Lin, Yi

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of non-Hodgkin lymphoma (NHL). Despite having an increased risk of NHL, patients with pre-existing autoimmune disease (AID) were excluded from pivotal CAR-T trials due to concerns that CAR-T may exacerbate AID. As a result, there are limited data on the safety and efficacy of CAR-T for NHL in patients with AID. Interestingly, there is also growing evidence that CAR-T can be therapeutically effective for AID, such as in the treatment of systemic lupus erythematosus (SLE). As CAR-T utilization for NHL increases, it is essential to characterize the safety and efficacy of this potentially curative therapy in patients with AID. This study aimed to evaluate the impact of AID on outcomes in patients treated with commercial CD19-targeted CAR-T for NHL. Methods: Following Institutional Review Board approval, we conducted a retrospective analysis of all patients who were treated with commercial CD19-targeted CAR-T for NHL and had a pre-existing AID across the Mayo Clinic Enterprise (Arizona, Florida, and Minnesota) between January 2018 and May 2023. Variables collected included age, gender, NHL type, AID type, and CAR-T product. Efficacy outcomes, including response rates at 6 and 12 months after CAR-T, were collected. Toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were collected and analyzed. Our chart review for AID included SLE, sarcoidosis, ulcerative colitis, celiac disease, pernicious anemia, Crohn's disease, psoriasis, Sjogren's syndrome, hypothyroidism (Hashimoto's disease), hyperthyroidism (Graves' disease), rheumatoid arthritis (RA), vasculitis, scleroderma, and mixed connective tissue disease (MCTD). Results: A total of 235 patients who received commercial CD19-targeted CAR-T for NHL across the Mayo Clinic Enterprise were identified (Table 1). Of these 235 patients, 27 had a pre-existing AID and 208 did not. The median age was 66 years (range 39-81) for patients with AID and 59 years (range 18-88) for patients without AID. Over half of the patients were male (59% of patients with AID and 51% of patients without AID). The most common NHL type was diffuse large B cell lymphoma (41% of patients with AID and 56% of patients without AID). Most patients received axicabtagene ciloleucel (85% of patients with AID and 84% of patients without AID). The most common AID was hypothyroidism (81%, n=22), although other conditions were also identified, including RA (11%, n=3), SLE (4%, n=1), pulmonary sarcoidosis (4%, n=1), psoriasis (4%, n=1), and MCTD (4%, n=1). Two patients had more than one AID. Median follow-up was 18 months (range 1-36) for patients with AID and 14 months (range 2-49) for patients without AID. Six months after CAR-T, the complete response (CR) rate was 77.2% and 45.1% in patients with AID and without AID, respectively (p=0.0042). Twelve months after CAR-T, the CR rate was 50% and 31.4% in patients with AID and without AID, respectively (p=0.0801). CRS of any grade occurred in 78% and 88% of patients with and without AID, respectively. ICANS of any grade occurred in 41% and 54% of patients with and without AID, respectively. Conclusion: AID did not appear to adversely impact the safety or efficacy of CAR-T for NHL. Limitations of our study include the small number of patients with AID and the fact that the most common AID was hypothyroidism. Larger studies are warranted to confirm these findings. Additional data are needed to characterize the impact of CAR-T for NHL on AID outcomes and to describe the effect of disease-modifying antirheumatic drugs on NHL outcomes after CAR-T.

