Treatment Of Large B-cell Lymphoma Research Articles

Efficacy of CAR T-cell therapy is not impaired by previous bispecific antibody treatment in large B-cell lymphoma

AbstractIn this retrospective study, chimeric antigen receptor T cells remained effective in patients with relapsed/refractory large B-cell lymphoma after prior exposure to bispecific antibodies (BsAbs) targeting different antigens. These results are relevant to clinical practice, particularly given the increasing use of BsAbs in earlier treatment lines.

Medicare Utilization and Cost Trends for CAR-T Cell Therapies in the Treatment of Large B-Cell Lymphoma

Medicare Utilization and Cost Trends for CAR-T Cell Therapies in the Treatment of Large B-Cell Lymphoma

Chimeric Antigen Receptor T-Cell Therapy in Acute Myeloid Leukemia: State of the Art and Recent Advances.

Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias-in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives.

Higher CD4+ T Cell Counts after CAR-T in Large B-Cell Lymphomas Are Significantly Associated with Better Overall Survival

Introduction Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of large B-cell lymphomas (LBCL), demonstrating remarkable efficacy. However, CAR-T therapy is also associated with significant toxicities, some arising from relative immunologic incompetence after treatment. A key knowledge gap persists regarding how the immune landscape changes post-CAR-T, defined as immune reconstitution (IR), and the influence of IR on patient outcomes. In this study, we set out to describe patterns and determinants of IR following CAR-T as well as impacts of IR on outcomes. Methods Adult patients with primary or transformed LBCL treated with CD19-CAR-T cells, namely axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), between 2017 and 2022 were included in this single center retrospective study. Immune cell levels were measured at various timepoints after CAR-T. Median cell counts and interquartile range (IQR) at pre-specified time windows (using the first available observation) were used to describe temporal IR patterns. Multivariable generalized estimating equation (GEE) models with cubic time variables were used to investigate the association between cell count trajectory and baseline characteristics. A multivariable Cox model with longitudinal cell count as a time-varying covariate was utilized to assess the association between IR and overall survival (OS), adjusted for confounding factors. Kaplan-Meier (KM) curves were generated for visualization. Results A total of 210 patients were included, of whom 153 had at least one CD4+ T cell measurement from time of CAR-T. The median age was 65 (range 20-86) and most were male (65.7%) and diagnosed with diffuse large B-cell lymphoma (79.5%). Axi-cel (49.5%) was the most common product, followed by tisa-cel (28.6%) and liso-cel (21.9%). Lymphodepletion was mostly cyclophosphamide and fludarabine (82.4%). Of the 210 patients, 58.1% achieved a complete response (CR) and 17.1% a partial response by 100 days after CAR-T. Following CAR-T, CD3+ T cells were the most abundant circulating lymphocyte. By 30 days (±15 days) after CAR-T, median (IQR) values of CD3+ T cells, B cells, and NK cells were 445 (162-776), 0 (0-0), and 90 cells/ul (57-146), respectively; by 60 days (±15 days), median (IQR) values were 498 (220-706), 0 (0-0), and 104 cells/ul (69-169), respectively. Proportions of CD4+ and CD8+ T cells remained similar through one year after CAR-T, with CCR7-45RA+ TEMRA and CCR7-45RA- effector memory cells dominating among CD8's, and CCR7-45RA- effector memory cells being the most abundant among CD4's. Regulatory T cells (CD25+CD127-) comprised about 10% of the CD4+ T cell lymphocyte population, with a median (IQR) of 9 cells/ul (4.5-15.5) by day 30 (±15 days) after CAR-T. Finally, receipt of tisa-cel was associated with greater levels of CD4+ EM T cells compared with axi-cel and liso-cel (median [IQR]: 253 [158-406] vs 81 [51-138] and 113 cells/ul [88-154], respectively), by 30 days (±15 days) after CAR-T. According to a multivariable GEE model, patients receiving tisa-cel had significantly higher CD4+ count trajectories compared to those receiving axi-cel or liso-cel ( p<0.001 for both) ( Figure A). In addition, patients with more extensive pre-treatment (i.e., 6+ prior lines) had significantly lower CD4+ count trajectories compared to those who received 2-3 or 4-5 prior lines ( p=0.015 and p=0.004, respectively). A multivariable Cox model, moreover, indicated that a higher CD4+ count (in units of 50 cells/ul) was significantly associated with better OS (adjusted HR: 0.845; 95% CI, 0.745-0.960; p=0.010), adjusted for product and prior lines of therapy. KM curves by patients above or below the median of the last observed CD4+ count further demonstrated this significant association between longitudinal IR and OS ( Figure B). Conclusion In this single-center retrospective study, we extensively characterized the immune environment at time of and following CAR-T. To the best of our knowledge, this is the largest study of its kind. Additionally, we identified several factors that impact IR, which in turn shapes OS. In doing so, we show that CD4+ T lymphocytes are key players in disease response post-CAR-T and suggest that tracking CD4+ recovery following CAR-T may provide both diagnostic and therapeutic benefit.

