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INTRODUCTION Prolonged cytopenias following Chimeric Antigen Receptor (CAR) T-cell therapy are common. The cytopenias are mainly due to the genotoxic effects of conditioning chemotherapy and systemic inflammatory insult to hematopoietic stem and progenitor cells from CAR T-cell activity. Tocilizumab, an anti-IL6 receptor antibody, reduces cytokine release syndrome (CRS), a clinical manifestation of CAR T inflammatory toxicity. We sought to determine if prophylactic tocilizumab can decrease the risk and/or severity of CRS. We secondarily hypothesized that decreasing the inflammatory injury to hematopoietic stem cells could improve bone marrow function after CAR T. Lastly, we analyzed the association between cytopenias and CAR T efficacy generally. METHODS In this single-institution, retrospective cohort study, we examined all patients who had received axicabtagene ciloleucel for relapsed/refractory diffuse large B cell lymphoma (DLBCL) between March 2018 and April 2021 (Table 1). Each patient was evaluated for prolonged cytopenias, defined as requiring granulocyte-colony stimulating factor (G-CSF), red blood cell or platelet transfusion beyond day 28 after CAR T infusion. After CAR T infusion, no patient was given any anti-lymphoma therapy prior to collection of blood count data. We compared response to CAR T 6 weeks post-infusion, progression-free survival (PFS), and overall survival (OS) for patients with and without prolonged cytopenias. A univariate regression analysis was performed, and between group differences were calculated using Chi-squared, Fisher's exact tests, and Cox Proportional hazard regression model. Kaplan-Meier and log-rank analyses were used to evaluate the PFS and OS. We also compared patients who did and did not receive prophylactic tocilizumab 36 hours after CAR T infusion for differences in prolonged cytopenias, PFS, OS, and development and severity of CRS and neurotoxicity. CRS and neurotoxicity were graded using the ASTCT consensus grading system. RESULTS The study included 54 patients, 31 (57.4%) met criteria for prolonged cytopenias. 1 (1.9%) patient died of progressive disease prior to day 28 and was excluded from analysis. All patients who died in this study did so on the basis of progressive lymphoma. Likelihood of no response to CAR T at 6 weeks was higher in patients who needed G-CSF support past day 28 (HR 2.20, p = 0.048), had a hemoglobin nadir less than 8 g/dL (HR 2.61, p = 0.031), were still requiring platelet transfusions after day 28 (HR 2.26, p = 0.038), or had a platelet nadir less than 25,000 per µl during the first 28 days (HR 4.01, p = 0.013, Table 2). For patients who had neutrophil counts below the median at day 28, the median PFS was 4.5 months vs. 17.9 months (HR 2.07, p = 0.035) compared to those above the median. In patients with a platelet nadir less than 25,000 per µl or below the median at day 28 (Figure 1), the median PFS was 4.5 months vs. not reached (HR 3.12, p = 0.003) and 3.9 months vs. not reached (HR 3.85, p = 0.0004) respectively. Median OS was 9.44 months in patients who required G-CSF support past day 28 (HR 2.79, p = 0.022) vs. not reached in those who didn't receive G-CSF past day 28. For patients with an ANC below the median on day 28, median OS was 19.87 months vs not reached (HR 2.65, p = 0.022). In patients with a platelet nadir less than 25,000 per µl or below the median at day 28, the median OS were 7.8 months vs not reached (HR 3.72, p = 0.006) and 7.79 months vs not reached (HR 3.39, p = 0.007) respectively. Among patients who received prophylactic tocilizumab, 12 (54.5%) had prolonged bone marrow failure compared to 19 (57.6%) among those who did not (p = 0.82). PFS, OS, and rates and severity of CRS and neurotoxicity did not differ between the prophylactic tocilizumab groups. CONCLUSIONS In this study of patients with relapsed/refractory aggressive B-cell lymphomas receiving a CD28 domain-containing CAR T product, severe short-term or prolonged cytopenias were associated with an increased risk of lymphoma progression and death. This effect was not ameliorated by administration of prophylactic tocilizumab, which also did not affect the development or severity of CAR T inflammatory toxicities. Further study is required to determine the mechanistic nature of the relationship between post-infusion cytopenias and CAR T efficacy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Aggressive non-Hodgkin's lymphoma (aNHL) with secondary central nervous system (sCNS) involvement has a poor prognosis. Studies have reported a response to induction treatment as low as 35%, leaving less than