CAR T-cell therapy in patients with large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment option for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, only a subset of patients will present long-term benefit. In this study, we explored the potential of PET-based radiomics to predict treatment outcomes with the aim of improving patient selection for CAR T-cell therapy. We conducted a single-center study including 93 consecutive R/R LBCL patients who received a CAR T-cell infusion from 2018 to 2021, split in training set (73 patients) and test set (20 patients). Radiomics features were extracted from baseline PET scans and clinical benefit was defined based on median progression-free survival (PFS). Cox regression models including the radiomics signature, conventional PET biomarkers and clinical variables were performed for most relevant outcomes. A radiomics signature including 4 PET-based parameters achieved an AUC=0.73 for predicting clinical benefit in the test set, outperforming the predictive value of conventional PET biomarkers (total metabolic tumor volume [TMTV]: AUC=0.66 and maximum standardized uptake value [SUVmax]: AUC=0.59). A high radiomics score was also associated with longer PFS and OS in the multivariable analysis. In conclusion, the PET-based radiomics signature predicted efficacy of CAR T-cell therapy and outperformed conventional PET biomarkers in our cohort of LBCL patients.

CT-045 Primary Results From OUTREACH: A Phase II Study of Lisocabtagene Maraleucel (Liso-Cel) Administered in the Community Setting as Outpatient or Inpatient Treatment in Patients With Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)

CT-045 Primary Results From OUTREACH: A Phase II Study of Lisocabtagene Maraleucel (Liso-Cel) Administered in the Community Setting as Outpatient or Inpatient Treatment in Patients With Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Retrospective Comparison of Survival Projections for CAR T-Cell Therapies in Large B-Cell Lymphoma.

Durable remission has been observed in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) treated with chimeric antigen receptor (CAR) T-cell therapy. Consequently, hazard functions for overall survival (OS) are often complex, requiring the use of flexible methods for extrapolations. We aimed to retrospectively compare the predictive accuracy of different survival extrapolation methods and evaluate the validity of goodness-of-fit (GOF) criteria-based model selection for CAR T-cell therapies in R/R LBCL. OS data were sourced from JULIET, ZUMA-1, and TRANSCEND NHL 001. Standard parametric, mixture cure, cubic spline, and mixture models were fit to multiple database locks (DBLs), with varying follow-up durations. GOF was assessed using the Akaike information criterion and Bayesian information criterion. Predictive accuracy was calculated as the mean absolute error (MAE) relative to OS observed in the most mature DBL. For all studies, mixture cure and cubic spline models provided the best predictive accuracy for the least mature DBL (MAE 0.013‒0.085 and 0.014‒0.128, respectively). The predictive accuracy of the standard parametric and mixture models showed larger variation (MAE 0.024‒0.162 and 0.013‒0.176, respectively). With increasing data maturity, the predictive accuracy of standard parametric models remained poor. Correlation between GOF criteria and predictive accuracy was low, particularly for the least mature DBL. Our analyses demonstrated that mixture cure and cubic spline models provide the most accurate survival extrapolations of CAR T-cell therapies in LBCL. Furthermore, GOF should not be the only criteria used when selecting the optimal survival model.

The Dutch CAR-T Tumorboard Experience: Population-Based Real-World Data on Patients with Relapsed or Refractory Large B-Cell Lymphoma Referred for CD19-Directed CAR T-Cell Therapy in The Netherlands.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020-May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

FDA Approval Summary: Axicabtagene Ciloleucel for Second-Line Treatment of Large B-Cell Lymphoma.