Effective sequencing of chimeric antigen receptor T-cell therapy in the treatment of LBCL in 2023

Over the last decade, CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has profoundly changed the management of relapsed/refractory large-B-cell lymphoma (LBCL). At present, there are three FDA-approved anti-CD19 CAR T-cell products for LBCL: axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). Two of these (axi-cel & liso-cel) are approved for use in the second-line setting under certain conditions. As CAR T-cell therapy continues to define a new role in the treatment armamentarium for LBCL, questions remain regarding which product to use and how to sequence CAR T-cell therapy with other therapeutic options. Here we will briefly review the key features of each FDA-approved anti-CD19 CAR T-cell product and the data that led to regulatory approval for each. Next, we will focus on the recent landmark studies that have established the use of CAR T-cell therapy as second-line treatment. While no direct prospective head-to-head comparisons exist of the 3 constructs, we will review some retrospective studies that suggest some emerging differences between the products. Lastly, we will turn our attention to the horizon as we explore some of the ongoing questions of how to best leverage the curative potential of CAR T-cell therapy for the most effective management of LBCL. These areas include the consideration of CAR T-cell therapy in the frontline setting, the optimal timing for CAR T-cell referral, the optimal bridging approach, and how to continue advancing novel CAR T-cell approaches in the context of the current treatment landscape.

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 Therapy and Imaging Applications for Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of large B-cell lymphoma (LBCL) and other hematologic malignancies. Its mechanism of action relies on recent biotechnological advances that allow clinicians to harness and enhance a patient's immune system to fight cancerous cells. The indications for CAR T-cell therapy continue to expand, with ongoing trials evaluating their use in other hematologic and solid organ malignancies. This review explores the vital role of diagnostic imaging in patient selection and treatment response in CAR T-cell therapy for LBCL and the management of specific therapy-related adverse events. For a patient-centered and cost-effective use of CAR T-cell therapy, it is crucial to select patients who are likely to derive long-term benefit and optimize their care during a lengthy treatment pathway. Metabolic tumor volume and kinetics assessed at PET/CT have emerged as powerful tools to predict outcome after CAR T-cell therapy in LBCL, allowing for the early identification of lesions refractory to treatment and identification of the severity of CAR T-cell therapy toxicity. Radiologists should be aware that the success of CAR T-cell therapy is mitigated by adverse events, most importantly neurotoxicity, which remains poorly understood and challenging to treat. Neuroimaging, with experienced clinical evaluation, is critical in the diagnosis and management of neurotoxicity and the exclusion of other central nervous system complications that can occur in this clinically vulnerable patient group. This review discusses current applications of imaging in the standard CAR T-cell therapy pathway for the treatment of LBCL, which serves as a model disease in the integration of diagnostic imaging and radiomic risk markers.

