Khurana, Arushi

Abstract Background Primary bone diffuse large B cell lymphoma (DLBCL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that is relatively rare, accounting for 3-15% of extranodal NHL and less than 1% of all NHL. Patients often present with pain and swelling or pathologic fracture of the affected area of the skeleton, and B symptoms are often less prevalent. Many cases are limited stage at presentation. Patients are usually treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or similar induction therapy. Based on older studies showing improved outcomes associated with the addition of radiation (many completed prior to the rituximab era), patients often still receive combined-modality therapy today. However, it remains unknown whether consolidative radiation therapy (RT) confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction. We sought to address this question in a multicenter retrospective study. Methods We conducted a retrospective analysis of outcomes in a modern cohort of patients who underwent treatment for primary bone DLBCL using chemotherapy regimens in the rituximab era either with or without consolidative RT. Data was collected from 13 academic medical centers in the U.S., with patients treated between 2005 and 2019. Patients were identified using each institution's hematologic malignancy registries. Analysis was limited to patients with primary bone DLBCL, with stage I-II disease (primary site +/- locoregional lymph nodes) that could be encompassed in a radiation field. Patients who received CIT alone or CIT followed by RT were included. Treatment selection was at the treating physician's discretion. Electronic medical records were reviewed for: demographics, chemotherapy regimens, radiation treatments, and PET scan data. Local IRB approval was obtained at sites. All data was distributed in a de-identified fashion. The primary outcomes were overall survival (OS), and relapse-free survival (RFS). Secondary outcomes included: response after induction CIT induction and the need for additional therapies. Chi-square test analysis was used to compare categorical variables and the Wilcoxon rank-sum test was used for continuous and ordinal measures. Survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. Multi-variable analysis (MVA) for OS and RFS was performed using RT vs no RT, PET status post CIT (negative vs positive) and rituximab in induction (Y/N) as variables. Results A total of 127 patients were included: 91 who received CIT and radiation (RT group), and 36 who received CIT alone (no RT group). The median age of patients at diagnosis in the RT group and no RT group was 58.5 and 57.0, respectively. For CIT, the majority of patients received R-CHOP (84%). Despite focusing on 2005-2019, a small percentage of patients (5 - 14%) in each group (RT and no RT) did not receive rituximab with their induction therapy. The OS at 10 years was 74.5% in the RT group and 86.5% in the no RT group (p = 0.29). The RFS at 10 years was 70.9% in the RT group and 78.2% in the no RT group (p = 0.85). Among the 91 patients who received RT, 67 (77.0%) received a dose of 36 Gy or higher. There was no difference in OS (p = 0.63) or RFS (p = 0.90) in patients who received > 36 Gy vs < 36 Gy of radiation. On MVA for OS, RT was not associated with improved OS, although rituximab as part of induction was (p = 0.048). On MVA for RFS, neither RT nor rituximab were associated with improved RFS. For rituximab the trend was in the direction of rituximab benefit (p = 0.11). Conclusion Our results demonstrate that, in the rituximab era, patients with limited stage primary bone DLBCL have excellent outcomes overall. In this study, neither RFS or OS appeared to be improved with the addition of consolidative RT. Rituximab, however, was associated with improved OS on MVA. Outcomes do not appear to differ based on the dose of RT (> 36 Gy vs < 36 Gy). Our data suggests that RT may have less benefit for primary bone DLBCL in the rituximab era, although it is possible that a subset of patients may benefit from consolidative radiation therapy. A larger data set would likely be needed to evaluate this. We plan to present data regarding PET responses at the meeting. Figure 1 Figure 1. Disclosures Lunning: Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Kyowa Kirin: Consultancy; Verastem: Consultancy; Kite, a Gilead Company: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Bartlett: Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Caimi: XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; TG Therapeutics: Honoraria; Seattle Genetics: Consultancy; Verastem: Consultancy; Kite Pharmaceuticals: Consultancy. Rodgers: MJH Lifesciences: Consultancy. Barr: Morphosys: Consultancy; Gilead: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Abbvie/Pharmacyclics: Consultancy. Epperla: Verastem: Speakers Bureau; Beigene: Speakers Bureau; Karyopharm: Other: Ad Board; Genzyme: Honoraria. Hill: AstraZenica: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Epizyme: Consultancy; Karyopharm: Consultancy; Janssen/Pharmacyclics: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; EUSA: Consultancy; Takeda: Research Funding; Genentech: Consultancy; Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Portell: Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Aptitude Health: Honoraria; Morphosys: Honoraria; Targeted Oncology: Honoraria; SeaGen: Research Funding; BeiGene: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Fenske: Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; Servier Pharmaceuticals: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau; Biogen: Consultancy; ADC Therapeutics: Consultancy; Kite (Gilead): Speakers Bureau; Beigene: Consultancy; AbbVie: Consultancy.