half of patients eligible for autologous stem cell transplant (ASCT). Outcomes of patients in these clinical scenarios are dismal and treatment is ill-defined. Small case series suggest chimeric antigen receptor (CAR)-T cell therapy may play a role in the management of relapsed/refractory (R/R) B-cell lymphoma (BCL) with sCNS involvement, but follow-up is limited and response duration is uncertain. Allogeneic hematopoietic stem cell transplant (alloHCT) offers a durable remission for a subset of patients with R/R systemic aNHL primarily mediated through a graft versus lymphoma (GVL) effect, but it is unclear if GVL properties include the immune-privileged CNS. The present study aims to describe outcomes of a cohort of patients with R/R aggressive B- and T-cell NHL with sCNS involvement who underwent alloHCT at a single academic institution. Methods: This is a retrospective analysis that includes all patients with R/R aNHL with sCNS involvement who underwent alloHCT at the University of California, Los Angeles from 2005-2020. The UCLA Institutional Board Review approved this study. Relevant clinical data was extracted from medical records. Hematopoietic cell transplantation comorbidity index (HCT-CI) and time to neutrophil and platelet engraftment were measured according to Center for International Blood and Marrow Transplant Research criteria. Results: Ten patients were included (3 females, 7 males). Histologic subtypes included anaplastic BCL (1), mantle cell lymphoma (1), blastic natural killer-cell lymphoma (1), peripheral T-cell lymphoma, not otherwise specified (1), primary mediastinal BCL (1), and diffuse large B-cell lymphoma (DLBCL) (non-germinal center=3, germinal center-like=2). Two DLBCL patients had histologic transformed lymphoma (follicular lymphoma =1, chronic lymphocytic lymphoma = 1). Four patients had sCNS involvement at the time of initial diagnosis or during frontline treatment; the remaining 6 patients developed sCNS lymphoma at relapse. sCNS lymphoma was identified in the parenchymal (n=4), leptomeningeal (n=3), or both (n=3) compartments. The median age at the time of alloHCT was 49.5 (range 28-68), and 1 patient was ˃ 60. At the time of alloHCT, 1 patient had residual disease in the CNS and the remaining 9 patients were in a complete remission. Eight patients received ˃ 3 prior lines of therapy, and 3 patients failed prior ASCT. HCT-CI scores were 0 (n=1), 1 (n=2), 2 (n=3), 3 (n=1), and unknown (n = 3). Donor types included 10/10 matched related (3), 10/10 matched unrelated (4), 9/10 mismatched related (1), and double umbilical cord blood (2). Graft source was peripheral blood in 8 patients and cord blood in 2 patients. Conditioning regimens included myeloablative, reduced intensity and non-myeloablative in 6, 3 and 1 patient(s), respectively. Six patients received total body irradiation-containing conditioning. The average time to neutrophil engraftment was 18 days (range 11-29), and the average time to platelet engraftment was 26.5 days (range 18-59). One patient had primary graft failure. Of the 6 patients with day 100 disease reassessment (CR at time of alloHCT=5, PR in CNS at time of alloHCT=1), all were in CR. With a median follow-up of 341 days, 2 patients relapsed (CNS=1 and systemic = 1), and 6 patients died. Cause of death included infection (n=3), lymphoma (n=1), primary graft failure (n=1), and organizing pneumonia (n=1). Six patients developed acute graft versus host disease (GVHD) (grade 1-2, n=1; grade 3, n=5), and 4 patients developed chronic GVHD (score 1-2, n= 2; score 3, n=2). The median overall and progression-free survival for the entire cohort was 341 days (range 23-4825) and 268.5 days (range 23-4825), respectively. Conclusions: AlloHCT in patients with R/R aNHL with sCNS involvement is feasible and may provide a durable response in a subset of patients. Four patients remained alive and free of disease one year post-alloHCT and one patient converted from a PR to a CR in the CNS 100 days post-alloHCT, suggesting effective donor immune surveillance within the CNS. Transplant-related morbidity and mortality limits the widespread application of this therapeutic modality and less toxic approaches are urgently needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

