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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 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 Background Diffuse large B-cell lymphoma (DLBCL) that fails to achieve a complete response (CR) or relapses early after standard immunochemotherapy (IC, e.g., R-CHOP or similar) is referred to as primary refractory DLBCL and has a poor prognosis. The clinical course with regards to frontline IC is heterogenous, and different definitions have been used in literature, e.g., progressive or refractory during therapy (narrow definition), or not achieving complete remission at the end of IC, or relapsing within 6 or 12 months after completing IC (broad definition). A small proportion of patients may still have chemosensitive disease and be able to achieve durable disease control with salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, it is challenging to identify such patients, with clinical and molecular predictors highly needed. In this study, we examined the association of time to refractory status with survival outcomes in patients with primary refractory disease. Methods Adult patients with newly diagnosed DLBCL between 2002 and 2015 and seen at Mayo Clinic Rochester were identified from the prospective Molecular Epidemiology Resource (MER) cohort study of the University of Iowa/Mayo Clinic Lymphoma SPORE. The current study included patients with primary refractory disease, which was defined as no response to frontline IC (primary progression), partial response (PR) at end of treatment (EOT PR), or relapse with 12 months after achieving CR at EOT (early relapse). Clinical characteristics, treatment and response data, and follow-up data were abstracted from MER and collected by medical record review if needed. Clinical characteristics between groups were compared using Chi-square test. Overall survival (OS) was defined as the time from confirmation of refractory disease to the time of death from any cause and was analyzed using the Kaplan-Meier method. Results Out of 949 newly diagnosed DLBCL patients, 122 (12.8%) had primary refractory disease, 36 with primary progression, 36 with EOT PR, and 50 with early relapse. The baseline clinical characteristics are summarized in Table 1. No significant differences in age, gender, ECOG performance status, number of extranodal sites, stage, International Prognostic Index, or cell of origin were found between the 3 groups. The proportion of MYC2 and BCL2/BCL6 rearrangements or Myc/Bcl2 double expressor was small and not different among the 3 groups. Salvage therapies were mainly platinum based high-dose chemotherapy (e.g., R-ICE, R-DHAP, or similar) for systemic disease, MTX-based therapy for CNS relapse, or radiotherapy or resection for localized disease (Table 1). The response to salvage chemotherapy was significantly different between the 3 groups. The CR/PR rate was 8.6%/28.6% for patients with primary progression, 16.7%/46.7% for patients with EOT PR, and 35.6%/33.3% for patients with early relapse (P<0.01, Table 1). At a median follow-up time (of living patients) of 113 months, 93 patients had died. The 2-year OS was 13.9% for patients with primary progression, which was significantly worse compared to that of patients with EOT PR (2-year OS 41.7%) or early relapse (2-year OS 44%), (P=0.001)(Figure 1A). In patients with early relapse, the 2-year OS was not significantly different among those who relapsed with 3 months, between 3-6 months, or between 6-12 months (Figure 1B). Conclusion Our data suggest that broadly defined primary refractory DLBCL has heterogenous survival outcomes. DLBCL patients with primary progressive disease represent an ultra-high risk group that has particularly poor survival outcomes with current standard salvage regimens. Novel therapies such CAR T-cell therapy or targeted agents should be studied in this patient population. In contrast, patient who only achieve PR at EOT and those who relapse within 1 year of achieving CR had better OS. A fraction of these patients may still have chemosensitive disease and benefit from salvage chemotherapy and ASCT. The survival difference in the two groups also has important implications for clinical trial design. The definition of primary refractory DLBCL in clinical trials should be carefully and clearly defined. When evaluating novel therapies in single arm trials, the benchmark for efficacy (i.e., historical outcomes) may differ according to the population included in the trial (e.g., time to refractory status). Figure 1 Figure 1. Disclosures Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Bennani: Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Kymera: Other: Advisory Board. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding. Witzig: Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding; Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Wang: Genentech: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; MorphoSys: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: 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.

