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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.

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.

Background: Recently, large B-cell lymphomas (LBCLs) have undergone major shifts in classification and treatment paradigm, particularly with the advent of CD19-targeted chimeric antigen receptor T cell therapy (CAR-T). Initially approved as third-line treatment in LBCL in 2017, as of early 2022 CAR-T is indicated for second-line therapy (2L) in patients with relapsed or refractory (R/R) disease within 12 months of frontline treatment or who are not candidates for autologous stem cell transplant (ASCT). Given this quickly changing landscape, we aimed to describe disease characteristics, patterns of care, and survival outcomes in patients with R/R LBCL receiving two or more lines of systemic therapy across modern treatment eras. Methods: We developed a database of patients with R/R LBCL from 8 U.S. academic centers in the Lymphoma Epidemiology of Outcomes (LEO) Cohort study (NCT02736357) and Consortium for Real World Evidence (CReWE). Unlike the SCHOLAR-1 dataset (M Crump et al, Blood 2017), our cohort included any patient receiving 2L, regardless of timing of progression/relapse. For this analysis, eligible patients were aged ≥18 years and received 2L between 2002-2022. Patients with histologic transformation, post-transplant lymphoproliferative disorder, primary CNS lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, or plasmablastic lymphoma were excluded. Prognostic factors, therapy details (including intent for ASCT and/or CAR-T), and outcomes, including treatment response, event-free survival (EFS), and overall survival (OS), were abstracted for all lines of therapy. Treatment eras were defined as pre-CAR-T (2002-2010), CAR-T available via clinical trial (2011-2017), and post-FDA approval of CAR-T (2018-2022). Results: Of 1760 patients initiating 2L for R/R disease, 1523 were eligible for analysis. Median age at start of 2L was 62 (interquartile range [IQR] 53-70), and 65% were male; 11% were non-White, and 8% were Hispanic. High-grade subtypes comprised 16% of all cases. IPI was available for 1013 patients at time of 2L therapy, with 54% having IPI 3-5. Median time from diagnosis to 2L was 8.7 months (IQR 5.6-18.5), with 834 patients not having achieved complete response (CR) to 1L, 285 patients relapsing <12 months after 1L, and 404 patients relapsing ≥12 months after 1L. The median number of total lines of therapy received was 4 (range 2-18), with 586 and 347 receiving ASCT and CAR-T, respectively, at any line of treatment. At a median follow-up of 48 months from the start of 2L, 926 patients (61%) had died. Progressive lymphoma was the primary cause of death in 75% of deceased patients, with 8% of reported deaths due to therapy. 2L was received at an academic medical center in 83% cases, and 209 patients (14%) received 2L on a clinical trial. ASCT and/or CAR-T was planned at 2L for 989 patients (65%), of whom 463 ultimately received ASCT, 88 received CAR-T, and 21 received allogeneic transplant at 2L. 494 patients were not considered for ASCT or CAR-T at 2L, and 40 were unknown for ASCT/CAR-T intent. Breakdown by treatment era (n = 1518 with available treatment start date) is shown in the Table. Median EFS from start of 2L was 4.2 months (95% confidence interval [CI]: 3.8-4.8). Median OS from start of 2L was 18 months (95% CI: 17-22), and 2- and 5-year OS estimates were 46% (95% CI: 44-49%) and 35% (95% CI: 33-38%), respectively. EFS and OS improved significantly for patients initiating 2L between 2011-2017 compared to 2002-2010. However, EFS and OS in the 2018-2022 era remained similar to 2011-2017 (Figure). Conclusions: To our knowledge, this study is the first-ever large-scale attempt to describe patterns of care and outcomes in LBCL 2L in the modern era, inclusive of all treatment approaches. The rich and unique LEO CReWE dataset captures evolving practice approaches over time in terms of both intent for and receipt of cellular therapies. Likely reflecting the rapid development of many novel immune effector cell products and bispecific antibodies, we observed increased enrollment on 2L clinical trials in the 2018-2022 period, including a substantial proportion of patients receiving CAR-T in 2L. Importantly, survival increased in treatment eras during which CAR-T was available. Ongoing analyses of factors associated with improved survival will be presented at the meeting.