Prognostic value of the International Metabolic Prognostic Index for lymphoma patients receiving chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma. The recently introduced International Metabolic Prognostic Index (IMPI) was shown to improve prognostication in the first-line treatment of large B-cell lymphoma. Here, we investigate the prognostic value of the IMPI for progression-free (PFS) and overall survival (OS) in the setting of CD19 CART. Consecutively treated patients with baseline 18F-FDG PET/CT imaging and follow-up imaging at 30days after CART were included. IMPI is composed of age, stage, and metabolic tumor volume (MTV) at baseline and was compared with the International Prognostic Index (IPI). Both indices were grouped into quartiles, as previously described for IPI. In addition, the continuous IMPI was subdivided into tertiaries for better separation of risk groups. Overall response rate (ORR), depth of response (DoR), and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of IMPI and IPI with PFS and OS. Thirty-nine patients were included. The IPI was 1 in 23%, 2 in 21%, 3 in 26%, 4 in 21%, and 5 in 10% of the patients. IMPIlow risk, IMPIintermediate risk, and IMPIhigh risk patients had 30-day ORR of 69%, 62%, and 62% and 30-day DoR of - 67%, - 66%, and - 54% with a PFS of 187days, 97days, and 87days, respectively. ORR and DoR showed no correlation with lower IMPI (r = 0.065, p = 0.697). Dividing patients into three risk groups showed a significant trend for PFS stratification (p = 0.030), while IPI did not (p = 0.133). Neither IPI nor IMPI yielded a significant association with OS after CART (both p > 0.05). In the context of CART, the IMPI yielded prognostic value regarding PFS estimation. In contrast with IMPI in the first-line DLBCL setting, we did not observe a significant association of IMPI at baseline with OS after CART.

CO76 Value of Axicabtagene Ciloleucel Versus Chemotherapy in the Large B-Cell Lymphoma Treatment: Health Outcomes Based on the Number of Patients Treated in Spain

CO76 Value of Axicabtagene Ciloleucel Versus Chemotherapy in the Large B-Cell Lymphoma Treatment: Health Outcomes Based on the Number of Patients Treated in Spain

Overcoming CD19-Negative Relapses in Patients with B-Cell Lymphomas Treated with Tisagenlecleucel