Abstract Background: While CD19 chimeric antigen receptor T cell therapy (CAR-T) therapy does not use myeloablative chemotherapy, patients with aggressive lymphoma treated with CAR-T are immunosuppressed from lymphodepletion chemotherapy, and prolonged B cell aplasia and hypogammaglobulinemia from CAR-T. The impact of CAR-T on immunologic protection from vaccine-preventable diseases (and thus the need to revaccinate) has not been formally studied. We report the vaccine titers of patients treated with CAR-T at Mayo Clinic, Rochester. Methods: We conducted a retrospective chart review of patients who received CAR-T from 9/2018 to 4/2021 for treatment of aggressive lymphoma at Mayo Clinic, Rochester. Data was collected on anti-viral and anti-bacterial titers prior to CAR-T infusion and at month 3 post CAR-T. Clinical assays for vaccine titers were used for patient assessment and threshold for clinical assays was used to define antibody titer as positive or negative. Results: In our cohort of 87 CAR-T patients, 83 (94%) patients were infused with axicabtagene ciloleucel, 4 (5%) patients received brexucabtagene autoleucel and 1 (1%) received tisagenlecleucel. Prior to CAR-T therapy, positive titer rate was highest for tetanus and lowest for Streptococcus pneumoniae (Strep PNA). Similar trends were seen whether patients had autologous stem cell transplant (ASCT) within 2 years of CAR-T (i.e. within immunization timeframe post ASCT) or not (Table 1). At 3 months post CAR-T, overall seropositivity rates were similar when compared to pre-CAR-T levels for the prior transplant and no prior transplant group. For patients who had received intravenous immunoglobulin (IVIG) supplement prophylactically (for IVIG<400 mg/dl), seropositivity rate for Strep PNA remained zero (Table 1). Among the 30 patients who received IVIG, variable rate of conversion from negative to positive titers were seen for measles (1/2, 50%), mumps (3/5, 60%), rubella (3/4, 75%), varicella-zoster (VZV, 4/4, 100%), hepatitis A (8/9, 89%) and hepatitis B (10/12, 83%). For patients who did not receive IVIG prophylaxis after CAR-T, seropositivity rate for hepatitis A and B was low. In addition, some of these patients had a loss of seropositivity for Strep PNA (2/5, 40%) and hepatitis A (1/4, 25%). Conclusion: The presence of protective vaccine titers is variable for patients receiving CAR-T therapy, regardless of recent ASCT. The loss of protective titers post CAR-T was low. The need for immunization post CAR-T may remain important regardless of transplant status prior to CAR-T. Prophylactic IVIG does not confer complete immunization protection. Optimal timing for immunization post CAR-T is probably unknown and may need to be considered earlier for patients not on prophylactic IVIG. Further study with longer follow-up is needed to inform the need for immunization and optimal timing post CAR-T. Figure 1 Figure 1. Disclosures Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Sorrento: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Juno: Consultancy; Legend: Consultancy; Gamida Cell: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Abstract Introduction Chimeric antigen receptor T cell (CAR-T) expansion has been consistently identified as a predictor of clinical response. However, there are no clinically available test to measure CAR-T presence after infusion for the FDA approved CAR-T therapy. We hypothesize that the lymphocyte expansion which can be readily measured as absolute lymphocyte count (ALC) in blood count differential could be a clinically accessible surrogate for CAR-T expansion in patients who receive FDA approved CD19 CAR-T to