BACKGROUND GVHD and non-relapse mortality (NRM) remain frequent complications of HLA-matched HSCT despite the use of standard immunosuppression like tacrolimus and methotrexate. Alternative GVHD prophylaxis (PPX) strategies like T-cell depletion and post-transplant cyclophosphamide negatively impact relapse, infection, and organ toxicity, and no strategy has yet demonstrated a clear benefit for GVHD-free survival. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Unlike point-of-care graft engineering approaches, Orca-T is produced in a central GMP laboratory and has been successfully distributed to multiple centers across in the U.S. Early clinical trials using Orca-T showed a good safety profile, promising GVHD control, and potentially improved immune reconstitution. Here, we present trial results from both a single-institution Phase 1/2 trial that has completed enrollment and an ongoing multicenter Phase 1b trial. METHODS As of 28 July 2021, 113 patients aged 18-72 have received Orca-T for AML, ALL, MDS, lymphoma, or myelofibrosis. We present here data from 80 patients that have ≥90 days follow-up. 28 and 52 patients, respectively, received Orca-T followed by single-agent GVHD prophylaxis on a single-center Phase 2 study (NCT01660607) and a multicenter Phase Ib (NCT04013685). Orca-T products were derived from HLA-matched related (n=46) or unrelated (n=34) donors. Patients received a variety of myeloablative conditioning regimens (e.g., non-TBI, n=66; TBI-based, n=14) followed by single-agent PPX with either tacrolimus (n=73) or sirolimus (n=7). Median follow-up for these patients is 541 days (single-center) and 248 days (multicenter). We identified a contemporaneous SOC cohort, and we reported on their clinical outcomes at Stanford (n=95) with both matched related (n=52) and unrelated (n=43) transplant recipients who received unmanipulated PBSC products (median f/u 546) and methotrexate plus tacrolimus prophylaxis. RESULTS The Orca-T investigational cell therapy was manufactured reliably, delivered in less than 72 hours for all patients, and every patient enrolled received Orca-T. The Treg drug product was characterized by high Treg purity of 93.8% +/- 3.1% and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between trials). An Orca-T product was produced and infused for all patients, and there were no logistics failures or infusion reactions. All patients engrafted and Orca-T patients showed earlier neutrophil (median of 12 days vs. 14 days, p On the single-center, Phase 2 clinical trial study at Stanford there is evidence of improved 1-year GVHD and relapse-free survival (GRFS) which was 77% (CI 51-88%) for Orca-T patients vs 34% (CI 25-44%) with SOC (Figure 1A). We observed improved rates of >grade 2 acute GVHD at Day +180 (aGVHD, 14% versus 33%), moderate-to-severe chronic GVHD at 1 year (4% versus 42%) and NRM at 1 year (0% versus 13%). Relapse-free (RFS) and overall survival (OS) trended upwards for Orca-T. Severe infectious complications were rare. Key clinical results from both Orca-T trials are summarized in Table 1; 23 of 80 patients had ≥1 year follow-up. Consistent with findings from the single-institution study, on the multicenter study, rates of moderate-to-severe cGVHD and non-relapse mortality were low at 1-year post-transplant at 3% and 4%, respectively. For all patients who received Orca-T across both studies, we observed GRFS of 72% (Figure 1B), RFS of 78%, and OS of 91% at 1 year. These survival rates compare favorably to the contemporaneous SOC control (33%, 71% and 78%, respectively). Immune reconstitution in Orca-T patients with single agent tacrolimus appears similar to SOC except for observable differences in the IL-2 pathway. CONCLUSIONS Manufacture of high precision Orca-T investigational cell therapy drug products was scaled in a central GMP with reliable distribution to centers. Patients that received Orca-T and single-agent PPX showed significantly reduced aGVHD, cGVHD and NRM. Orca-T shows promise to improve GRFS and other transplant outcomes. Orca-T has been granted Regenerative Medicine Advanced Therapy status by the FDA, and a phase 3 prospectively, randomized study is planned. Figure 1 Figure 1. Disclosures Gandhi: Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees; CareDx Inc: Honoraria. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Mehta: Kadmon: Research Funding; Incyte: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding. McGuirk: Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Bellicum Pharmaceuticals: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding. Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Arai: Magenta Therapeutics: Research Funding. Rezvani: US Department of Justice: Consultancy; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; Kaleido: Other: One-time scientific advisory board. Weng: Kite Pharma: Research Funding. Miklos: Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Allogene Therapeutics: Research Funding. Fernhoff: Orca Bio: Current Employment. Putnam: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy.