In April 2022, the FDA approved axicabtagene ciloleucel (axi-cel) for adults with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Approval was based on ZUMA-7, a randomized (1:1), open-label trial in 359 patients with primary refractory LBCL (74%) or early relapse who were transplant candidates. The study compared a single course of axi-cel to standard therapy, consisting of chemoimmunotherapy followed by high-dose therapy and autologous hematopoietic stem cell transplantation (HSCT) in responding patients. Overall, 94% of the experimental arm received chimeric antigen receptor (CAR) T-cell product, and 35% of the control arm received on-protocol HSCT. The primary endpoint was event-free survival, which was significantly longer in the axi-cel arm with an HR of 0.40 (95% confidence interval, 0.31-0.51; P value < 0.0001) and estimated median of 8.3 months, versus 2.0 months with standard therapy. Among 168 recipients of axi-cel, cytokine release syndrome occurred in 92% (Grade ≥ 3, 7%), neurologic toxicity in 74% (Grade ≥ 3, 25%), prolonged cytopenias in 33%, and fatal adverse reactions in 1.8%. This is the first FDA approval of a CAR T-cell therapy for LBCL in the second-line setting and reflects a potential paradigm shift.

Chimeric antigen receptor T-cell treatment patterns in relapsed or refractory large B-cell lymphoma.

Aim: To investigate real-world chimeric antigen receptor (CAR) T-cell therapy treatment patterns. Patient & methods: Relapsed/refractory large B-cell lymphomapatients who received CAR T-cell therapy were identified. Patient characteristics, setting of CAR T-cell infusion, incidence of CAR T-cell therapy-associated adverse eventsand healthcare resource utilization were assessed. Results: Of 1175 patients, 83% were infused inpatient. Within threedays postinfusion, inpatient-infused patients had a significantly higher risk of CAR T-associated adverse events (hazard ratio: 2.67; 95% CI: 2.09-3.42) compared with outpatient-infused patients. By day 30, 67% of outpatient-infused patients were hospitalized at least once. Conclusion: These findings suggest that physicians were able to select lower-risk patients for outpatient infusion, but postinfusion hospitalizations still occur.

Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma.

LBA107 Background: In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) was superior to standard of care (SOC; hazard ratio [HR], 0.398; P&lt;.0001) in the primary analysis of event-free survival as second-line therapy in patients with early relapsed or refractory large B-cell lymphoma (R/R LBCL; Locke et al. NEJM. 2022). In a preplanned interim analysis, median overall survival (OS) was not reached in the axi-cel arm and was 25.7 mo in the SOC arm (HR, 0.71; 95% CI, 0.52-0.97; Locke et al. TCT 2022. Abstract 1). We now report the primary OS analysis of ZUMA-7. Methods: Study procedures and eligibility were previously reported. The intention-to-treat (ITT) primary OS analysis occurred 5 years after the first patient was randomized (01/25/2018) per protocol. A log-rank test stratified by randomization stratification factors compared OS between the 2 arms. In addition to the ITT analysis and to account for subsequent treatment with cellular immunotherapy off protocol in the SOC arm, prespecified sensitivity analyses of OS were conducted using the Rank-Preserving Structural Failure Time (RPSFT) and Inverse Probability of Censoring Weights (IPCW) models. Other endpoints included progression-free survival (PFS) per investigator assessment, OS in key subgroups, and safety. Results: In total, 359 patients were randomly assigned, 180 to axi-cel and 179 to SOC. As of 01/25/2023, at a median follow-up of 47.2 mo, axi-cel demonstrated a statistically significant improvement in OS over SOC (HR [95% CI], 0.726 [0.540-0.977]; stratified log-rank 1-sided P=0.0168 [efficacy boundary, 0.0249]). Median OS was longer with axi-cel vs SOC (not reached vs 31.1 mo, respectively); 48-mo OS estimates were higher with axi-cel (54.6% vs 46.0%, respectively). OS benefit with axi-cel vs SOC was consistent in prespecified key subgroups, including age ≥65 years, primary refractory, early relapse, high-grade B-cell lymphoma, and high second-line age-adjusted IPI. In the SOC arm, 102 (57%) patients received subsequent cellular immunotherapy off protocol. Prespecified OS sensitivity analyses, conducted to address the confounding effects of treatment-switching in the SOC arm, showed an even greater OS benefit with axi-cel vs SOC, with stratified HR (95% CI) of 0.608 (0.449-0.824) by RPSFT and 0.633 (0.409-0.981) by IPCW. PFS by investigator confirmed benefit of axi-cel over SOC (HR [95% CI], 0.506 [0.383-0.669]), with 48-mo PFS estimates of 41.8% vs 24.4%, respectively. No new cytokine release syndrome or neurologic events and no new treatment-related deaths occurred since the primary EFS analysis. The safety profile of axi-cel remained consistent with prior studies. Conclusions: Axi-cel as second-line therapy demonstrated a significant improvement in overall survival over historical standard of care in patients with early relapsed/refractory LBCL. Clinical trial information: NCT03391466 .

Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma

BackgroundIn an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes.MethodsIn this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization.ResultsA total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P=0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival.ConclusionsAt a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.)

ZUMA‐24: A PHASE 2, OPEN‐LABEL STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA GIVEN OUTPATIENT WITH CORTICOSTEROIDS

ZUMA‐24: A PHASE 2, OPEN‐LABEL STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA GIVEN OUTPATIENT WITH CORTICOSTEROIDS

PRIMARY OVERALL SURVIVAL ANALYSIS OF THE PHASE 3 RANDOMIZED ZUMA‐7 STUDY OF AXICABTAGENE CILOLEUCEL VERSUS STANDARD OF CARE IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA

PRIMARY OVERALL SURVIVAL ANALYSIS OF THE PHASE 3 RANDOMIZED ZUMA‐7 STUDY OF AXICABTAGENE CILOLEUCEL VERSUS STANDARD OF CARE IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA

Transfusion needs after CD19 CAR T‐cells for large B‐cell lymphoma: predictive factors and impact on outcome. A DESCAR‐T study.

Introduction: Patients undergoing CAR T-cell therapy may experience severe cytopenias due to lymphodepleting chemotherapy and/or CAR T-cells. Transfusion needs represent a surrogate marker of severe anemia and thrombocytopenia. Transfusion needs may impact patients’ quality of life and CAR T-cells efficacy through transfusion-related immunomodulation. Here, we aimed to describe transfusion needs of patients receiving commercial CD19 CAR T-cells for relapse or refractory large B-cell lymphoma (LBCL), identify predictive factors associated with transfusions and search for correlations with CAR T-cells efficacy. Methods: Clinical data were collected form the DESCAR-T registry, the French national real-life registry for all patients treated with commercial CAR T-cells. Transfusion data were collected from the French national blood bank. We included all LBCL patients with at least 6-months follow-up from CAR T-cell infusion. Patients were censored for transfusions at relapse, new treatment onset, or death. Results: From August 2018 to September 2022, 671 patients in the DESCAR-T registry met the eligibility criteria. Overall, 382 patients (56.9%) received at least one transfusion after CAR T-cell infusion: 53.5% at the early phase (i.e. within the first month), and 37.8% at the late phase (i.e. beyond one month). Only 6% of the patients required transfusions beyond 3 months. The mean number of red blood cells (RBC) units and platelets transfusion per patient after CAR T-cell therapy were 3.5 (range, 0–90) and 5.1 (range, 0–127), respectively. Factors associated with transfusion needs after CAR T-cells therapy are presented in Table 1. Age, international prognostic index, primary refractory status, prior ASCT, bulk disease, and severe cytokine release syndrome (CRS) were associated with early but not late RBC transfusions. Early and late platelets transfusion shared the same risk factors except for severe CRS. No association was found between transfusions and response rate after CAR T-cell therapy. However, early transfusions (RBC and platelets) were associated with a shorter progression-free survival (median PFS = 3.2 vs. 6.0 months, p = 0.0168) and overall survival (median OS = 9.3 vs. 23.6 months, p < .0001). Late platelets transfusions were associated with decreased PFS (median = 5.6 vs. 12.0 months, p = 0.0072) and OS (median = 13.8 vs. NR, p < .0001) whereas late RBC transfusions did not impact PFS nor OS. Conclusion: In our study, 56.9% of patients received transfusions after CAR T-cell therapy. We identified risk factors associated with early and late transfusion needs. Early transfusions (RBC and platelets) and late platelets transfusion were associated with worse survival. Our data shed light on the mechanisms of early and late anemia and thrombocytopenia, and on the potential impact of transfusions on CAR T-cells efficacy. Encore Abstract - previously submitted to EHA 2023 Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract. E. Bachy Honoraria: Kite, a Gilead Company, Bristol Myers Squibb, Novartis, Pfizer, Incyte, ADC Therapeutics Research funding: Amgen, BMS Other remuneration: Kite, a Gilead Company, Bristol Myers Squibb, Novartis, Pfizer G. Cartron Consultant or advisory role: Roche, Celgene-BMS, Onwards Therapeutics, MedxCell, EmerCell, MabQi Honoraria: Sanofi, Abbvie, Takeda, Roche, Janssen, Roche, Celgene, Novartis, Incyte Other remuneration: Consulting fees from from Roche and Celgene-BMS T. Gastinne Consultant or advisory role: Takeda, Gilead Sciences Honoraria: Pfizer, Takeda, Gilead Sciences Educational grants: Roche, Pfizer F. Morschhauser Consultant or advisory role: Novartis and Gilead K. Bouabdallah Consultant or advisory role: Kite/Gilead, Takeda Honoraria: Kite/Gilead, Takeda Educational grants: Kite/Gilead O. Casasnovas Consultant or advisory role: ROCHE, TAKEDA, GLIEAD/KITE, MSD, BMS Honoraria: ROCHE, TAKEDA, GILEAD/KITE, MSD, BMS, AMGEN, ABBVIE, JANSSEN Educational grants: ROCHE, TAKEDA, GILEAD/KITE, MSD, BMS, AMGEN, ABBVIE, JANSSEN Other remuneration: ROCHE, TAKEDA, GILEAD/KITE (research funding to the institution) S. Choquet Other remuneration: Novartis, Kite Gilead C. Castilla-Llorente Honoraria: Gilead/Kite S. Guidez Honoraria: Gilead, Novartis, Incyte, Roche M. Loschi Honoraria: Alexion, BMS Celgene, Gilead, Iqone, MSD, Novartis, Pfizer, Sanofi and Sobi L. Drieu La Rochelle Consultant or advisory role: Gilead/kite Educational grants: TAKEDA, Gilead/kite R. Houot Consultant or advisory role: Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte, Miltenyi Honoraria: Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda and Roche