Anti-CD19 chimeric antigen receptor T cell (CART) immunotherapy has revolutionized the treatment of large B-cell lymphomas (LBCL). However, up to 70% of LBCL patients (pts) ultimately fail CART treatment. Several mechanisms of relapse have been described, such as T cell exhaustion, an immunosuppressive tumor microenvironment, and antigen-negative escape. While antigen-negative relapse after anti-CD19 CART (CART19) is well studied in acute B lymphoblastic leukemia, less data are available for LBCL, especially in pts treated with the 4-1BB costimulated CART19, tisagenlecleucel (tisa-cel, formerly CTL019). In this study, we evaluated the frequency of CD19 loss in LBCL pts treated with tisa-cel and identified CD79 as an antigen highly expressed by immunohistochemistry (IHC) in CD19-negative biopsies. We then generated and optimized an anti-CD79 CART (CART79) and subsequently cloned a dual anti-CD79b/anti-CD19 CART that showed high potency against CD19-neg models. We first studied an exploratory cohort of 38 pts treated at the University of Pennsylvania on the first single-center clinical trial of CTL019 for B-cell lymphomas (NCT02030834 and Chong, NEJM, 2021). Among relapsed or refractory pts (n=23, 60.5%), 17 pts had a biopsy at disease progression (PD). We analyzed CD19 and CD79a expression in these biopsies by IHC. Four biopsies (23.5%) showed no CD19 expression by neoplastic cells. Also, 12 pts had available matched biopsies pre-CTL019 infusion (performed within 1 year before infusion) and at PD. We observed that 3/12 (25%) pts converted from a CD19-positive to a CD19-negative tumor after CTL019. Notably, 100% of biopsies at PD showed high CD79a expression. We then studied a confirmatory cohort including 110 LCBL pts treated with commercial tisa-cel. In this retrospective cohort, 63 pts had PD, and 31 had an available biopsy at PD. In line with previous observations, 10/26 (38%) showed loss of CD19 at PD, and, of note, 5/23 (22%) loss of CD20, a B-cell marker targeted by previous therapies. Again, 100% of pts maintained CD79a expression. (Figure A). These data confirm that loss of detection of CD19 at the level of sensitivity of IHC is frequently observed at PD and may be a cause of resistance in LBCL pts treated with tisa-cel. In addition, persistence of CD79 expression suggests that it may be an optimal therapeutic target for potentially preventing CD19-negative PD. Therefore, we aimed to generate and optimize a CART79 product. We cloned and screened a large panel of anti-CD79 CAR constructs (n=32) generated using 6 different scFvs (targeting either CD79a or CD79b), two scFv chain orientations (H to L vs. L to H), three hinges (derived from CD8a, IgG4, or truncated IgG4). We used the CD8 transmembrane and 4-1BB co-stimulatory domains of tisa-cel, given its established clinical safety and efficacy profile. The constructs were initially screened in-vitro against LBCL cells (OCI-Ly18), evaluating cytotoxicity, proliferation, and cytokine production. The six top candidates were then tested in-vivo using human xenograft models (NSG mice subcutaneously engrafted with OCI-Ly18 cells). When the tumor was palpable, mice were randomized to receive one dose (2.5x106/mouse) of CART79 candidates, CART19, or untransduced T cells (UTD) intravenously. An anti-CD79b CAR construct (CART79#3: H-L orientation, truncated IgG4 hinge), demonstrated the strongest anti-tumor effect. This construct was incorporated into a bicistronic vector also containing anti-CD19 CAR (FMC63-based). We tested the activity of this novel anti-CD19/CD79b dual CART in-vitro, using CRISPR/Cas9 gene editing to knock out (KO) either CD19 or CD79b in HBL-1 LBCL cells. CD19 KO and CD79b KO HBL-1 cells were mixed 1:1 to simulate the heterogeneity of lymphomas and tumor targeting was tested for CART19, CART79b, dual CART79b/19, and UTD. In both in-vitro and in-vivo models, dual CART19/79b demonstrated a strong anti-tumor effect, possibly preventing or treating CD19-negative escape (Figure B). In conclusion, our study demonstrates that CD19 loss by IHC is a marker of treatment failure in tisa cel-treated LBCL pts. We also demonstrate that CD79, as opposed to CD20, is expressed in virtually all cases of PD and is an ideal target for next-generation CART immunotherapy. Finally, we developed a dual CART19/79b that shows high activity against CD19-negative disease progression. This construct will be taken to phase I clinical studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SY08-1 Recent advances in chimeric antigen receptor T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapies have brought paradigm shift in treatment of lymphoma. Following the pivotal studies in CD19-targeted CAR T-cell therapies, three products, axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) were approved by FDA for third-line treatment of large B-cell lymphoma (LBCL). The indication for axi-cel was recently expanded to follicular lymphoma (FL) after two or more lines of systemic therapy.

EE181 An Economic Model to Estimate Costs of Cytokine Release Syndrome (CRS) and Neurological Events (NE) Among Patients Treated with Lisocabtagene Maraleucel (LISO-CEL) or Axicabtagene Ciloleucel (AXI-CEL) for Second-LINE (2L) Treatment of Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T cell therapies have demonstrated good clinical responses in populations that have historically been difficult to treat; however, they are associated with potentially severe adverse events, including CRS and NEs. An economic model was created to estimate total weighted costs of CRS and NEs for 2L treatment of transplant-eligible relapsed/refractory large B-cell non-Hodgkin lymphoma treated with liso-cel and axi-cel based on rates reported in the TRANSFORM (NCT03575351) and ZUMA-7 (NCT03391466) studies.

P1462: POPULATION-BASED REAL WORLD RESULTS OF CD19-DIRECTED CAR T-CELL THERAPY FOR PATIENTS WITH RELAPSED OR REFRACTORY LARGE B-CELL LYMPHOMA: A DUTCH CAR T-CELL TUMORBOARD EXPERIENCE