treat aggressive B-cell non-Hodgkin lymphoma (NHL). We examined the ALC levels in the first 2 weeks after CAR-T infusion and correlation with clinical outcomes in NHL patients who received CAR-T at our institution. Methods Records were reviewed for patients who received CAR-T between 6/2016 and 1/2021 at Mayo Clinic, Rochester. CAR+ T cells were identified by flow cytometry using an anti-FMC63 antibody. Receiver operator curve was generated using nominal logistic regression to predict complete response (CR) as best response. Progression-free survival and overall survival were calculated using Kaplan-Meier method and between-group differences were assessed using log-rank test. Continuous variables were compared using wilcoxon text and categorical variables were compared using chi-square test. Results Among the 87 patients who received CAR-T for NHL, majority of the pts received axicabtagene ciloleucel (86, 99%). The highest ALC level (ALC peak) in the first 15 days were identified for all patients and median ALC peak was 0.44 X10 9/L (range, 0 - 2.55x10 9/L). The median time to ALC peak was 10 ±3 days. Increasing ALC peak levels correlated with increased CAR+ T cells in blood measured by flow cytometry (n=16, R=0.63, p=0.0008). Using ROC analysis, an ALC peak level of 0.67 was identified as the cut point for best association with CR (AUC=0.68, p=0.0004). Baseline demographics were similar between the high ALC peak (N=35) and low ALC peak (N=52) groups, as shown in Table 1. There was no difference in the incidence, high grade, or duration of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) between the two groups (Table 2). Patients who received a higher cumulative dose of steroid for management of CRS and ICANS had lower ALC peak. A higher ALC peak was associated with an increased CR rate and durable CR at month 6. Similarly, a higher ALC peak was associated with increased progression-free survival (PFS, 6.4 months vs. 2.7 months, p=0.004) and overall survival (OS, 31 months vs. 12 months, p=0.04), as shown in figure 1. Conclusion Given the typical CAR-T expansion seen in the first 2 weeks post infusion, ALC peak in the first 15 days is a clinically accessible, reliable surrogate for CAR-T expansion and predicts durable CR and longer PFS, OS. This study was supported in part by the Mayo Clinic Center for Individualized Medicine, Bernard E. and Edith B. Waterman, Henry J. Predolin Foundation and other generous benefactors of Mayo Clinic. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Janssen: Consultancy, Research Funding; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Research Funding; Merck: Research Funding; Sorrento: Consultancy; Juno: Consultancy.

Abstract Background: Polatuzumab vedotin (Pola), an antibody drug conjugate targeting CD79b received FDA approval in combination with bendamustine and rituximab (Pola-BR) in June 2019. With CAR-T as destination therapy, the option of Pola-BR appears appealing with its superior efficacy and lack of potential interference with CAR-T due to different target antigens. However, clinical concerns remain regarding prolonged lymphopenia associated with benda and CAR-T manufacturing if used before apheresis. We reviewed the single center experience of all patients with exposure to polatuzumab around CAR-T for R/R aggressive NHL treated at Mayo Clinic Rochester. Methods: A review of patients that received at least one dose of Pola with the intent to proceed to CAR-T between July 1, 2019 and March 31st, 2021 at Mayo Clinic, Rochester were included. Response to therapy was based on 2014 Lugano criteria. Overall survival (OS) was defined as the time from CAR-T infusion to death, and event-free survival (EFS) as the time from CAR-T infusion to disease progression, next treatment, or death. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results: A total of 22 patients were identified during the study period. Of these 18 (82%), made it to CAR-T infusion (17 axi-cel, and 1 -tisa cel). 3 patients died due to progressive disease (PD) before CAR-T and one achieved complete remission (CR). In the pre-CAR-T Pola cohort (n = 22), the median age was 65.5 years (39-73), 50% were males, 96% had advanced stage and IPI ≥ 3. Median prior lines of treatment were 4.5 (2-6), 73% had primary refractory disease and 50% had myc rearrangement. 19 (86%) patients received Pola as bridging therapy and 8 were exposed to Pola before T-cell apheresis. Bendamustine was included in the treatment for 79% (15/19) for bridging therapy and 63% (5/8) with exposure pre-apheresis. For those in the bridging group, the overall response rate (ORR) was 26% (5/19), with one patient achieving CR with Pola-BR. Disease control (defined as those in a partial response [PR] or stable disease [SD]) was seen in 47% (9/19) patients. One of the 8 patients with pre-apheresis exposure to Pola, required an additional attempt at CAR-T manufacturing after the initial failure. At a median follow up of 48 weeks, the EFS and OS in 18 patient cohort with pre-CAR-T Pola exposure were 6.7 weeks (95% CI, 4.3-not reached [NR]) and 15 weeks (95% CI, 9.7-NR), respectively. At the data cut off (7/25/2021), 78% patients had died. As traditional chemo for bridging is a particularly poor prognostic group, we compared Pola-BR bridging group (n = 15), to other traditional chemo bridge group (n = 16) in our CAR-T database. Both groups had comparable baseline characteristics as shown in Table 1 except for higher proportion of patients with B-symptoms in the Pola-BR group at time of CAR-T. There was also no difference in the inflammatory markers (CRP and ferritin) at LD or peak level after CAR-T. Table 2 shows outcomes between the 2 groups with comparable any grade CRS, neurotoxicity, pre and post CAR-T infection rates. Best response ORR to CAR-T was higher in the other chemo group vs. Pola BR (81.2% vs. 33%, p = 0.027). There was a significant difference in the 6-month OS rate (other 81.3% [95%CI, 54.5-96] vs. pola 33.3% [95%CI, 11.8- 61.6], p = 0.007) but no significant difference in the 6-month EFS rate (other 37.5% [95%CI, 15.2-64.6%] vs. pola 13.3% [95%CI, 1.7-40.5%] p = 0.12) between the 2 groups (figure 1). On univariate analysis within the chemo type bridging cohort (Pola-BR + other traditional chemo, n = 31), presence of B-symptoms (HR 4.72, p = 0.002), ECOG PS > 2 at CAR-T (HR 6.75, p = 0.0008), and type of bridge therapy (pola HR 6.57, p = 0.009) were associated with worse OS whereas a response to bridge (PR+SD, HR 0.39, 0.031) was favorable. On MVA, association was maintained for bridge type (pola, p <0.001) and response to bridge (p <0.001). Discussion: Pola based bridge was feasible in this US based cohort without significant issues with CAR-T manufacturing or increased infection rates. However, in this retrospective analysis, use of Pola-BR was associated with inferior outcomes compared to other traditional chemotherapy options. Future studies are required to elucidate whether these difference in outcomes stem from a biological basis versus bias in patient selection. Figure 1 Figure 1. Disclosures Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; InnoCare: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Juno: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Legend: Consultancy; Sorrento: Consultancy.