Introduction Older adults with AML are often ineligible for high intensity chemotherapy and potentially curative allogeneic hematopoietic cell transplantation (HCT) due to poor performance status at presentation, comorbidities, and/or adverse genetic features associated with refractory disease and chemoresistance. Recently, the lower intensity combination of a hypomethylating agent and venetoclax (HMA/Ven) was shown to achieve durable responses in patients with AML. Despite this combination having been studied primarily in older, transplant-ineligible adults, a small subset of patients on the Phase 1b trial were successfully bridged to HCT (Pratz et al, 2019). We conducted a multi-center analysis assessing patient characteristics and clinical outcomes of patients treated with HMA/Ven who subsequently proceeded to HCT. Methods We retrospectively identified 51 adults who received HMA/Ven in either the front-line or relapsed/refractory (R/R) setting and underwent subsequent HCT between 2017 - 2019 at Stanford University, the University of California, San Francisco, and the University of California, Los Angeles. Patients received either azacitidine or decitabine in combination with venetoclax. Patients were evaluated for efficacy endpoints including: best response prior to HCT (complete remission [CR], CR with incomplete hematologic recovery [CRi], morphologic leukemia-free state [MLFS]), measurable residual disease (MRD) prior to HCT by flow cytometry (sensitivity threshold ≤1x10-4), and post-HCT relapse and survival. Results The median age at HCT was 65.5 years (24 - 76). Fifty-three percent of patients had a KPS of ≤ 80, and 29% had an HCT-CI of ³ 3. Fifty-seven percent had adverse-risk disease by 2017 European Leukemia Net criteria. The majority (63%) received decitabine; 23 (45%) received HMA/Ven as front-line induction and 28 (55%) for R/R disease. Compared to patients with R/R disease, patients who received front-line HMA/Ven were more likely to be older (67 vs 54 years, p = 0.003) and have a KPS ≤ 80 (65% vs 47%, p = 0.03). Patients with R/R disease had a median of 2 (1 - 4) lines of therapy prior to receiving HMA/Ven and 2 patients had undergone prior HCT. The number of HMA/Ven cycles prior to HCT varied considerably, with a median of 3 (1 - 11). The majority (78%) of patients achieved a complete remission prior to HCT. Of the patients who received front-line HMA/Ven, 83% achieved CR, 13% CRi, and 4% MLFS; 17 (74%) patients had a pre-HCT MRD assessment, of which 71% were MRD-negative. Of the patients who received HMA/Ven for R/R disease, 41% achieved CR, 22% CRi, 33% MLFS, and 4% had refractory disease; 24 (86%) of patients had a pre-HCT MRD assessment, of which 54% were MRD-negative. Across the full cohort, 49% of patients received non-myeloablative, 35% myeloablative, and 16% reduced intensity conditioning. The majority (94%) of patients received peripheral blood stem cell grafts; donor sources were 35% HLA-matched related, 43% HLA-matched unrelated, and 22% haploidentical. Following HCT, 100-day non-relapse mortality was 4%, 6-month overall survival (OS) was 85% and 6-month relapse-free survival (RFS) was 63%. Among patients who received front-line HMA/Ven, 6-month OS was 88% and 6-month RFS was 80%; among patients with R/R disease, 6-month OS was 81% and 6-month RFS was 51%. Patients who were MRD-negative had a 6-month OS of 87% and RFS of 75%; MRD-positive patients had 6-month OS of 73% and RFS of 46%. Among the 27 patients transplanted prior to July 1, 2019, 1-year OS and RFS were 78% and 59% for the entire cohort, 90% and 80% for the 10 patients receiving frontline HMA/Ven, and 71% and 47% for the 17 patients with R/R disease. Conclusion In patients with AML, an HMA in combination with venetoclax can achieve complete remissions-MRD-negative in many cases-thus providing a viable pathway to potentially curative HCT. This treatment pathway is especially important in older/unfit patients receiving front-line HMA/Ven due to ineligibility for high intensity induction chemotherapy, as well as those with relapsed/refractory and previously chemoresistant disease. Following HCT, patients treated in both settings had low NRM and favorable rates of disease response. Prospective studies are warranted to further explore the optimal use of HMA/Ven therapy as a bridge to successful transplant outcomes. Disclosures Muffly: Amgen: Consultancy; Adaptive: Research Funding; Servier: Research Funding. Logan:Abbvie: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Amphivena: Research Funding; Autolus: Research Funding; Jazz: Research Funding; Kadmon: Research Funding; Kite: Research Funding; Pharmacyclics: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