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an approved treatment for patients with refractory or relapsed (R/R) LBCL that has changed the prognosis of patients with chemoresistant LBCL. However, data regarding efficacy and safety of CART cell treatment in patients with active CNS involvement are limited since they are excluded from most of clinical trials. Methods: We retrospectively collected data from 75 patients with LBCL, treated with CART cells from January 2020 to January 2023 in Henri Mondor Hospital. We identified 13 patients with active CNS involvement at the time of CAR-T cell treatment decision: 12/13 had abnormal neurological examination, 8/11 had head and/or medullar MRI abnormalities consistent with lymphoma and 9/10 had detectable lymphoma cells in the cerebrospinal fluid. We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). Median age was 69 and 59 years, respectively (p = 0.05). CNS+ patients received a median of 2 previous lines of treatment versus 3 for CNS- patients (p = 0.34). Performance status prior to CART-cell injection was 2 or more in 9/13 (69%) and 11/62 (18%) p < 0.001, respectively. 5/13 (38%) CNS+ patients had high grade B-cell lymphomas versus 11/62 (18%) CNS- (p = 0.13). CAR-T-cell was axi-cel in 10/13 (77%) CNS+ patients versus 42/62 (68%) CNS– (p = 0.74). It is noteworthy that 7/13 (54%) CNS+ patients had pre-existing low-grade B-cell lymphomas versus 15/62 (24%) CNS- (p = 0.046). Results: The best overall response rate was identical in both groups: 12/13 (92%) in CNS+ patients versus 51/61 (92%) in CNS-, including 11/13 (85%) and 44/61(72%) complete metabolic response. As shown in the figure, median progression free survival and overall survival was 5.5 and 8.4 months, respectively in CNS+ patients versus 11.5 and 21 months in CNS- patients (not significant). Regarding safety, 13/13 (100%) CNS+ patients had a cytokine release syndrome (10 grade 1–2 and 3 grade 3) versus 54/62 (87%) CNS- (49 grade 1–2 and 5 grade 3–4) and 10/13 (77%) experienced ICANS (6 grade 1–2 and 4 grade 3–4) versus 28/62 (45%) CNS- (27 grade 1–2 and 1 grade 3–4) (p = 0.06 and 0.02 for grade 3–4). Transfer into an intensive care unit occurred in 4/13 (31%) CNS+ patients versus 9/62 (15%) CNS- (p = 022). Median time of hospitalization was 37 days for CNS+ patients versus 20 days for CNS- patients (p = 0.007). Six CNS+ patients died from which 5 died of progression and 1 of infection. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. F. Lemonnier Consultant or advisory role: BMS, Kiowa, Miltenyi Educational grants: Gilead, Janssen, Roche L. Roulin Educational grants: Kite gilead, Novartis, Bristol myers squibb