Abstract Background: Bridging therapy (BT) was not allowed in the ZUMA-1 pivotal trial for axicabtagene ciloleucel (axi-cel) chimeric antigen receptor T-cell therapy (CAR-T) . Since then, several real-world studies have shown the use of bridging therapy to be associated with worse overall survival, duration of response, and complete remission rates. In addition, patients requiring BT during CAR-T manufacturing have a more aggressive and higher tumor burden of disease, also factors associated with poor outcomes. Therefore, factors that can predict outcomes in this high-risk patient cohort are required. We herein examine the impact of response to BT on CAR-T outcomes in large B-cell lymphoma (LBCL). Methods: A retrospective review of patients who received axi-cel for NHL from June 2016 - July 2020 at Mayo Clinic, Rochester, was performed. BT was defined as any lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing, reducing the likelihood of eligibility to receive CAR-T. The decision and choice of BT were at the discretion of the treating physician. Response to all lymphoma-directed therapy was evaluated using the 2014 Lugano criteria. Response to BT included patients with a partial response (PR) or stable disease (SD) on PET-CT before initiating lymphodepletion chemotherapy. Event-free survival (EFS) was defined as the time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as the time from axi-cel infusion to death. Survival curves were calculated using Kaplan-Meier estimates and were compared between subgroups using the log-rank test. Cox regression was used for univariate and multivariate analysis (MVA). Results: A total of 73 patients underwent car T therapy during this period. Of these, 67% (49/73) received BT therapy. Table 1 shows baseline characteristics of the total BT cohort (n = 49). The median age at CAR-T infusion was 59 years (IQR 46-64); 57% were males and comprised of 47% (23/49) DLBCL followed by 31% (15/49) high-grade B-cell lymphoma types. Based on the Lugano criteria on PET-CT, 22/49 (45%) patients responded to BT. The baseline characteristics were comparable between the responders and non-responders to BT except for a higher proportion (73%) of patients receiving systemic chemotherapy as BT in the responders (Table 1). At a median follow-up of 24 months, 75% had either progressed, died, or started the next treatment (event), and 59% (29/49) had died. The median EFS was significantly longer in the responders as compared to the non-responders to BT, figure 1 (13.04 months (95%CI, 3.54-not reached [NR]) vs. 2.56 months (95%CI, 1.18-3.02), p = 0.002). The OS also trended in favor of the responders (median OS 18.4 months (95% CI, 13.44-NR) vs. 11.84 months (95% CI, 5.05-NR), p = 0.092). The responder group also had a higher 6-month CR rate of 50% than 11.1% in the non-responder group (p = 0.004). There were no differences in any grade or grade ≥ 3 cytokine release syndrome and neurotoxicity rates in the two groups. On univariate analysis within the bridging group (n = 49), type of bridge (non-chemo) and response to bridge (PR+SD) were associated with a better EFS. In the MVA, only response to BT maintained significance for EFS (HR 0.34, p = 0.025). Conclusions: Having some control of lymphoma after BT was associated with better EFS and 6-month CR rate. Future studies need to prospectively evaluate the type and response to BT as a prognostic factor for improving outcomes in patients receiving CAR-T. Figure 1 Figure 1. Disclosures Wang: InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Takeda: Research Funding.

Abstract Background: Generalizability of results from clinical trials with narrow in-/exclusion criteria are a concern as significant deviations in efficacy or toxicity may occur when treatments are used in populations of elderly and more comorbid patients. The cost-effectiveness of novel therapies may also be less favorable if real-world treatment effects are inferior to clinical trial results. In diffuse large B-cell lymphoma (DLBCL), a recent US study showed that baseline organ function-based eligibility criteria had substantial impact on survival with ineligible patients being at higher risk of dying from progressive lymphoma (1). Aims: The present study explored the impact of commonly used in-/exclusion criteria in key completed and ongoing first line DLBCL trials on survival in a Danish population-based study of patients with de novo DLBCL. Patients and methods: DLBCL patients enrolled in the Danish Lymphoma Registry (LYFO) and treated with R-CHOP in the period 2008-19 were screened for completeness of data to match trial eligibility criteria. The key organ/hematology eligibility criteria of completed or ongoing all-comers DLBCL studies (REMoDL-B, Goya, Polarix and Hovon84) were collected (bilirubin, ALAT, creatinine, eGFR, leucocytes, neutrophils, thrombocytes