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: The goal of clinical trial eligibility criteria is to identify a population of patients that have high risk disease or have unmet needs with standard of care therapy. Frontline trials of diffuse large B-cell lymphoma (DLBCL) include patients with International Prognostic Index (IPI) scores of 3-5 as a way to identify a high risk population. Trials typically include patients with IPI score=2, and sometimes IPI score=1, to expand the eligible patient population. However, broader patient populations must be balanced by the potential inclusion of low-risk patients with excellent outcomes to standard of care therapy, leading to potentially underpowered trials. IPI is a sum of dichotomous variables which makes implementation easy but can result in heterogeneity in outcomes within IPI scores. This heterogeneity may be caused by unequal prognostic information across IPI variables, loss of information within IPI variables due to the use of cutoffs, as well as information captured by variables that are not included in the IPI. In prior modeling of outcomes in DLBCL (Maurer et al, AJH 2016), we identified that: i) LDH has a strong prognostic ability beyond the upper limit of normal (ULN) and ii) bulky disease is an independent variable for prognosis. Here we evaluate if the presence of either of these two variables, easily captured at diagnosis within the current standard clinical work-up, can identify a high-risk subset of patients within the population of those with IPI scores of 1-2. Methods: Patients with newly diagnosed lymphoma were enrolled within 6 months of diagnosis in the LEO Cohort at 8 academic medical centers from 2015-2020 and prospectively followed. Inclusion criteria for this analysis was aggressive B-cell lymphoma typically included in frontline trials (e.g. DLBCL, high grade B-cell lymphoma, FL3B), IPI 1-5, frontline therapy with rituximab and anthracycline-based chemotherapy, stage II-IV disease and ages 18-80 years. Event-free survival (EFS) was defined as the time from diagnosis until progression, initiation of 2 nd line therapy, or death due to any cause; EFS was evaluated at 24 months (EFS24). Very high LDH was defined as LDH>1.3xULN based on prior modeling (Maurer et al, AJH 2016) and bulky disease was defined as maximum tumor diameter (MTD) of 7cm or greater. IPI 1 and 2 were first evaluated separately and then combined due to similar outcomes in patients with very high LDH and/or bulky disease. High risk IPI1-2 was defined as the presence of either bulky disease and/or very high LDH within an IPI score of 1-2. Confirmation was performed in a similar cohort of patients enrolled in the Iowa/Mayo SPORE Molecular Epidemiology Resource (MER) from 2002-2015; bulky disease was defined using a 10cm cutoff per availability in MER data collection forms. Results: 1560 patients from LEO were analyzed; median age was 64 years (IQR: 54-71), 42% were female and 83% had stage III/IV disease; subtype was DLBCL, NOS in 1335 (86%). IPI was 1-2 in 766 patients, 3 in 496 patients and 4-5 in 298 patients ( table). 391 (51%) with IPI1-2 had either bulky disease and/or very high LDH (high risk IPI1-2) and 375 had low-risk IPI1-2. EFS24 in high risk IPI1-2 (71.6%, 95% CI: 67.2-76.3) was significantly inferior to IPI1-2 without bulky disease or very high LDH (85.2, 95% CI: 81.7-88.9 logrank p=0.0035, figure) and similar to patients with IPI3 (70.7%, 95% CI: 66.8-74.9). Consistent results were observed in 1014 patients analyzed in the MER using a higher cutoff for bulky disease (10cm) due to data availability ( table). Patients with high risk IPI1-2 had significantly shorter diagnosis to treatment interval (DTI) in both the LEO (per-week OR=0.83, 95% CI: 0.77-0.88) and MER (per-week OR=0.77, 95% CI: 0.68-0.87) cohorts compared to low risk IPI1-2, both p<0.0001). In sensitivity analysis, LEO results were similar when performed in the subset of patients with DLBCL, NOS. Conclusion: The presence of either bulky disease and/or very high LDH at presentation identifies a high-risk subset of patients with IPI 1-2 that have similar outcomes to patients with IPI 3 disease. These simple criteria can be easily implemented within existing clinical trial diagnostic work-ups. Future trial designs in frontline aggressive B-cell lymphoma should include patients with IPI 3-5 and patients with IPI 1-2 with either bulky disease and/or very high LDH to better define a high-risk population of patients for clinical trial eligibility.