Introduction While chimeric antigen receptor (CAR)-T cell therapy has transformed the management of hematologic malignancies, it requires frequent monitoring for acute toxicities, almost universally achieved through mandatory hospitalizations, therefore utilizing a significant amount of healthcare resources. At Mayo Clinic in Rochester, MN, our standard practice is administering CAR-T cell therapy in the outpatient setting through a multi-disciplinary hospital-based outpatient (HBO) unit and remote patient monitoring (RPM) program. Our CAR-T RPM program consists of in-home, electronic health record-integrated technology to monitor vital signs and neurologic symptoms for 30 days post CAR-T infusion. Here we report the healthcare utilization outcomes of CAR-T patients managed in the outpatient setting enrolled in the RPM program. Methods Patients undergoing FDA-approved CAR-T cell treatment in the outpatient setting and participating in the CAR-T RPM program at Mayo Clinic Rochester were included in this IRB-approved study. Patient characteristics, healthcare utilization metrics, inpatient interventions, and patient satisfaction data regarding the RPM program were reviewed. Length of stay (LOS) includes any hospitalizations for which the admission date falls within the RPM monitoring period (CAR-T cell infusion to day +30), even if the hospitalization continued past day +30. Results A total of 123 patients participated in the CAR-T RPM program and underwent treatment in the outpatient setting. Median age at CAR-T infusion was 63 years (range 22 - 83), and most patients were male (n=78, 63%). Non-Hodgkin lymphoma was the most common diagnosis (n=74, 60%), followed by multiple myeloma (n=47, 38%), ALL (n=1, 1%) and other (n=1, 1%). During the PRM monitoring period, 19 (16%) patients were managed entirely in the outpatient setting. The remaining 104 (84%) patients required at least one hospitalization, with most patients (n=70, 57%) hospitalized only once [26 (21%) patients were hospitalized twice, and 7 (6%) patients were hospitalized 3 times, and 1 (1%) patient hospitalized 4 times during the monitoring period]. When considering the first hospitalization post CAR-T infusion, the median LOS was 6 days (range 2 - 47). When considering all hospitalizations post CAR-T, the median LOS was 8 days (range 2 - 47). Only 7 (6%) patients required an ICU stay, with a mean ICU stay of 0.2 days (standard deviation 0.9). Cytokine release syndrome (CRS) was noted in 92 (75%) of patients at a median of 3 days (range 0 - 18) post CAR-T infusion. All patients with CRS received tocilizumab, at a median of 4 days post CAR-T infusion. Steroids for CRS were administered in 63 (68%) of these patients. Neurotoxicity was reported in 45 (37%) patients at a median of 7 days (range 1 - 19) post CAR-T infusion. During the RPM monitoring period, patients were seen in our HBO unit with a median of 18 outpatient visits (range 4 - 30). Patient survey data, obtained at the end of the RPM monitoring period, were available from 37 patients. The majority of patients felt that the RPM program helped them feel comfortable managing their health at home, were able to reach a team member, and receive an appropriate response promptly. The majority of patients felt comfortable using the RPM equipment and interacting with providers virtually. Overall, 83% of patients were satisfied with the RPM program and 6% were neither satisfied nor dissatisfied. When asked about the reason for disappointment, technical difficulties/issues with the devices were the themes mentioned by the few patients (11%) who were unsatisfied with the RPM program. Conclusion: Despite the complexities and frequent monitoring associated with CAR-T cell therapy, outpatient CAR-T cell treatment is a feasible model of care. As the standard practice at our institution, the CAR-T RPM program was part of the management of nearly all patients undergoing an FDA-approved CAR-T product in the outpatient setting. RPM in the acute setting post CAR-T infusion is a well-received practice initiative by the majority of patients, including a high level of comfort utilizing the RPM equipment and virtual interaction with the RPM providers.