Abstract Introduction: Up to 40% of newly diagnosed diffuse large B cell lymphoma (DLBCL) will relapse after frontline rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (RCHOP), with subsequent poor prognosis. Identification of patients (pts) at high risk of relapse early in the treatment can allow for development of risk adapted therapies to improve outcomes. Positron Emission Tomography scan after 2 cycles of therapy (PET2) has been evaluated as a predictor of relapse but study treatments were heterogenous and results were conflicting. A substudy of CALGB 50303 trial did not find association of PET2 response by Deauville Score (DS) with survival in RCHOP and DA-EPOCH-R treated pts. In the UK National Cancer Research Institute Prospective Study, DS of 5 on PET2 predicted worse progression free survival but not overall survival (OS) in RCHOP-21 and RCHOP-14 treated pts. Here we report impact of PET2 response on outcomes in two large independent, prospective cohorts of newly diagnosed DLBCL treated homogenously with two RCHOP-based regimens of similar efficacy. Methods: Discovery was done in adult pts with DLBCL enrolled into a single arm phase 2 trial of lenalidomide plus standard RCHOP (R2CHOP) (MC078E, NCT00670358). The validation cohort comprised of adult pts with newly diagnosed DLBCL treated with standard RCHOP prospectively enrolled into the Mayo component of the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER). Both MC078E and MER cohorts included patients who received at least 3-6 cycles of therapy and had a PET2. Pts who progressed on PET2 were excluded. End of treatment (EOT) PET was done 3-12 weeks after last cycle of therapy. The revised response criteria for malignant lymphoma (Cheson, et al 2007) was used to assess PET in MC078E. In MER, revised response criteria for malignant lymphoma (Cheson et al 2007) or Lugano classification was used, depending on era of diagnosis. Positive PET was defined as FDG uptake above background (Cheson 2007) or DS 4 or 5 (Lugano 2014). Study endpoints were event-free survival (EFS) and OS by PET2 status. Results: Out of 118 pts treated on MC078E, 102 had PET2 (MC078E). The median age at diagnosis was 64 years (range 19-87), 61 (60%) were male, 89 (87%) had advanced stage disease, 46 (45%) had international prognostic index (IPI) of 3-5. 58 (57%) were PET2 Negative (PET2-ve) and 44 (43%) were PET2 Positive (PET2+ve). At EOT PET, 83 (81%) had -ve PET and 15 (15%) had +ve PET. Out of 44 PET2+ve pts, 15 remained +ve at EOT PET. Out of 58 PET2-ve pts, 56 had EOT PET available and all were -ve. Out of 866 DLBCL pts enrolled into MER between August 2005 and June 2015, 621 were treated with RCHOP for 3-6 cycles and 272 had available PET2 (MER). The median age was 65 years (range 55-73), 152 (56%) were male, 174 (64%) had advanced stage, 103 (38%) had IPI 3-5. 186 (68%) were PET2-ve and 86 (32%) were PET2+ve. Out of 235 with EOT PET available, 182 (77%) had -ve EOT PET and 25 (11%) had +ve EOT PET. PET2+ve pts had higher odds of +ve EOT PET (OR: 17.4 (CI 95 8.3-40.0), p<0.001) and progression on EOT PET (OR: 4.3 (CI 95 1.9-10.2), p<0.001) in MER cohort. This analysis was not possible on MC078E as all PET2-ve had -ve EOT PET. In MC078E, 2-year EFS and OS were 69.5% (CI 95 61.1-79.1) and 88.1% (CI 95 82-94.7). In MER, 2-year EFS and OS were 71.6% (CI 95 67.7-76.8) and 82.3% (CI 95 79.3-85.3). Compared to PET2-ve, PET2+ve pts had significantly inferior EFS in both MC078E (HR 4.0, CI 95 2.1-7.88, p<0.0001, figure 1a) and MER (HR 2.9, CI 95 1.9-4.1, p<0.0001, figure 1c). Compared to PET2-ve , PET2+ve pts had a trend towards lower OS in MC078E (HR 2.0, CI 95 0.9-4.9, p=0.1, figure 1b) and a significantly lower OS in MER (HR 2.3, CI 95: 1.5-3.4, p<0.0001, figure 1d). In subgroup analysis of MC078E, PET2+ve pts had lower EFS and a trend towards lower OS in all subgroups except IPI 0-2 (Table 1). In MER, PET2+ve pts had lower EFS and OS in all the subgroups except stage I-II and IPI 0-2 (Table 1). Conclusions: Positive PET2 was associated with increased risk of disease progression and death in newly diagnosed DLBCL. Results of our study provide robust evidence of importance of PET2 as an early predictor DLBCL pts at high risk of progression in two independent prospective cohorts. PET2-guided risk-adapted strategies using chimeric antigen receptor T-cell therapy and bispecific antibodies may potentially improve outcomes, should be explored in clinical trials and results of our study serve as a benchmark for such studies. Figure 1 Figure 1. Disclosures Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; MorphoSys: Research Funding; 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; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; NanoString: Research Funding; Genentech: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding; Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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.