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.

Purpose The predominant pattern of relapse for patients with B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) involves sites previously involved by NHL. Bridging radiotherapy (BRT) has shown to be an effective bridging treatment with excellent local control rates. Our previous work defined limited/oligometastatic lymphoma as disease involving <5 sites. This study is the first to report on the role of BRT for patients with limited (<5 involved sites) disease prior to CART. Methods Following Institutional Review Board approval, a retrospective review from 2018 to 2023 across 3 Mayo Clinic sites (Arizona, Florida, and Minnesota) was performed and identified 139 patients with relapsed/refractory (r/r) B-cell NHL without bone marrow involvement who received CART and had <5 disease sites prior to leukapheresis. Ann Arbor staging was used to define the number of involved disease sites. An involved disease site included the Ann Arbor anatomical lymph node region(s) harboring the pathological lymph node(s) or any extranodal lesion. Bridging treatment (radiation and/or systemic therapy) was defined as treatment administered between leukapheresis and CART infusion. The primary endpoint was event-free survival (EFS),defined from CART infusion to any disease progression or initiation of post-CART consolidative/salvage therapy. Secondary endpoints included progression -free survival (PFS),defined from CART infusion to any disease progression, and overall survival (OS), defined from CART infusion to death. Results Prior to CART infusion, 44 (32%) patients received BRT and 95 (68%) did not. Bridging systemic therapy was given to 5 (11%) and 34 (36%) patients in the BRT and no BRT groups, respectively (p=0.003). The median number of involved disease sites prior to leukapheresis was 2 (range: 1-4). There was no significant difference in the baseline characteristics prior to CART infusion between the BRT and no BRT groups, except for extranodal involvement that was more common in the BRT group (Table 1). The median equivalent 2 Gy dose was 27 Gy (Interquartile range 23-34), and the most common BRT regimen was 20 Gy in 5 fractions. Among the 44 BRT patients, 34 received radiation to all visible PET-avid disease sites, and 10 received radiation to some but not all disease sites. The median follow-up was 20 months. The rate of grade ≥2 cytokine release syndrome was 41% in both groups (p=0.99). The rate of grade ≥2 immune effector cell-associated neurotoxicity syndrome was 21% and 37% in the BRT and no BRT groups, respectively (p=0.059). There were no observed grade ≥3 BRT-related toxicities. Objective response rate by PET 5 point scale was higher in the BRT group (93% versus 79%; p=0.036). Crude rates of progression were 30% in BRT and 55% in no BRT patients, with 9/13 (69%) and 43/52 (83%) patients relapsing in pre-existing sites of disease present prior to CART infusion in the BRT and no BRT group, respectively. Seven (16%) BRT patients relapsed in the radiation field. The 2-year EFS was 50% in the BRT group and 39% in the no BRT group (p=0.01). The 2-year PFS was 55% in the BRT group and 45% in the no BRT group (p=0.017). The 2-year OS was 55% in the BRT group and 62% in the no BRT group (p=0.7). Intriguingly, patients who received BRT to all visible PET-avid disease sites (n=34) had further improvement in 2-year EFS (67% vs 39%, p=0.003) and 2-year PFS (71% vs 46%, p=0.008) compared to no BRT or patients who received BRT to some but not all visible disease sites (n=105). Nine patients (2 in BRT and 7 in no BRT groups) received consolidative radiotherapy for day 30 residual disease with only one patient subsequently experiencing progression. Twenty-five patients (6 in BRT and 19 in no BRT groups) received salvage/palliative RT for post-CART relapsed disease. Thirty-seven (39%) patients in the no BRT group remained without disease progression and did not receive radiation in the bridging, consolidative or salvage/palliative setting. Conclusion Bridging radiotherapy prior to CART infusion for patients with limited (<5 involved disease sites) r/r NHL appears to improve response rate, EFS, and PFS without causing significant toxicities. Approximately one third of patients who do not receive BRT will require subsequent post-CART radiation, and another third will remain free of radiation and disease progression.