Introduction: Lymphodepletion (LD) chemotherapy is critical for the efficacy of CAR-T therapy by eradicating immunosuppressive cells, inducing costimulatory molecules, and promoting expansion and persistence of CAR-T cells. It also can contribute to an increased risk of infections, cytopenia, and other toxicities. We evaluated the utilization of varying LD regimens used in standard-of-care (SOC) autologous B-cell maturation antigen-directed (BCMA) CAR-T therapy with ide-cel or cilta-cel for relapsed/refractory multiple myeloma (RRMM) and the effect on outcomes and toxicity. Methods: Data were retrospectively collected from patients with RRMM who underwent LD and CAR-T cell infusion by December 31, 2022, from 13 US academic institutions with SOC ide-cel or cilta-cel. Response rates and other categorical variables, specifically LD regimen, were tested for association using Wilcoxon rank-sum (or Kruskal-Wallis for three or more groups) or Fisher's exact tests, respectively. Results: A total of 523 patients were infused at the time of data cut-off with 489 patients evaluable for safety and survival analyses; 368 (75%) were infused with ide-cel and 121 (25%) with cilta-cel. The median age was 65 years old (range 30-90) with 206 females (42%) and 283 males (58%), and 13% with ECOG performance status ≥ 2 at time of LD. Fludarabine and cyclophosphamide (Flu/Cy) LD was used in 422 patients while 67 patients received other LD regimens including bendamustine-based (n = 35, 52%), cladribine-based (n = 25, 37%) or cyclophosphamide alone (n = 7, 10%). The primary reason for use of Flu/Cy LD was institutional guidance or SOC in 378 patients (90%), while the primary reason for use of other LD regimens was due to the fludarabine shortage in 65 patients (97%) with 3% citing physician's choice or institutional guidance. No significant difference was identified among response outcomes, with those receiving Flu/Cy LD achieving an ORR of 84% compared to 81% with other LD regimens (p = 0.59) and no difference observed in rates of ≥ VGPR (66% Flu/Cy LD vs 60% other LD; p = 0.48). Of those evaluable for MRD at 1 and 3 months, the MRD negative rate at 10 -6 for those with Flu/Cy LD was 77% (n= 137) and 77% (n=113) and with other LD regimens was 66% (n=35) and 79% (n=28), respectively. At a median follow-up of 9.7 months, no statistically significant difference was noted in median progression free survival (mPFS) with Flu/Cy vs other LD regimens (9.3 mos vs NR) or overall survival (OS) (19.4 mos vs NR). When stratified by type of CAR-T therapy, treatment with bendamustine-based LD was associated with an inferior mPFS compared to those receiving Flu/Cy LD in patients treated with ide-cel (3.8 vs 8.5 mos; p=0.0056), though not by multivariate analysis. Univariate analysis of patients treated with ide-cel between Flu/Cy and bendamustine LD did not reveal any significant differences in age, gender, ECOG, R-ISS stage, extramedullary disease, high-risk cytogenetics or renal dysfunction (Cr < 45 ml/min). LD regimen was not a predictor for PFS on multivariable analyses amongst patients treated with ide-cel, while ECOG ≥ 3 (hazard ratio [HR]= 4.44, 95% confidence interval [CI]= 1.40, 14.08) and t(4,14) (HR= 2.02, 95% CI=1.14, 3.59) were associated with worse PFS. No difference in mPFS by LD regimen was observed in patients receiving cilta-cel, which was a smaller cohort (mPFS: Flu/Cy 11.7 mos, bendamustine-based NR, cladribine-based NR, cyclophosphamide NR). Rates of all grade CRS (81% vs 70%), Grade ≥ 3 CRS (3% vs 3%), all grade ICANS (19% vs 12%, and Grade ≥ 3 ICANS (4% vs 2%) were similar among those receiving Flu/Cy or other LD regimens, respectively. Patients receiving Flu/Cy LD were less likely to have any grade cytopenia at 1 month (33% vs 55%, p < 0.001) and 3 months (52% vs 69%, p < 0.001), with no observed difference in infection rate. Conclusions: The fludarabine shortage experienced in the US in late 2022 necessitated the use of alternative LD regimens with BCMA-directed CAR-T therapy with most centers relying on bendamustine- or cladribine-based regimens. Use of bendamustine-based LD was associated with inferior PFS in patients receiving ide-cel on univariate analysis, but not on multivariate analysis after adjusting for other prognostic factors. In summary, there is no clear difference in efficacy or safety between Flu/Cy and non-Flu/Cy LD in patients receiving BCMA-directed CAR-T therapy. *Authors contributed equally

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