Background: CD19-directed CAR T-cell therapy has become standard of care for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and durable responses are seen in up to 40% of treated patients. Optimal selection of patients who will benefit from CAR T-cell therapy is important. In the real world reasons for ineligibility of patients who meet the registration label are often not reported. Additionally, data on health-related quality of life (HR-QoL) after infusion are scarce. Real world (in)eligibility and HR-QoL can play an important role in guiding treatment choices with novel therapeutic options becoming available. In the Netherlands, population-based referral and eligibility assessment for CAR T-cell therapy are centralized in a national tumorboard. A multicenter expert team discusses cases and data are collected in a national registry from time of referral. The aims of the tumorboard and registry are to capture population-based data on patients potentially eligible for CAR T-cell therapy and to optimize (cost-) effective, high quality care. Aims: To evaluate real world results of axicabtagene ciloleucel (axi-cel) for R/R LBCL on a population level, including reasons for ineligibility, efficacy, toxicity and (in a subset of patients) HR-QoL. Methods: For this prospective multicenter cohort study, all adult patients referred to the tumorboard for treatment of R/R LBCL with axi-cel were included from May 1st 2020 – October 19th 2021. Descriptive statistics were used for baseline characteristics, Kaplan Meier methods for survival analysis, regression models for univariate/multivariate analysis and linear mixed models for HR-QoL over time. Results: In total, 186 patients were referred to the tumorboard, 57 were not approved for axi-cel during the online tumorboard meeting, mostly (n=23) due to rapid progression (RP). The 129 approved patients were screened at a CAR T center, 32 were rejected (n=21 RP). Ninety-seven patients underwent apheresis of whom 7 did not receive axi-cel, mostly due to RP (n=6). Ninety patients were infused with CAR T-cells. Data of 74 of these patients are currently available for toxicity/efficacy analysis and updated results, including HR-QoL, will be presented during the EHA meeting. Median age was 59-years (min-max 27-79), 81% received bridging therapy. Best overall response rate was 82.4 %, including 66.2% complete remissions (CR). Median time to response was 1 month and all patients achieved their best response within 3 months. Four patients with PR at 1 month achieved a CR at month 3. The PFS and OS curves are shown in Figure 1. All grades CRS occurred in 89%, including ≥grade 3 in 2.7%, median time to onset was 3 days (min-max 0-14) and median duration 6 days (min-max 1-17). All grades ICANS occurred in 58%, including ≥ grade 3 in 27%, with a median time to onset of 7 days (min-max 1-28) and a median duration of 7 days (min-max 1-28). Non-relapse mortality was 1.4% due to one grade 5 ICANS event. Image:Summary/Conclusion: The merit of a national tumorboard is to enable prospective, in-dept evaluation of rejected as well as CART-infused patients. Twenty-eight percent of the referred patients in the Dutch population that fulfilled the indication criteria for R/R LBCL treatment with axi-cel could not receive the therapy due to rapidly progressive disease. A relatively low percentage of patients, 7%, underwent leukapheresis but eventually did not receive axi-cel. Efficacy and toxicity in our cohort are comparable with ZUMA-1 study results and other large real world cohorts.

Real-world outcomes of axicabtagene ciloleucel (Axi-cel) for the treatment of large B-cell lymphoma (LBCL) by race and ethnicity.