Background: Shorter diagnosis to treatment interval (DTI) has been shown to be associated with more aggressive disease features and inferior outcomes in diffuse large B-cell lymphoma (DLBCL; Maurer et al, JCO 2018). Additional confirmatory studies have also shown that DTI is related to tumor volume (Alig et al, JCO 2021) and molecular phenotype (Aluaij et al, Blood 2023). Here we evaluate DTI in a large multicenter cohort of patients prospectively enrolled and followed as part of the Lymphoma Epidemiology of Outcome (LEO) cohort. Methods: Patients were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the United States between 2015 and 2020. Patients in this analysis had aggressive B-cell lymphoma (BCL) treated with anthracycline-based chemotherapy. DTI was defined as the initial lymphoma biopsy date until the start of initial chemotherapy; patients with DTI between 0-100 days were evaluated. Short DTI was defined as DTI ≤ 14 days (DTI≤14) as previously described in prior publications (e.g. Maurer et al, JCO 2018) and confirmed via examination of functional forms via splines. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. Results: 2565 patients with aggressive B-cell lymphoma were evaluated. Median age was 62 years (IQR 51-71) and 1469 (57%) were male. 297 patients (12%) were self-reported non-White race and 314 patients (12%) were self-reported Hispanic or Latino. The majority had DLBCL, NOS subtype (N=1927, 75%), while 227 (9%) had high-grade BCL with MYC and BCL2 and/or BCL6 rearrangements (HG, DH) and 90 (4%) had high-grade BCL NOS (HG, NOS). Clinical characteristics are summarized in the table. At median follow-up of 49 months (IQR 36-68), 800 patients (31%) had an event and 578 patients (23%) died. EFS at 24 months (EFS24) was 76% (95% CI: 74-77). Median DTI across all subtypes was 21 days (IQR 12-33) and 845 patients (33%) had DTI≤14. Patients with DTI≤14 were significantly younger (median age 59 years) but there was no association between DTI and gender, race, or ethnicity. Patients with DTI≤14 were more likely to have HG, DH or HG NOS subtypes, ECOG PS 2-4, advanced stage, elevated LDH, CNS involvement, B symptoms, and bulky disease ( see table). Patients with DTI≤14 were more likely to receive R-EPOCH-based or intensive therapies (41%) and less likely to receive 1L therapy on a clinical trial (3.8%) compared to DTI>14 (26% and 10.1%, respectively). Consistent with previously reported data, DTI≤14 was associated with inferior EFS (HR=1.62, 95% CI: 1.41-1.87, figure), OS (HR=1.73, 95% CI: 1.47-2.04), and EFS24 (OR=1.93, 95% CI: 1.60-2.38). The association between DTI and outcomes remained significant after stratifying for subtype (EFS HR=1.68, 95% CI: 1.46-1.94; OS HR=1.78, 95% CI: 1.50-2.10) and adjustment for IPI (EFS HR=1.43, 95% CI: 1.24-1.65; OS HR=1.47, 95% CI: 1.24-1.74). In subset analysis, DTI≤14 was significantly associated with inferior outcomes within the subtypes of HG, DH (EFS HR=2.70, 95% CI: 1.82-4.01; OS HR=2.97, 95% CI: 1.92-4.60); HG, NOS (EFS HR=2.07, 95% CI: 0.93-4.60; OS HR=2.36, 95% CI: 1.03-5.43); and DLBCL, NOS (EFS HR=1.51, 95% CI: 1.27-1.78; OS HR=1.52, 95% CI: 1.45-1.85). Analysis was limited in other subtypes due to number of events. Notably, within the subset of patients with DTI>14, there was no significant difference in EFS between subtypes for DLBCL, NOS (EFS24=80%, EFS HR=ref), HG, DH (EFS24=73%, EFS HR=1.26, 95% CI: 0.92-1.73) and HG, NOS (EFS24=83%, EFS HR =0.84, 95% CI: 0.40-1.78), logrank p=0.29; similar results were observed for OS (p=0.22). Conclusions: Patients requiring early initiation of therapy for aggressive B-cell lymphoma represent a distinct population of patients with more aggressive clinical features and inferior outcomes. In patients with longer DTI, high grade subtypes had similar outcomes to DLBCL, NOS. Efforts should be made to include patients with anticipated short DTI in clinical trials and translational studies to fully capture the spectrum of patients with aggressive B-cell lymphoma.