Introduction: DH/THL also classified as high-grade B cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements have higher risk of progression after initial treatment and poor response to salvage therapies compared to diffuse large B cell lymphoma (DLBCL), NOS. Recently, CART cell therapy has shown encouraging responses in treatment of relapsed refractory (R/R) DLBCL. In this retrospective study, we evaluated whether survival of (R/R) DH/THL is improved in the CART era. Methods: In this multicenter retrospective study, adult pts (pts) with R/R DH/THL after anthracycline-based therapy were included. Demographic and clinical variables were obtained from electronic health records. Study objectives was overall survival (OS) at 2 year landmark. We utilized full propensity score matching to compare progression free survival (PFS) and OS of CART with 2 nd line chemoimmunotherapy. Results: 278 DH/THL pts treated between 2010-2020 were included. Median age was 63 years (range 52-74), 163 (58%) were male, 119 (43%) were classified as DLBCL and 116 (42%) as HGBCL; 40 (14%) were transformed from follicular lymphoma. 225 (82%) had advanced stage, 161 (67%) had elevated LDH, 85 (33%) had bulky disease, 74 (59%) had B symptoms. 105 (38%) pts treated for relapsed disease before 2018 were included in the pre-CART era cohort. 168 (60%) pts treated from 2018 onwards were included in the CART era cohort. 102 (60%) pts in CART cell era received CART cells, 40 (14%) received polatuzumab vedotin (pola), 10 (3.5%) received loncastuximab tesirine, tafasitamab and bispecific antibody each. Characteristics at relapse were similar in both groups. Median follow up was 8.9 (0.2-146) months. 2-year OS estimate was 36% (CI 95: 30-42%) in entire population. Patients treated in CART cell era had significantly higher OS (2 yr OS: 43% [CI 95: 35-53]) compared to pts treated in pre-CART cells era (2-year OS: 24% [CI 95: 16-34], p=0.0006) (Figure 1). In multivariable analyses, increasing age (HR = 1.02 (CI 95: 1.01, 1.04), p=0.003), extranodal disease (HR = 1.41 (CI 95: 1.00, 1.99), p<0.001), elevated LDH (HR = 1.57 (CI 95: 1.11, 2.24), p=0.01) were associated with inferior OS. Increasing time to relapse (HR = 0.98 (CI 95: 0.97, 0.99), p<0.001) was associated with superior OS. BCL6 rearrangement did not affect OS. When adjusted for these factors, treatment with CART cells was associated with higher 2 yr OS (HR = 0.33 (CI 95: 0.22, 0.49), p<0.001). Treatment with polatuzumab (HR = 1.07 (CI 95: 0.71, 1.6), p=0.07) was not significantly associated with OS in univariable analysis. 102 pts underwent CART cell therapy at any point for relapse; 94 (93%) were refractory to prior chemotherapy. 62 (60%) responded and 52 (50%) had CR after CART cells. 2-year PFS and OS after CART cell therapy were 28% (CI 95: 19-40) and 40% (CI 95: 30-53), respectively. Increasing time to CART was associated with inferior OS (HR: 1.02 (CI 95: 1.0-1.03, p=0.03) but not PFS (HR: 1.02 (CI 95: 0.99-1.04), p=0.2). 219 (79%) pts received curative intent salvage chemotherapy for 2 nd line. 2-year PFS and OS were 15% (CI 95: 11-20) and 38% (CI 95: 31-45), respectively. 21 pts received CART cell therapy for 2 nd line. 2 year PFS and OS in this small number of pts were 52% (CI 95: 35-79) and 70% (CI 95: 52-94), respectively. Due in part to the small number of pts who received CART cells in 2 nd line, we utilized full propensity score matched analysis to compare each patient in CART cell group to all possible matched controls in salvage chemotherapy group. Variables matched were age, LDH, extra nodal disease and time to relapse. In propensity score matched analysis, pts who received CART cells had significantly higher 2 year PFS (HR: 10.5 (CI 95: 3.4-17.5), p=002) and 2 year OS (HR: 7.5 (CI 95: 1.4-13), p=0.01). Conclusions: Survival of r/r DH/THL appears to have improved in the era of CART cell therapy. About 2/3 of pts refractory to chemotherapy respond to CART cells, and in multivariable analysis, receipt of CART cells was associated with improved OS. Increasing time to CART cells was associated with inferior survival. In a propensity score matched analysis utilizing full matching, CART cell therapy in 2 nd line was associated with significantly higher 2 year PFS and OS compared to curative intent salvage therapy. Other CD 19 and CD 20 targeting agents approved after CART cell therapy might contribute to favorable survival, effect of these agents could not be assessed because of small numbers.