and ECOG). First, high-level trial matching on disease risk group (Ann Arbor, bulky disease, international prognostic index (IPI)) and age-groups were performed so that patients assessed for trial eligibility had a relevant risk profile. Subsequently, patients were divided into eligible or ineligible based on selected in/exclusion criteria. For each trial, overall survival (OS) from treatment start were compared for eligible and ineligible patients using inverse probability of treatment weighted Kaplan-Meier and log-rank tests. Crude OS and OS adjusted for residual imbalances in IPI and age were estimated. When possible, the OS curves from standard arms of the original trials were superimposed on OS plots. For each trial, the Shapley value of each criterion was calculated, using the HRs as well as the 5y restricted loss of lifetimes (RLOLs). The Shapley value measures the average influence of each eligibility criterion on the estimated IPI- and age-adjusted HR/5y RLOL. Results: A total of 3,150 R-CHOP treated DLBCL patients without discordant low-grade lymphoma were identified in the surveyed period. A total of 1,666 patients (52.89% of surveyed population) were available for the REMoDL-B trial, 1,431 (45.43%) for Goya, 1,125 (35.71%) for Polarix, and 1,432 (45.46%) for Hovon84. The variations of numbers for each trial evaluation were explained by trial inclusion criteria and missing data in LYFO. Crude OS estimates for patients with and without all necessary information were similar (data not shown). OS curves for eligible and ineligible patients are shown in Figure 1 and, when possible, with superimposed trial results (Goya, REMoDL-B, Hovon84). Survival differences between trial eligible and ineligible patients were robust to further adjustment of imbalances in age and IPI. Associated crude and adjusted 2 and 5-year OS rates for trial eligible and ineligible are shown in Table 1. The largest numerical difference in 2-year crude OS between eligible and ineligible was observed in the REMoDL-B trial (ineligible had 26% lower 2-year OS rate). The largest numerical difference in 2-year OS adjusted for IPI and age between eligible and ineligible was observed for the Polarix trial (ineligible had 17% lower 2-year OS rate). The strongest drivers of OS differences between trial eligible and ineligible patients in terms of the tested eligibility criteria were thrombocyte count (HR-contribution calculated from Shapley values -0.11; -0.14) and ECOG (HR-contribution -0.09; -0.21). Liver function parameters (bilirubin and ALAT) had low impact on OS (HR-contribution 0.00; -0.05 and 0.00; 0.07). Conclusions: The present population-based study confirms that trial ineligible patients have worse survival even after adjustments in imbalances in age and disease risk category. Thus, trial eligibility criteria have substantial impact on generalizability of results to a wider unselected population. Interestingly, the trial eligible patients identified in the present study had very similar outcomes to R-CHOP treated patients in the original trials supporting the possible use of RWD as synthetic control arms. Figure 1 Figure 1. Disclosures Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jørgensen: Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Celgene: Consultancy. Larsen: BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Odense University Hospital, Denmark: Current Employment; Gilead: Consultancy. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Abbvie: Consultancy; Janssen: Consultancy. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months.

Abstract Background Patients (pts) with aggressive B-cell non-Hodgkin lymphoma (NHL) progressing after anti-CD19 chimeric antigen receptor T (CART) cell therapy have poor prognosis and may benefit from new therapy options through clinical trials. However, in a single center report, only 12% of such pts were treated in trials (Chow et al. Am J Hematol, 2019). Identifying the reasons for this low enrollment is needed to design future studies for this population. Here, we evaluated the eligibility criteria for recent landmark trials for relapsed/refractory aggressive B-cell NHL to learn what eligibility barriers are present. Methods Pts with aggressive B-cell NHL who received FDA-approved CART cell therapy at Mayo Clinic (Rochester, Arizona, Florida) since 2018 and progressed after CART cell therapy were identified. The potential eligibility for the following key trials was evaluated: a) polatuzumab + bendamustine + rituximab, b) tafasitamab + lenalidomide, c) selinexor and d) loncastuximab. The eligibility for each trial was retrospectively assessed at the time of disease progression after CART cell therapy based on hemoglobin (Hb), absolute neutrophils count (ANC), platelet count (Plt), renal and liver function tests, ECOG performance status (PS), and