Multiple CD19-directed therapies are available for the treatment of relapsed and refractory (R/R) DLBCL, including CAR T cells, tafasitamab/lenalidomide (TL), and loncastuximab tesirine (lonca-T) (Sermer D., Blood Rev 2023). However, there are few data available on the efficacy of sequential CD19-directed therapies. We performed a retrospective study evaluating all patients with R/R LBCL treated consecutively with TL at 11 institutions from 8/2020 to 8/2022, identifying 178 patients. In this study, we specifically evaluate outcomes in patients who received anti-CD19 therapy prior to or after TL. The primary outcome of interest was progression-free survival (PFS) in TL recipients who previously received CD19-directed CAR T therapy, with overall response rate (ORR), complete response rate (CRR), and overall survival (OS) also evaluated. Outcomes of lonca-T and CAR T after TL therapy were evaluated. Data on CD19 expression was assessed on biopsies after TL; this was determined locally using flow cytometry or immunohistochemistry per institutional protocols. In subgroup analyses, ORR and CRR were compared using Fisher's exact test. PFS and OS were estimated using the Kaplan-Meier method, with differences tested using the log-rank test. Of 178 patients who received TL, 52 had received prior anti-CD19 CAR T therapy, at a median of 7.4 months before TL (Table 1). Median PFS was lower in prior CAR T recipients (1.6 mo, 95% CI 1.1-2.5) vs no prior CAR T (2.1 mo, 95% CI 1.8-3.2), with hazard ratio 1.46 (p = 0.04; Figure 1). Best ORR was lower in patients with prior CAR T exposure (15% vs 33%, p = 0.02) though CRR was not significantly different (15% vs 18%, p = 1.0). We specifically evaluated TL outcomes based on prior response to CAR T, given the previously identified association of refractory disease with poor TL outcomes (Qualls D et al., presented at ASH 2022). Of 19 patients who had progressive disease more than 6 months after CAR T, ORR and CRR to TL therapy were 31.6% (all responses were CRs); in 33 patients with refractory disease (less than CR or relapse within 6 months) after CAR T, ORR and CRR to TL were significantly lower, at 6.1% (p = 0.04). Median PFS after TL was shorter in CAR-refractory than CAR-relapsed disease, at 1.4 vs 3.5 months (HR 2.2, p = 0.02). Of 88 patients who received therapy after TL, 20 (23%) received lonca-T and 14 (16%) received CAR T. Data on survival and initiation of new treatment after CAR T or lonca-T was available, but response and progression data after CAR T or lonca-T therapy is pending. These data allowed an estimate of OS and event-free survival (EFS), defined as survival without initiation of a new treatment after CAR T or lonca-T. With a median 3.9 months' follow-up, median EFS after CAR T administration was 3.7 months (95% CI, 0.9 - 6.5), and median OS was 8.1 months (95% CI, 0.6 - 15.7). In patients who received lonca-T, with median 2.7 months' follow-up from initiation, median EFS was 2.8 months (95% CI, 0.9 - 4.7), and median OS was 3.5 months (95% CI, 1.2 - 5.7). When comparing CAR T and lonca-T to polatuzumab vedotin- or chemotherapy-based therapies after TL, there were no significant differences in OS or EFS. In patients who discontinued TL, 24 had a biopsy a median of 18 days after the last dose of tafasitamab. Of these, 13 (54%) were CD19-positive and 11 (46%) were CD19-negative. All samples obtained more than 21 days after tafasitamab (6/6) were CD19-positive, while 46% obtained within 21 days were CD19-positive. These time-dependent findings may reflect “epitope masking” by tafasitamab rather than CD19 loss, reflecting other recent reports (Fitzgerald K., Leuk Lym 2022; Duell J., Leuk Lym 2022). In patients receiving TL after CAR T, responses and PFS were lower than in patients without prior CAR T therapy; however, with disease that was not refractory to prior CAR T, results were similar to patients who had not had prior CAR T. This may reflect that refractory disease, regardless of prior therapy, is associated with shorter PFS, though the possibility of CD19-mediated mechanisms of resistance remains. Modest EFS and OS were seen in patients receiving CAR T therapy or lonca-T after already receiving TL, though this may also reflect the high-risk disease characteristics of this cohort. Overall, in a high-risk, real-world cohort of TL-treated patients, these data suggest that some patients may benefit from subsequent CD19-directed therapies, but better therapeutic options are needed.

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with two-year overall survival (OS) rates of 66-70% reported in prospective clinical trials. Induction therapy with high-dose methotrexate (HD-MTX) followed by consolidation has become the mainstay of treatment, however, there are few contemporary and robust prognostication indices widely available for clinical use. Some of the most used indices were developed prior to the routine use of rituximab and include the International Extranodal Lymphoma Study Group (IELSG; 1980-1999), Memorial Sloan-Kettering Cancer Center (MSKCC; 1983-2003), Nottingham/Barcelona (NB; 1986-2001), and Taipei Score (TS; 2003-2015). Herein, we describe a contemporary comparison of clinical prognostication indices using a single-center cohort of PCNSL patients treated at the Mayo Clinic. Methods: Patients with a diagnosis of PCNSL who received HD-MTX as part of induction therapy at Mayo Clinic between October 2010 and June 2022 were identified and retrospectively reviewed. Patients with prior or concurrent systemic lymphoma were excluded. Primary endpoints were progression-free survival (PFS) defined as time from diagnosis to relapse, progression, or death due to any cause; and OS defined as time from diagnosis to death due to any cause. PFS and OS were evaluated using Kaplan-Meier curves and compared by risk scores using a log-rank test. The association between baseline characteristics and survival outcome were assessed in univariate Cox regression models. Any characteristics showing significant (p-value <0.05) association with outcome were combined using a multivariate Cox regression model. All characteristics that maintained significant association with outcome were combined into a new prognostic model. We compared the performance of each prognostic index model using Harrell's C (HC). Results: A total of 148 patients were identified (50.7% female) with median age at diagnosis of 66 years (range 29-85), with 48 patients (32.4%) age >70 (Table 1). Most had multifocal disease (60.1%) and deep brain involvement (67.6%) at diagnosis with elevated CSF protein (58.1%) but no documented CSF involvement (93.9%). In total, 117 patients (79.1%) received methotrexate, rituximab, and temozolomide (MRT) induction therapy, and the remaining 31 patients (20.9%) received methotrexate and rituximab (MR) induction therapy with various consolidation strategies. The median follow-up for all patients was 4.5 years and the two-year OS was 79% (95% CI: 73-86%). This cohort was stratified using previously published prognostication indices (Table 1). Upon analysis, PFS was not accurately predicted using the IELSG (score 4-5: HR 0.7 (CI 0.3-2.0); HC 0.6), MSKCC (3: 1.3 (0.4-4.0); 0.5), NB (3: 0.9 (0.4-2.5); 0.6), or TS (3: 0.9 (0.1-7.2); 0.5) prognostication indices. Furthermore, OS was not accurately predicted using the IELSG (4-5: 1.5 (0.6-4.0); 0.6), MSKCC (3: 1.2 (0.5-3.2); 0.6), NB (3: 1.2 (0.5-3.2); 0.6), or TS (3: 1.3 (0.2-9.8); 0.6) prognostication indices. Upon multivariate analysis, no variables listed in Table 1 were associated with PFS within this cohort. The two variables predicting a worsened OS were an ECOG performance status of 2 or more (1.9 (1.01-3.6)) and an MR induction regimen instead of MRT (2.1 (1.05-4.3)) (Figure 1). The two-year OS with no risk factors was 86.1% (95% CI: 78.8-94.1%), one risk factor was 75.7% (95% CI: 63.6-90.1%), and two risk factors was 61% (95% CI: 43-86%) (Figure 1). Conclusions: This study reports overall improved outcomes in patients with PCNSL compared to prior prospective and retrospective cohorts, likely in part due to treatment advances and supportive care strategies. This single-center, retrospective cohort of rituximab-exposed patients with PCNSL were not well prognosticated using previously published indices, indicating that further study and more sophisticated approaches to prognostication are warranted. Although multivariate analysis did not demonstrate any variables associated with PFS, it did demonstrate an inferior OS with a performance score of 2 or more and in patients treated with MR rather than MRT.