Background Teclistamab, the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy was recently approved by the FDA for the treatment of triple-class exposed relapsed or refractory multiple myeloma (MM) after ≥ 4 prior lines of therapy. Because of the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the step-up dosing (SUD) of teclistamab is commonly administered in an inpatient setting among early users. Mayo Clinic has a well-established hospital-based outpatient program for novel immunotherapies. Since the FDA approval, teclistamab SUD has been administered as part of this program. Each dose of the SUD is administered in an outpatient setting, and the patient is given a remote monitoring kit to regularly measure vital signs and stay connected with the command center for signs and symptoms of CRS and ICANS throughout the entire SUD period. This study aimed to evaluate early safety outcomes and healthcare resource utilization during SUD in real-world (RW) patients who initiated teclistamab under the outpatient administration model across 3 Mayo Clinic locations (Rochester, MN, Phoenix/Scottsdale, AZ, Jacksonville, FL). Methods This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022 to June 12, 2023. Eligible patients were adults diagnosed with MM who had initiated commercial teclistamab at any of the 3 Mayo Clinic locations. Patient characteristics, rates and severity of CRS and ICANS, as well as healthcare resource utilization during SUD were described. Time between teclistamab administration and patient check-out was reported for SUD and treatment doses, respectively. Results At the time of data cutoff, 39 patients received at least 1 teclistamab dose across the 3 locations (median age 67.2 years; male: 74%; White: 87%; non-Hispanic: 92%), including 36 patients who initiated teclistamab SUD directly in an outpatient setting. A total of 8 (21%) patients had MM with high-risk cytogenetics and 14 (36%) had prior exposure to other BCMA-targeted therapies. Prevalent comorbidities prior to receiving teclistamab included anemia (77%), hypertension (56%), lytic bone lesions (51%), neutropenia (49%), and hypogammaglobulinemia (41%). Renal impairment or failure was observed in 31% of the patients (Table 1). Almost all patients received acetaminophen (95%), diphenhydramine (95%), and dexamethasone (92%) as pre-medications on the same day as teclistamab administrations during SUD. Of the teclistamab doses with clinic time data, the majority (62%) of doses during SUD required 30 minutes to 1 hour of clinic time for monitoring between administration and check-out. After SUD, the clinic time for weekly treatment doses decreased to less than 30 minutes for most (79%) doses (Figure 1). In patients who completed SUD by data cutoff (n = 37), most patients (70%) received the SUD on a 3-day dose interval (i.e., day 1, 4, 7). The mean time between the first and third doses was 6.3 days. Among the 37 patients with complete SUD, 12 (32%) developed CRS. The highest CRS grade was grade 1 for 10 patients; 1 patient had a grade 2 CRS, and 1 patient had a grade 4 CRS. The patient with grade 4 CRS concurrently decompensated during a dialysis session and all symptoms were considered for CRS grading. A total of 6 patients had recurrent CRS, including 1 patient with 3 events during SUD. All patients who developed CRS during SUD (n=12) were admitted to the hospital for treatment, with a total of 19 admissions across all patients and a median length of stay of 1.7 days per admission. Among patients who were admitted for CRS (n=12), the majority were treated with acetaminophen (92%), diphenhydramine (83%) and dexamethasone (83%); tocilizumab was given to the 2 patients with CRS grade 2 or higher. Only 1 ICANS event (grade 2) was observed in 1 patient during SUD, after dose 3, and the patient was admitted to the hospital for treatment. Conclusion This study evaluated early RW safety outcomes of teclistamab under an outpatient administration model and found the CRS rate and severity to be comparable with other RW evidence generated from various data sources. Outcomes related to teclistamab SUD from Mayo Clinic supported the safety and feasibility of outpatient administration model as a potential option to reduce healthcare resource utilization and improve treatment experiences.

Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after 1 prior therapy as a result of ZUMA-7 (NCT. In ZUMA-1 (NCT02348216), the pivotal study which initially led to the approval of axi-cel in the 3L+ setting, the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019) and at 5 years follow up an OS rate of 42.6%, 5 years durable response and 5 years disease specific survival at 51% ( Neelapu et al. Blood 2023). T cell-related biology (Immunosign 21; Immunoscore®IC) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel ( Scholler et al., 2022). Increased density of activated PD-1+LAG-3+/−TIM-3−CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post-axi-cel. This expanded analysis characterized the impact of axi-cel treatment on the TME immune contexture and examined associations between immune cell subsets and relapse. Methods: Baseline and post-infusion tumor biopsy samples were analyzed by multiplex immunohistochemistry ( Brightplex®). Four panels were developed and applied to assess T cell infiltration (CD3 CD8 FOXP3 TIM3 PD1 LAG3 TOX), regulatory T cell subtyping (CD3 CD8 GATA3 TBET RORg BCL6), T cell activation & exhaustion (CD3 CD8 TIM3 LAG3 PD1 GZMB KI67), macrophage (CD68 CD64 CD163 CD204 CD206 PDL1) and MDSC (CD3 CD11B CD68 CD14 CD15 LOX1 S100A9) subsets. Transcriptomic analysis was performed using nCounter® Pan Cancer panel. The association between T cell subtypes and macrophages cell subset density, and probability to relapse was evaluated. T test values were based on Brightplex analysis. Results: 34 tumor biopsies (16 at baseline, 18 post-infusion) from 26 pts were analyzed including 11 relapsed (6 CR/5 PR) and 15 durable response (15 CR). The baseline and post-infusion TME comprised all major macrophages, MDSC and T cell subsets, with diverse distribution across samples analyzed. Low proinflammatory M1 macrophage density was observed at baseline and post-infusion across patients. In relapsed patients, baseline tumors were enriched with a significantly higher proportion of protumoral M2 macrophage (p<0.0001). A shift of M1-M2 polarization was observed between baseline and post-infusion (Baseline 33%M1M2 / 65%M2, post infusion 76%M1M2 / 21%M2, p<0,0001) across the cohort. In contrast, in relapsed patients, M-MDSC cell density was significantly increased post treatment (p=0.0420). In addition, Innate lymphocyte cells subtype 2 (ILC2) cell density, previously described to be positively correlated with improved overall survival in CRC ( Huang et al. 2021 Cancers), was significantly decreased in relapsed patients post infusion (p=0.019).Post-infusion, durable response was associated with a significant increase in pan-Macrophages (p=0.0360) and cytotoxic T cell subset densities: CD8 naïve T cells (p=0.016); Activated Cytotoxic T cell (GZMB+)(p=0.0203); PD1+TIM3+LAG3- cytotoxic T cell (p=0.0117); CD8 regulatory T cell (FOXP3+)(p=0.012). Regarding T helper lineage, ongoing response was associated with a significant increase of: CD4 naïve T cells (p=0.021); T helper Th2 (p=0.020); cytotoxic T lymphocyte TC2 and TC1/TC2 cell densities (respectively p=0.0052 and 0.011).Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusion: These results suggest that baseline proportions of protumor M2 macrophages may predict disease relapse after axi-cel treatment. Following infusion, relapse is also associated with spatial enrichment of M-MDSC, whereas durable response is related to increases in T cell subpopulation densities inclusive of cytotoxic T cells, T helper, TC1/TC2 ratios and innate T-subpopulations. These findings suggest that axi-cel treatment drastically impacts tumor immune mobilization, infiltration and contexture, which correlates with long term response.

Background: Cytopenias are a common complication of and prolonged (beyond month 3 post CAR-T infusion), severe (grade 3 or higher) cytopenias can be difficult to manage. Stem cell boosts have been reported to restore hematopoiesis; however, stem cells would need to be available prior to CAR-T therapy for potential use post CAR-T. Most lymphoma patients and limited number of myeloma patients may have pre-collected stem cells in storage. Identifying patients at high risk for prolonged and severe cytopenia post CAR-T at the time of CAR-T evaluation (baseline), before leukapheresis, can help identify the patients for coordination of stem cell collection during CAR-T manufacturing and increase the likelihood that the collected stem cells would be used. In this study, we aim to identify clinical variables at the time of CAR-T evaluation, prior to leukapheresis, that are associated with severe cytopenias at month 3 post CAR-T infusion and identify patients who could be considered for pre-emptive stem cell collection prior to CAR-T therapy. Methods: We conducted a retrospective analysis of patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) who received CAR-T products at Mayo Clinic from 01/2016 to 06/2022. Patients with progressive disease in the first year post CAR-T were excluded from the analysis. Baseline (at CAR-T evaluation, prior to leukapheresis) variables were compared between those with and without severe cytopenia at month 3 post CAR-T. Severe cytopenias were defined as hemoglobin (Hg) < 8 g/dL, absolute neutrophil count (ANC) < 0.5 x 10 9/L, and/or platelet count (PLT) < 50 x 10 9/L. Statistically significant variables (p<0.05) by analysis were examined for statistical significance in multivariate analysis (MVA). Results: Among the 166 patients who received CAR-T (88 NHL, 78 MM) during the study period, 31 (18.67%) had a severe cytopenia at month . Twenty baseline variables were examined; HGB, PLT, ANC, and c-reactive protein (CRP) We devised a cytopenia risk score using 1 point each for Hg<10 or PLT<100k at baseline, with a range of 0 to 2. Demographics and clinical outcome by cytopenia risk score is shown in Table 1B. A higher percentage of patients with a score of 1 or 2 had a severe cytopenia at month 3 (Figure 1). In particular, there was a . In addition Conclusion: Baseline cytopenias before leukapheresis may identify patients with increased risk for severe cytopenias at month 3 post CAR-T. These patients can have continued slow hematopoietic recovery in the first year. Stem cell collection, if feasible, could be considered before CAR-T to alleviate post-CAR-T severe prolonged cytopenias.

Background: Axicabtagene ciloleucel (axi-cel), an autologous chimeric antigen receptor (CAR) T-cell therapy, achieved an overall response rate (ORR) of 94% and a complete response (CR) rate of 79% in patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more prior lines of therapy in the ZUMA-5 trial ( Jacobson et al. Lancet Oncol. 2022). Since its FDA approval in March 2021, there has been little evidence on comparative effectiveness (CE) studies of axi-cel vs standard-of-care (SoC), except ones using ZUMA-5 and historical SCHOLAR-5 data (eg, Ghione et al. Blood. 2022). This study was aimed to address this evidence gap in CE of axi-cel vs SoC used to treat r/r FL in real-world settings. Methods: The two data sources in this study were patients who received commercial axi-cel between March 2021 and May 2023 from the CIBMTR and patients who received historical SoC (eg, chemotherapy, anti-CD20 mAb + chemotherapy, immunomodulatory imide drugs) between July 2014 and December 2020 from SCHOLAR-5, which served as an external control of ZUMA-5 trial. The index date was defined as the initiation date of either the infusion for axi-cel patients or the last eligible systemic therapy for SoC patients. Patients were included if they were age ≥ 18, had documented r/r FL with histological grade 1, 2 or 3a, and received at least 2 prior lines of therapy at the index. Patients were excluded if they had transformed diffused large B-cell lymphoma, central nervous system involvement, prior receipt of CAR T or other non-CAR T cellular therapies or allogeneic stem cell transplant, or no post-index information on outcomes. Four effectiveness outcomes were ORR, CR rate, progression-free survival (PFS), and overall survival (OS). Imbalance in observed prognostic risk factors between the two was adjusted via a propensity score analysis using the standard mortality ratio weighting (SMRW). The primary analyses included weighted univariable analysis and multivariable logistic (ORR and CR rate) or Cox (PFS and OS) regressions that were adjusted for the covariates after the SMRW. A sub-analysis of patients age ≥ 65 was conducted using the same methods as the primary analyses. Results: The unweighted study cohort included 376 patients, in which 256 (68%) received axi-cel . Thepatients who received axi-cel were more likely to be younger (median age 61 for axi-cel vs 67 for SoC), have grade 3a FL (37% vs 12%), received 3 or more prior lines of therapy (83% vs 58%), or remained refractory to the last prior therapy (79% vs 73%) vs those who received SoC. The imbalance in the observed prognostic risk factors was mitigated via the SMRW. The weighted univariable analysis, in which the sample size by treatment reflected the SMRW, is shown in Table 1. In patients of all ages, ORR was 92% in axi-cel vs 67% in SoC, and CR rate was 84% vs 37%. Because of varying follow-up lengths by treatment (median 7 months for axi-cel and 37 months for SoC), survival outcomes were reported at month 6, at which time PFS rate was 88% in axi-cel vs 64% in SoC and OS rate was 97% vs 85%. The corresponding proportions for patients age ≥ 65 were similar to those reported for patients of all ages. In the weighted multivariable regressions, axi-cel was associated with statistically significantly better outcomes by all 4 effectiveness measures vs SoC (Table 1). Specifically, in patients of all ages, the odds ratios for axi-cel were 4.93 (95% CI, 2.35−10.34) for ORR and 16.72 (95% CI, 7.03−39.73) for CR rate, and the hazard ratios for axi-cel were 0.41 (95% CI, 0.22−0.77) for PFS and 0.15 (95% CI, 0.06−0.34) for OS. Similar to the patients of all ages in the primary analyses, patients age ≥ 65 in the sub-analysis also demonstrated improved outcomes associated with axi-cel (Figure 1). Conclusions: This study showed that patients with r/r FL after two or more prior lines of therapy treated with axi-cel experienced better outcomes compared with patients treated with SoC, and that older patients also benefited significantly from axi-cel. These findings suggest that axi-cel addresses an important unmet medical need in patients with r/r FL. Future research should include longer follow-up data on outcomes of axi-cel and CE of axi-cel vs other contemporary SoC therapies.