7571 Background: In clinical trials of CAR T-cell therapies and real-world studies published to date, there is a paucity of data on outcomes by race and ethnicity. Here, we examined outcomes by race and ethnicity among LBCL pts who received axi-cel in the real-world setting. Methods: A total of 1389 pts with LBCL were identified from a non-interventional post-authorization safety study with pts receiving commercial axi-cel between 10/2017 and 08/2020. Race (African American or Asian vs White) and ethnicity (Hispanic vs non-Hispanic) were self-reported by pts. Pts with rescinded consent, enrolled in trials, having prior non-HCT cellular therapy, primary CNS lymphoma, unknown comorbidity or data in query were excluded. Median follow-up was 12.7 mo. Outcomes included ORR, CR rate, DOR, PFS and OS, grade ≥ 3 CRS (Lee 2014 criteria) and ICANS (ASTCT consensus grade). ORR and CR were evaluated in pts with ≥ 180 days of follow-up. Kaplan-Meier estimates were calculated for PFS and OS. Multivariable analyses comparing race and ethnicity were conducted via logistic and Cox regression. Results: Among all, 1127 (81%) were White, 70 (5%) African American and 81 (6%) Asian; 152 (11%) were Hispanic including 104 White, 2 Black, and 1 Asian Hispanic. African Americans, compared to White, were younger (median age 55.5 vs 62.8 years), more likely to have pulmonary impairment (41% vs 28%) and tended to have longer time from diagnosis (≥ 12 mo 71% vs 59%). Hispanic pts were younger (median age 58.5 vs 62.6 years) than non-Hispanic pts. ORR was 74% (CR 57%, 12-mo PFS and OS 48% and 63%) for White, 57% (CR 45%, 12-mo PFS and OS 36% and 62%) for African American, 67% (CR 53%, 12-mo PFS and OS 55% and 65%) for Asian and 73% (CR 55%, 12-mo PFS and OS 50% and 65%) for Hispanic pts. Grade ≥ 3 CRS and ICANS occurred in 7% and 18% of African American, 10% and 19% of Asian, and 8% and 27% of White pts, respectively. Hispanic pts had lower rates of grade ≥ 3 CRS and ICANS (4% and 15%) vs non-Hispanic (9% and 27%). African American race was associated with inferior ORR (OR 0.40; 95% CI, 0.24-0.69) and CR rate (OR 0.55; 95% CI 0.32-0.93) vs White. Asian pts had favorable DOR compared to both White (HR 0.46; 95% CI 0.24-0.87) and African American (HR 0.39; 95% CI 0.17-0.88). No statistical differences were found in OS and PFS across races, nor in any efficacy outcome between Hispanic and non-Hispanic pts. Asian (OR 0.52; 95% CI 0.29-0.96 vs White) and Hispanic pts (OR 0.51; 95% CI 0.31-0.85 vs non-Hispanic) had lower risk of grade ≥ 3 ICANS. Conclusions: Overall, axi-cel showed favorable OS, PFS and safety profile regardless of race and ethnicity in the real-world setting. No notable differences in outcomes were observed for Hispanic or Asian pts. Lower response rates in African American pts noted here warrant further investigation including any underrepresentation not explained by a lower incidence rate for DLBCL (SEER), access to care, and disease burden.

Patient preferences for second-line treatment options in diffuse large B-cell lymphoma: A discrete choice experiment.

e19558 Background: Standard of care (SOC) treatment in second-line (2L) large B-cell lymphoma (LBCL), including diffuse LBCL (DLBCL), involves salvage chemotherapy followed by autologous hematopoietic cell transplant (AHCT) for those with chemo-sensitive disease. However, many patients do not respond adequately to chemotherapy or are otherwise ineligible for AHCT. Chimeric antigen receptor T-cell (CAR T) therapy is a promising 2L therapy for LBCL that differs from SOC agents in terms of mechanism of action, therapeutic benefit, and safety profile. Given these differences, this discrete choice experiment (DCE) quantified 2L treatment preferences among patients with DLBCL. Methods: We conducted an online DCE with patients with DLBCL residing in the United States (US) and Europe (United Kingdom, France, Italy, Germany, and Spain). Attributes of 2L treatments were parameterized based on clinical trial data and included the probability (percent of patients) of surviving one year after treatment, the change in survival rate from one to three years, the risks of severe cytokine release syndrome (CRS) and neurological events, the risk of severe infection, and expected time until the patient’s functioning would return to pre-treatment levels. A willingness-to-accept measure was used to assess how much of an increase in one-year survival was needed for a patient to accept elevated risks of severe CRS and neurological events, which can be associated with CAR T treatment. Results: A total of 224 patients were included in the analysis (US: 105; Europe: 119). The mean age of respondents was 50 years (range 34 - 76); 74% were male, and 94% were actively receiving cancer treatment. Patients considered the probability of surviving one year after treatment to be the most influential treatment attribute, followed by risk of severe CRS/neurological events. The third most influential attribute was the change in probability of survival for three years post-treatment for US patients and time needed to return to pre-treatment functioning for European patients. The willingness-to-accept calculation found that patients required a 13-14 percentage point increase in the probability of surviving one year to accept a 28% risk of a serious neurological event and a 13% risk of serious CRS. Conclusions: Patients with DLBCL showed their willingness to accept increased risks of CRS and neurological events to achieve a greater probability of survival. This preference tradeoff (efficacy over risk of adverse events) has been shown previously for lymphoma patients. Patients also valued a quicker return to baseline functioning, which is notable given recent data on the quicker recovery of quality of life with CAR T compared with SOC. These patient preferences provide important context for 2L LBCL treatment decisions, and may lead to shared decision-making that reflects both clinical and patient priorities.