ZUMA-23: A global, phase 3, randomized controlled study of axicabtagene ciloleucel versus standard of care as first-line therapy in patients with high-risk large B-cell lymphoma.

TPS7578 Background: The nearly 40% of patients (pts) with large B-cell lymphoma (LBCL) who are refractory to or relapse after current first-line (1L) standard-of-care (SOC) regimens, such as R-CHOP (rituximab [R] + cyclophosphamide [C], doxorubicin [H], vincristine [O], and prednisone [P]) and DA-EPOCH-R (dose-adjusted etoposide [DA-E]), have poor prognoses. High International Prognostic Index (IPI) score and the subtype of high-grade B-cell lymphoma (HGBL) are associated with shorter progression-free and overall survival (PFS and OS; Nastoupil LJ and Bartlett NL. J Clin Oncol. 2023). Strategies to improve outcomes in these subgroups have been largely unsuccessful; therefore, therapeutic options with a different mechanism of action are needed. Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved to treat pts with relapsed/refractory (R/R) LBCL after demonstrating significant clinical benefit as 2L (ZUMA-7; Locke FL, et al. N Engl J Med. 2022) and ≥3L (ZUMA-1; Neelapu SS, et al. N Engl J Med. 2017) therapy. Additionally, in the Phase 2 ZUMA-12 study in pts with refractory 1L LBCL, axi-cel showed a high rate of durable responses with an objective response rate of 89% (complete response rate, 78%) and an ongoing response rate of 73% (median follow-up, 15.9 mo; Neelapu SS, et al. Nat Med. 2022). ZUMA-23 is the first Phase 3, randomized controlled study to evaluate CAR T-cell therapy as a 1L regimen for any cancer and will assess axi-cel versus SOC in pts with high-risk LBCL, defined as IPI 4-5. Methods: The Phase 3 trial design will enroll ≈300 adult pts with high-risk, histologically confirmed LBCL based on the 2016 WHO classification, including diffuse large B-cell lymphoma (DLBCL), HGBL, and transformed follicular or marginal zone lymphoma (Swerdlow SH, et al. Blood. 2016). Eligible pts will receive 1 cycle of R-chemotherapy and then be randomized 1:1 to receive axi-cel or continue with SOC. Pts in the axi-cel arm will undergo leukapheresis and then receive R-CHOP or DA-EPOCH-R as bridging therapy, followed by lymphodepleting chemotherapy (fludarabine/cyclophosphamide), and a single axi-cel infusion (2×106 CAR T cells/kg). Prophylactic corticosteroids may be administered to reduce the incidence and severity of cytokine release syndrome at the investigator’s discretion. Pts in the SOC arm will receive 5 additional cycles of R-CHOP or DA-EPOCH-R (investigator’s choice). The primary endpoint is event-free survival by blinded central review. Key secondary endpoints are OS and PFS. Safety, quality of life, and pharmacokinetics will also be assessed. Pts with a history of HIV and/or hepatitis B or C and undetectable viral loads may enroll. Key exclusion criteria include LBCL of the central nervous system. ZUMA-23 is open for enrollment (NCT05605899). Clinical trial information: NCT05371093 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

EE51 A Cost-Consequence Analysis of Adopting Chimeric Antigen Receptor T-Cell Therapy for Patients with Relapsed or Refractory Large B-Cell Lymphoma in Saudi Arabia: a Multi-Center Comparison

There is currently only 1 referral center in Saudi Arabia for patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) prescribed chimeric antigen receptor T-cell (CAR T) therapy. In this study we assessed the potential economic consequences of broader adoption of CAR T treatment at tertiary hospitals versus referring patients for treatment either in-country or abroad.

EARLY CTDNA CLEARANCE AFTER CAR T‐CELL INFUSION PREDICTS OUTCOME IN PATIENTS WITH LARGE B‐CELL LYMPHOMA : RESULTS FROM ALYCANTE, A PHASE 2 LYSA STUDY

Introduction: CAR T-cells have significantly improved the outcome of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, more than half of the patients fail to obtain a prolonged remission, resulting in a poor prognosis. Early identification of these patients would allow early intervention to improve their outcome. Circulating tumor DNA (ctDNA) assessment is a promising tool to monitor early response in LBCL, but few data are available regarding ctDNA monitoring after treatment with CAR T-cells. The aim of our study was to monitor ctDNA before and after CAR T-cell infusion and correlate the results with clinical outcome in the ALYCANTE trial. Methods: Patients’ samples were prospectively collected in the ALYCANTE trial, an open-label, phase 2 study (NCT04531046), designed to evaluate the efficacy and safety of axi-cel in 62 patients with R/R LBCL not intended for autologous stem cell transplantation after 1 prior line of therapy. DNA was extracted from 2 to 4 mL of plasma. Libraries were generated from 129 kb captured-DNA custom panel (Agilent, XTHS2). Variant calling and phased variant annotation were performed using Unique Molecular Identifiers (UMI). Concentrations of ctDNA were expressed as hGE/mL and were measured at leukapheresis, after bridging/before lymphodepletion, at time of CAR T-cell infusion (D0) and at day 14 (D14), month 1 (M1), 3, 6, 9, and 12 after infusion. These results were correlated with clinical outcome. Results: With a median of 85 variants (range 1–707), a mutational profile could be identified from ctDNA in 88% (55/62) of patients at time of leukapheresis (n = 54) or after bridging (n = 1). The median ctDNA load was 77 hGE/mL (range 0–6803) at leukapheresis and 39 hGE/mL (range 2–17,354) after bridging therapy. Only 2/55 (4%) patients experienced ctDNA clearance after bridging. To date, we report the clinicobiological correlations for the first 40 patients included in the ALYCANTE trial. Early ctDNA evaluation was performed in 38/40 (95%) patients: at D14 and M1 (n = 34), at D14 only (n = 2), or at M1 only (n = 2). For patients with D14 and M1 evaluation, the results were concordant in 32/34 (94%) patients, either both positive (n = 19) or both negative (n = 13). A negative ctDNA at D14 (n = 14/36, 38.9%) or at M1 (n = 16/36, 44.4%) was associated with a complete metabolic response at 3 months in 93% (p = 0.03) and 94% (p = 0.009) of cases, respectively. After a median follow-up of 10 months, the median progression-free survival was not reached in patients with negative ctDNA at D14 and M1 versus 7.6 months and 5.8 months for patients with positive ctDNA at D14 and M1, respectively (Figure 1). Encore Abstract—previously submitted to EHA 2023 The research was funded by: Kite-Gilead, as a prespecified exploratory analysis Keywords: cellular therapies, liquid biopsy, minimal residual disease Conflicts of interests pertinent to the abstract M. Delfau-Larue Other remuneration: Education, symposia: TAKEDA, AMGEN, ROCHE, GILEAD, ABBVIE G. Cartron Consultant or advisory role: Advisory Board: Ownards Therapeutics, MAbQi. Consultancy: Roche, BMS, Abbvie. Honoraria: Jansen, Gilead, Takeda, Novartis, Milteny. F. Morschhauser Consultant or advisory role: Roche, Gilead, Genmab, Novartis, Abbvie Honoraria: Chugai (scientific lectures) L. Oberic Consultant or advisory role: Roche, Kite Gilead, Incyte Honoraria: Speaking: Roche, Kite Gilead, AstraZeneca, Jansen, BMS E. Bachy Consultant or advisory role: Kite, a Gilead Company, Bristol Myers Squibb, Novartis, Pfizer; Honoraria: Kite, a Gilead Company, Bristol Myers Squibb, Novartis, Pfizer, Incyte, ADC Therapeutics Research funding: Amgen, BMS R. Dulery Honoraria: Takeda, Novartis, and Biotest C. Laurent Educational grants: Janssen R. Houot Consultant or advisory role: Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte and Miltenyi. Honoraria: Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda and Roche

Cost-Effectiveness Analysis of Relmacabtagene Autoleucel for Relapsed or Refractory Large B-Cell Lymphoma in China

ObjectivesRelmacabtagene autoleucel (relma-cel) was recently approved in China for treating relapsed or refractory large B-cell lymphoma (r/r LBCL). We conducted a cost-effectiveness analysis from the perspective of Chinese healthcare system. MethodsA mixture-cure model was developed to project life-years (LYs), quality-adjusted LYs (QALYs), and overall direct cost with a lifetime horizon for patients with r/r LBCL treated with relma-cel versus salvage chemotherapy. Patient-level data from RELIANCE trial and published data from Collaborative Trial in Relapsed Aggressive Lymphoma extension study were used to inform the model. The incremental cost-effectiveness ratio (ICER) was estimated and cost-effectiveness was evaluated at the willingness-to-pay threshold of 3 times the national gross domestic product per capita. ResultsThe model projected that treatment with relma-cel was associated with incremental gains of 5.11 LYs and 5.26 QALYs compared with salvage chemotherapy at an increased cost of ¥1 067 430 (∼$154 152), resulting in an ICER of ¥203 137 (∼$29 435) per QALY. The model was most sensitive to the uncertainty around the estimated cure rate. The ICER of relma-cel was within the willingness-to-pay threshold in the base case and the probability of relma-cel treatment being considered cost-effective was approximately 74%. ConclusionsCompared with salvage chemotherapy, treatment with relma-cel for r/r LBCL in patients who have failed at least 2 lines of systemic therapy is within the cost-effective range from the perspective of Chinese healthcare system and represents a good use of healthcare resources.

Cost-Effectiveness of Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel and Tisagenlecleucel in the Third-Line or Later Treatment Setting for Relapsed or Refractory Large B-cell Lymphoma in the United States.

The objective of this study was to evaluate the cost-effectiveness of lisocabtagene maraleucel (liso-cel) versus other available chimeric antigen receptor T-cell therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), in patients who had received at least two prior therapies from a United States (US) commercial third-party payer perspective. To capture this heterogeneity in survival outcomes, we used mixture cure models to extrapolate progression-free survival (PFS) and overall survival (OS). Patient-level data from TRANSCEND NHL 001 for liso-cel and reconstructed patient-level data from ZUMA-1 for axi-cel, JULIET for tisa-cel, and SCHOLAR-1 for salvage chemotherapy, derived using the Guyot method, were used for OS and PFS. The model included adverse events associated with liso-cel, axi-cel, and tisa-cel. Liso-cel was less costly (incremental cost of - $74,980) and marginally more effective (0.002 incremental quality-adjusted life-years [QALY]) than axi-cel and had an incremental cost of $67,925 and 2.02 incremental QALYs over tisa-cel in the base case. Results remained consistent in sensitivity analyses, with the liso-cel OS cure fraction being the main driver of cost-effectiveness compared with both axi-cel and tisa-cel. This analysis estimated that liso-cel is cost-effective compared with tisa-cel and axi-cel from a commercial US payer perspective.

Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma

AbstractIn phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.

507 - Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/ Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-up of Zuma-1 Cohort 6

507 - Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/ Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-up of Zuma-1 Cohort 6