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed/refractory (R/R) LBCL. ZUMA-12 (NCT03761056) is a Phase 2, multicenter, single-arm study of axi-cel as part of first-line treatment in patients with high-risk LBCL. In the primary efficacy analysis (n=37; median follow-up of 15.9 months), axi-cel demonstrated a high rate of investigator-assessed complete response (CR; 78%; 95% CI, 62-90) and an 89% objective response rate (ORR; 95% CI, 75-97). Axi-cel also had a manageable safety profile, with no new safety signals observed in the first-line setting (Neelapu et al. Nat Med. 2022). Here, we report updated efficacy and safety outcomes from ZUMA-12 in all patients treated with axi-cel after a median follow-up of ≥40 months. Methods: Eligible adults had high-risk LBCL, with MYC and BCL2 and/or BCL6 rearrangements (double- or triple-hit histology) per investigator or an International Prognostic Index (IPI) score ≥3, plus a positive interim PET per Lugano classification (Deauville score 4/5) after 2 cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen. Patients underwent leukapheresis, followed by lymphodepleting chemotherapy (cyclophosphamide and fludarabine) on Days -5, -4, and -3, and a single axi-cel infusion of 2×10 6 CAR T cells/kg on Day 0. Per investigator discretion, non-chemotherapy bridging could be administered. The primary endpoint was investigator-assessed CR rate per Lugano classification (Cheson et al. J Clin Oncol. 2014). Secondary endpoints included ORR, duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), safety, and levels of CAR T cells in blood and cytokines in serum. Results: As of May 3, 2023, 42 patients were enrolled and 40 were treated with axi-cel, with a median follow-up of 40.9 months (range, 29.5-50.2). In total, 37 patients were evaluable for response (centrally confirmed double- or triple-hit histology or IPI score ≥3). The CR rate was 86% (95% CI, 71-95), and 92% (95% CI, 78-98) of patients had an objective response. Patients with centrally confirmed double- or triple-hit histology (n=10) had a CR rate of 90%. Responses were ongoing in 73% of response-evaluable patients at data cutoff. Medians for DOR, EFS, PFS, and OS were not reached. The 36-month estimates for DOR, EFS (Figure 1), PFS, and OS (Figure 2) were 82%, 73%, 75%, and 81%, respectively. All treated patients (n=40) experienced adverse events (AEs) of any grade and 88% of patients had grade ≥3 AEs. Similar to the primary analysis, the most common any-grade AEs were pyrexia (100%), headache (70%), and neutrophil count decreased (55%). No new cases of cytokine release syndrome (CRS) or neurologic events of any grade occurred since the prior data cut and all cases of CRS and neurologic events reported were resolved by data cutoff. Prolonged cytopenias of any grade (present Day ≥30 post-infusion) occurred in 9 patients (n=7 neutrophil count decreased) and were resolved by data cutoff. There were 8 deaths due to progressive disease (n=5) and other causes not related to axi-cel (1 COVID-19, 1 esophageal adenocarcinoma, 1 septic shock on Days 350, 535, and 287 post axi-cel infusion, respectively). Two of the 8 deaths (1 progressive disease and 1 esophageal adenocarcinoma) occurred after the primary analysis. Among treated patients, post-infusion CAR T-cell expansion by peak and area under the curve was 36.9 cells/µL and 368.0 cells/µL×days, respectively, in those with ongoing responses at data cutoff (n=17), 45.1 cells/µL and 413.4 cells/µL×days in those who relapsed (n=6), and 34.7 cells/µL and 566.8 cells/µL×days in non-responders (n=3). Conclusion: In this updated analysis of ZUMA-12 with a median follow-up of ≥40 months, axi-cel demonstrated a high rate of durable responses and no new safety signals. Axi-cel may benefit patients exposed to fewer prior therapies and those with high-risk LBCL, a population with high unmet need and poor outcomes after standard first-line chemoimmunotherapy.