Updates in the Diffuse Large B-Cell Lymphoma Treatment Landscape.

During JADPRO Live Virtual 2021, presenters discussed updates in the treatment of diffuse large B-cell lymphoma (DLBCL), including novel agents and chimeric antigen receptor (CAR) T-cell therapy, and how the treatment and management of patients with DLBCL has been affected by the COVID-19 pandemic.

Real-World Outcomes of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Large B-Cell Lymphoma (LBCL): Impact of Age and Specific Organ Dysfunction

Real-World Outcomes of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Large B-Cell Lymphoma (LBCL): Impact of Age and Specific Organ Dysfunction

The impact of bridging therapy prior to CD19‐directed chimeric antigen receptor T‐cell therapy in patients with large B‐cell lymphoma

In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n=75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P=0·18 and P=0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P=0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P=0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.

Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial.

Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes. Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity. A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion (P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached (P < .0001) and 19 months versus not reached (P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed (P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion. Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

Real-world evidence of axicabtagene ciloleucel (Axi-cel) for the treatment of large B-cell lymphoma (LBCL) in the United States (US).

7552 Background: Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. Post-market long term follow up study of commercial Axi-cel recipients using the Center for International Blood and Marrow Transplant Research was recently completed. Methods: From October 2017 to August 2020, 1,500 Axi-cel recipients from 79 centers were enrolled. Of these, 1001 patients with at least 6 months of follow-up were included in this analysis. Outcomes include complete and overall responses rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS), cytokine release syndrome (CRS) (Lee D 2014 and American Society for Transplantation and Cellular Therapy [ASTCT]), immune effector cell associated neurotoxicity syndrome (ICANS), hematologic recovery and subsequent neoplasm (SN). Subgroup analysis by sensitivity to therapy, defined as responsive to the last line of therapy prior to Axi-cel. Median follow-up was 12 months (range, 6-28 months). Results: The median age overall was 62 years, 37% were ≥ 65 years, 83% with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, 28% with transformed lymphoma, 14% with high grade lymphoma, 29% with prior autologous transplant, and 66% with chemotherapy-resistant disease prior to Axi-cel. The median time from diagnosis to Axi-cel infusion was 15 months. Best ORR was 70% (CR 53%). Landmark analysis of patients in CR at 6 months post Axi-cel demonstrates a low number of subsequent progression/death events. With respect to outcomes for chemotherapy-sensitive disease versus resistant disease, the ORR, CR, 12-month PFS and OS were 78% vs. 66%, 60% vs. 48%, 55% (95% CI, 48-62%) vs. 40% (95% CI, 37-44%), and 70% (95% CI, 63-76%) vs. 54% (95% CI, 50-58%), respectively. CRS of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS was 10% according to Lee et al 2014, and 13% according to ASTCT Consensus Grading. Median time to any grade CRS was 4 days (range, 1-28 days), and 93% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). ICANS were reported in 576 (57%) patients, grade &gt;3 was 26%. The median time to onset of ICANS was 7 days (range, 1-82 days), and 86% resolved with a median duration of 9 days (range, 1 to 115 days). Twenty-nine patients (2.9%) reported SN: hematologic (N = 17), solid tumors (N = 12). Conclusions: This is the largest report on Axi-cel in the real-world setting and demonstrates consistent efficacy outcomes and further characterizes safety outcomes. Patients in CR at 6 months have sustained disease control with low number of relapse events. Although patients with therapy-sensitive disease experience better outcomes than patients with therapy-resistant, the overall outcomes on both groups of patients are favorable.