central nervous system (CNS) involvement. Results Seventy-five pts had disease progression to axicabtagene ciloleucel (N=73, 97%) or tisagenlecleucel (N=2, 3%) and are included in this analysis. Median time to progression after CART was 2.1 months (IQR: 1.0 - 3.1). Thirteen (17%) pts were treated in clinical trials after progression following CART cell therapy, while 46 (61%) were treated off trials, and 16 (22%) pts never received any treatment after progression. At a median follow-up of 13.6 months (IQR: 9.1 - 26.7) from CART progression, the median overall survival (mOS) from CART progression was 5.8 months (95% CI 3.5 - 10.1) and 53 (71%) pts died. Thirty-eight pts (51%) did not meet eligibility criteria for any of the 4 recent landmark trials. Hematologic impairment was the most common barrier to inclusion of these patients in clinical trials: Hb < 9 g/dL n=23 (31%) or Hb < 10 g/dL n=36 (48%), ANC < 1.0 x 10 9/L n=19 (25%) or ANC < 1.5 x 10 9/L n=32 (43%), and Plt < 75 x 10 9/L n=30 (40%) or Plt < 90 x 10 9/L n=34 (45%). Renal (n=11, 15%) or liver dysfunction (n=5, 7%), CNS involvement (n=8, 11%) and ECOG PS > 2 (n=3, 4%) were less common reasons leading to exclusion from trials. Post CART trial ineligible pts had significantly shorter time to progression (median 1.7 months, IQR: 1.0 - 2.6 vs. 3.0 months IQR: 1.9 - 3.4, p < 0.01) and inferior overall response to CART (45% vs 67%, p = 0.06) compared to pts who met trial eligibility post CART. Baseline Hb (median Hb 9.5 g/dL, IQR: 8.5 - 10.5 vs. 10.9 g/dL, IQR: 9.7 - 12.2, p < 0.01) and Plt (median Plt 106 x 10 9/L IQR: 54 - 165 vs. 201 x 10 9/L IQR: 141 - 243, p < 0.01) were also significantly lower in pts ineligible for trials post CART. There were no significant differences between pts eligible or ineligible for trials with regards to age (median 59 vs. 60 years), number of prior therapies (median 3 vs. 3), prior autologous stem cell transplant (41% vs. 37%), bridging therapy (65% vs. 63%), baseline ANC (median 4,1 vs. 3,0 x10 9/L), or high-grade (grade ≥ 2) cytokine release syndrome (19% vs. 21%) or neurotoxicity (32%, vs. 42%), respectively. Survival after CART progression was significantly shorter (mOS 2.5 months, 95% CI: 1.6 - 5.1) for the 38 pts ineligible for trials compared to pts eligible for trials (mOS 10.6 months, 95% CI: 8.9 - NA), (p < 0.01). In the 59 pts who received therapy post CART progression, the mOS of pts treated on (n = 13) or off (n = 46) trials was 13.8 months (95% CI: 9.2 - NA) vs. 6.6 months (4.9 - 10.7), respectively (p = 0.047). Conclusion Approximately half of the pts (51%) with aggressive B-cell NHL progressing after CART cell therapy would have be excluded from landmark clinical trials. The current hematologic exclusion criteria are a major barrier to enrollment in clinical trials, which would exclude many pts who have disease progression within 3 months of CART cell therapy (ie, primary refractory disease), in whom cytopenia as a toxicity from therapy is prevalent. Given the known delayed hematologic recovery after CART cell therapy and the unmet need of pts progressing to CART cell therapy, the hematologic exclusion criteria should be adjusted to increase trial participation of this population, especially of those with primary refractory disease. Figure 1 Figure 1. Disclosures Munoz: Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Janssen: Research Funding; Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy; Seattle Genetics: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Portola: Research Funding; Merck: Research Funding; Celgene: Research Funding; Gilead/Kite Pharma: Research Funding; Bayer: Research Funding; Seattle Genetics: Honoraria; Physicians' Education Resource: Honoraria; Targeted Oncology: Honoraria; OncView: Honoraria; Kyowa: Honoraria. Murthy: CRISPR Therapeutics: Research Funding. Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; InnoCare: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lin: Vineti: Consultancy; Takeda: Research Funding; Sorrento: Consultancy; Novartis: Consultancy; Juno: Consultancy; Legend: Consultancy; Janssen: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding.

Abstract Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion. Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use. Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD. Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each). While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2). Additional patients and follow-up will be presented. Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients’ outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9–35) and 82 months (95% CI: 39–115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91–20) versus SMR 1.72 (95% CI: 1.26–2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma–related causes in those achieving EFS 24.