AbstractMonoclonal B‐cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL) are clonal B‐cell disorders associated with an increased risk of infections and impaired vaccination responses. We investigated the immunogenicity of recombinant zoster vaccine (RZV) in these patients. Individuals with MBL/untreated CLL and Bruton tyrosine kinase inhibitor (BTKi)‐treated CLL patients were given two doses of RZV separated by 2 months. Responses assessed at 3 and 12 months from the first dose of RZV by an anti‐glycoprotein E ELISA antibody assay and by dual‐color Interferon‐γ and Interleukin‐2FLUOROSPOT assays were compared to historic controls matched by age and sex. About 62 patients (37 MBL/untreated CLL and 25 BTKi‐treated CLL) were enrolled with a median age of 68 years at vaccination. An antibody response at 3 months was seen in 45% of participants, which was significantly lower compared to historic controls (63%, p = .03). The antibody response did not significantly differ between MBL/untreated CLL and BTKi‐treated CLL (51% vs. 36%, respectively, p = .23). The CD4+ T‐cell response to vaccination was significantly lower in study participants compared to controls (54% vs. 96%, p < .001), mainly due to lower responses among BTKi‐treated patients compared to untreated MBL/CLL (32% vs. 73%, p = .008). Overall, only 29% of participants achieved combined antibody and cellular responses to RZV. Among participants with response assessment at 12 months (n = 47), 24% had antibody titers below the response threshold. Hypogammaglobulinemia and BTKi therapy were associated with reduced T‐cell responses in a univariate analysis. Strategies to improve vaccine response to RZV among MBL/CLL patients are needed.

AbstractBecause there have been a dvances in frontline treatment for mantle cell lymphoma (MCL) over the last 2 decades, we sought to characterize the changes in frontline treatment patterns and their association with outcomes. Patients with newly diagnosed MCL from September 2002 through June 2015 were enrolled in a prospective cohort study, and clinical characteristics, treatment, and clinical outcomes were compared between patients diagnosed from 2002 to 2009 (Era 1) compared with 2010 to 2015 (Era 2). Patient age, sex, and simplified MCL International Prognostic Index (sMIPI) score were similar between the 2 groups. In patients age 65 years or younger, there was less use of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-Hyper-CVAD) (16.1% vs 8.8%) but more use of rituximab plus maximum-strength cyclophosphamide, doxorubicin, vincristine, and prednisone (R-maxi-CHOP) alternating with rituximab plus high-dose cytarabine (R-HiDAC), also known as the Nordic regimen, and R-CHOP alternating with rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) (1.1% vs 26.4%) and less use of R-CHOP or R-CHOP-like regimens (64.5% vs 35.2%) but more use of R-bendamustine (0% vs 12.1%) in Era 2 (P &lt; .001). These changes were associated with improved event-free survival (EFS; 5-year EFS, 34.3% vs 50.0%; P = .010) and overall survival (OS; 5-year OS, 68.8% vs 81.6%; P = .017) in Era 2. In patients older than age 65 years, there was less use of R-CHOP or R-CHOP-like therapy (39.0% vs 14.3%) and nonstandard systemic therapy (36.6% vs 13.0%) but more use of R-bendamustine (0% vs 49.4%). These changes were associated with a trend for improved EFS (5-year EFS, 25.4% vs 37.5%; P = .051) in Era 2. The shift from R-CHOP or R-CHOP-like regimens to R-bendamustine was associated with improved EFS (5-year EFS, 25.0% vs 44.6%; P = .008) in Era 2. Results from this prospective cohort study provide critical real-world evidence for improved outcomes with evolving frontline patterns of care in patients with MCL.