Introduction: Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, phase II study of Tafasitamab (TAFA) plus lenalidomide (LEN) in patients with relapsed/refractory (R/R) DLBCL ineligible for autologous stem cell transplantation (ASCT). A durable progression-free survival of 16 months in a poor-risk subgroup of patients treated with TAFA plus LEN was recently presented (Salles et al., 2019 ICML Meeting. Abstract 124). Treatment with CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown promising results for patients with R/R DLBCL after failure on ≥ 2 lines of systemic therapy (Neelapu S, et al. N Engl J Med 2017). Despite recent advances in anti-CD19 therapy, relapse remains frequent after each treatment modality. There is no clinical evidence to direct the sequencing of CAR T cell therapy after anti-CD19 therapy. Here, we present the first published case of an outcome after anti-CD19 antibody treatment TAFA/LEN as part of the L-MIND trial, followed by anti-CD19 CAR T therapy. Case Presentation: The patient is a 58 year old female who initially presented in March 2013 with an 8 cm mesenteric mass, workup revealed stage III germinal center B cell-like (GCB) DLBCL arising from follicular lymphoma, Ki-67 proliferation index 80%, and IGH/BCL2 fusion. The patient received 6 cycles of dose-adjusted R-EPOCH. Despite achieving a complete remission (CR) to this frontline therapy, the patient experienced disease relapse within two years. Subsequently, the patient received rituximab plus ifosfamide, carboplatin, and etoposide (RICE) chemotherapy, to which a second CR was achieved. The patient declined ASCT. Second relapse occurred approximately two years later. After meeting eligibility criteria, she was enrolled in the L-MIND trial in October 2017 and received TAFA plus LEN for 6 cycles (1 cycle = 28 days; TAFA 12mg/kg intravenously, weekly x 3 cycles, biweekly thereafter; LEN 25mg daily on days 1-21 of each cycle). TAFA/LEN was well tolerated. Stable disease was achieved with this investigational regimen, followed by progression in April 2018. Fourth-line treatment consisted of rituximab, gemcitabine, oxaliplatin, (R-GEM-OX) for 4 cycles, to which the patient had a partial response. Shortly thereafter, the patient received anti-CD19 CAR T therapy (axicabtagene ciloleucel [Yescarta]) in September 2018 (Figure 1). Treatment course was complicated by grade 2 cytokine release syndrome. A complete response was achieved one month after treatment, and has been sustained since then. As of this report (July 2019), patient remains without clinical evidence of relapse. Discussion: An important question to address in the era of targeted cellular therapy is: can the same tumor antigen be targeted with a different cancer immune therapy modality after disease progression following a previous therapy against that same antigen? In such a clinical scenario, there is concern for sustained antigen blockade from the prior line of therapy. In addition, there is concern for the selective pressures of prior therapy targeted against a specific antigen allowing for progression of a clone that does not express that antigen, rendering subsequent therapy against the same target ineffective (antigen escape). The half-life of TAFA is approximately 16 days, suggesting that it was eliminated prior to CAR T-cell infusion five months later. Although a biopsy was not done upon progression after TAFA, we assume that CD19 antigen escape did not account for the relapse, since the patient has achieved sustained remission with subsequent anti-CD19 CAR T cell therapy. Therefore, disease progression following treatment with anti-CD19 monoclonal antibody Tafasitamab may not preclude patients from anti-CD19 CAR T cell therapy, despite previously targeting the same antigen. Figure 1 Disclosures de Vos: Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy.