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Introduction: Initial studies from Wuhan, China reported patients infected with SARS-CoV-2 have uncontrolled coagulopathy and an increased risk for thrombotic complications, including pulmonary embolism (PE), deep vein thrombosis (DVT), and arterial thrombosis.1 The incidence of thrombosis attributed to coronavirus disease 2019 (COVID-19) ranged from 9.5% in all hospital-admitted patients to 31% in the critically ill.2,3 COVID-19 has had a major impact on the Chicago metropolitan area with over 121,000 confirmed cases as of August 2020, Cook county being the 4th highest affected county after Maricopa, Miami-Dade and Los Angeles counties.4 The primary goal of this study is to describe the rate of thrombotic events in the Chicago metropolitan area, highlighting an ethnically diverse population, and identify new risk factors for thrombosis between three university health systems. Methods: We conducted a retrospective analysis between three university health systems in the Chicago metropolitan area: Loyola University Health System (LUHS): comprised of one tertiary and two community hospitals, Rush University System for Health (RUSH): comprised of one tertiary and two community hospitals, and University of Illinois-Chicago (UIC): a tertiary hospital. All patients had positive SARS-CoV-2 testing and were hospitalized for COVID-19. PE, DVT or arterial thrombosis were confirmed by supportive imaging modalities. Wilcoxon rank sum test were used to test the associations of continuous variables; Chi-square test or Fisher's exact test were used to test the associations of categorical variables. All analyses were performed with SAS 9.4 and two-sided p-value < .05 were deemed statistically significant. Results: Between March and May 2020, 2,180 patients from LUHS, RUSH and UIC were hospitalized for COVID-19 and were included in our analysis. Baseline patient demographics are described in Table 1. Race/ethnicity demographics are as follows: Hispanics (H)/ African Americans (AA) represented 47%/17% of LUHS patients, 32%/42% of RUSH patients, and 36%/51% of UIC patients, respectively (Figure 1). Intensive care admissions were needed in 33% of all patients. Documented total thrombotic events are as follows: LUHS = 5.4% (41 VTE/PE, 10 arterial and 5 with both venous and arterial); RUSH = 9.7% (70 VTE/PE, 7 arterial and 4 with both venous/arterial); UIC = 6% (14 VTE/PE, 4 arterial and 0 with both venous/arterial). Patients that developed a thrombotic event were similar by age, sex, and BMI to those without a thrombotic event. Anticoagulation prophylaxis was given to 82% of pts at LUHS and UIC at time of admission. Collectively, those with thrombotic events (N=156) had higher incidence of intensive care admission, elevated white blood cell (WBC) count and a d-dimer >5X upper limit normal (ULN) at presentation. Furthermore, a higher proportion of pts that had a thrombotic event were diabetic at LUHS and RUSH (Table 2). Mortality in COVID-19 patients was 13-16% and patients that had a thrombotic event had a higher risk of death in the RUSH and UIC cohorts. Conclusions: In a racially diverse, multi-institutional cohort of patients, we demonstrate that 7.2% of COVID-19 patients had a thrombotic event. Consistent risk factors for thrombosis across the different centers included an initial d-dimer levels >5X ULN, elevated initial WBC count, diabetes, and being critically ill. Mortality differences and anticoagulation practices between the institutions as well as race/ethnicity differences regarding thrombosis will be explored in future combined multivariate analyses. Finally, based off these risk factors, identification of patients at most risk for thrombosis is needed to reduce the morbidity and mortality when diagnosed with COVID-19. References -Tang et. al. J Thromb Haemost. 2020;18:844-847. -Klock et. Al. Thrombosis Research 2020;191:145-147. -Al-Samkari H, Laef RS, Dzik WH et. Al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500. -https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/county-map.html; accessed 8/7/20. Disclosures Arain: Astellas: Other: Spouse is employed. Stiff:Macrogenics: Research Funding; Delta-Fly: Research Funding; Unum: Research Funding; Atara: Research Funding; Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Gamida Cell: Research Funding. Saraf:Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Pfizer, Global Blood Therapeutics, Novartis: Research Funding.

Introduction: Liposomal daunorubicin/cytarabine (Vyxeos®) is a dual drug liposomal encapsulation of cytarabine and daunorubicin, delivering drugs at a fixed 5:1 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, liposomal cytarabine/daunorubicin (lipo-cytara/dauno) patients had improved survival and remission rates in a pivotal phase III study of elder adults with high-risk acute myelogenous leukemia (AML). Furthermore, more lipo-cytara/dauno patients went to allogeneic stem cell transplantation (HCT), with lower mortality and improved survival compared to those induced with 7+3. With its enhanced pharmacokinetics, lipo-cytara/dauno may provide a potent bridge to transplant. We report our experience using lipo-cytara/dauno as a bridge to same donor lymphocyte infusion (DLI) or different donor HCT in high-risk AML. Methods: We retrospectively reviewed all patients who received lipo-cytara/dauno at our institution since the FDA approval in August 2017. Of the 21 patients who have been treated, 9 received it as a bridge to cell therapy. All patients received the drug by usual means under the FDA label. Results: The median age of the 9 patients who received lipo-cytara/dauno as a bridge to cell therapy was 59 years. Seven were male, and two were female. Patients had had 1-4 prior lines of chemotherapy (median 2) with 7 of 9 patients having received prior standard 7+3 induction (cytarabine 100-200 mg/m2 x 7 days infusion and daunorubicin 60-90 mg/m2 x 3 days). Most had adverse cytogenetics, and all 9 patients received full lipo-cytara/dauno induction (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy [Table]. Of the 9 patients, 6 had AML with very early relapse after HCT, with median time to relapse of 4 months (range 3 to 7 months). All 6 successfully proceeded to their planned cell infusion: 5 received same donor DLI after melphalan at 140 mg/m2, and 1 underwent second HCT from a different donor with busulfan/fludarabine conditioning at Days 15-40 after lipo-cytara/dauno. Of the remaining 3, two had relapsed AML after an initial remission (one was in first complete remission (CR1) for 3 months after 7+3/midostaurin induction and the other was in CR1 for 7 months after 7+3 induction/high dose cytarabine consolidation) and one had primary refractory disease (PREF) after 7+3 and azacitidine/venetoclax induction regimens. All 3 successfully underwent first HCT at Days 15-100 days after lipo-cytara/dauno bridge. The PREF patient received fludarabine/cyclophosphamide/TBI conditioning followed by matched unrelated donor transplant. Of the 2 with relapsed AML after initial remission, one received busulfan/fludarabine/thiotepa conditioning followed by umbilical cord stem cell transplantation and the other patient received fludarabine/cyclophosphamide/TBI conditioning prior to matched related donor transplant. Six of 9 had Day 14 bone marrow biopsies after lipo-cytara/dauno: 2 were in CR, 2 had >80% cytoreduction, and 2 had similar blast count. Three with persistent disease underwent reinduction with lipo-cytara/dauno (Days 1 and 3) and proceeded straight to cell therapy after. Median days to hospitalization after outpatient lipo-cytara/dauno was 6 days (range 3 to 14 days). Four out of 9 patients remain alive. Two were very early post HCT relapses (relapsed at 3 and 6 months post-HCT), both of which are remarkably in CR at 14 and 17 months after second cell therapy. Interestingly, both had CNS relapse, which were successfully treated, and both remain alive and in remission today. The other two had relapsed AML and PREF AML and underwent first HCT after lipo-cytara/dauno bridge. They remain alive and in remission at 1 and 8 months. Conclusion: In this retrospective study, outpatient lipo-cytara/dauno as a bridge to cell therapy is feasible and effective in very high-risk AML with no other viable options. While preliminary, survival appears favorable to that reported elsewhere at 14-23% at 1 year in this poor risk group, including those with adverse cytogenetic and/or very early post-HCT relapse. Prospective multi-center trials are planned to further evaluate lipo-cytara/dauno as a bridge to DLI/HCT in those with early relapse post-HCT and in those with refractory disease, with therapy to include CNS prophylaxis. Disclosures Stiff: Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Tsai:Jazz pharmaceuticals: Speakers Bureau; Jazz pharmaceuticals: Consultancy.

Introduction: Chimeric antigen receptor (CAR) T cells targeting either CD19 or CD22 have yielded striking complete remission (CR) rates of 70%-90% in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), but CD19 negative and CD22 low relapse limits the curative potential of these single-antigen CAR T cell approaches. We hypothesized that a bivalent CAR-T construct that can target CD19 and/or CD22 would prevent antigen negative/low relapse. Here we present the combined single institution experience to date of pediatric and adult patients with R/R ALL treated with this novel bispecific CAR. Methods: We conducted parallel Phase I clinical trials of CD19/CD22 bispecific CAR T cells in pediatric and adult patients with relapsed/refractory ALL. We utilized lentiviral transduction of a bivalent CAR construct incorporating the fmc63 CD19 and m971 CD22 single chain variable fragments (scFvs) and a 41BB costimulatory endodomain. After lymphodepletion with fludarabine and cyclophosphamide, patients were infused with fresh or cryopreserved CAR T cells manufactured using a 7-11 day process. Two dose levels were tested during dose escalation: Dose level 1 was 1x106 CAR T cells/kg and dose level 2 was 3x106 cells/kg. Primary objectives assessed the ability to successfully manufacture CAR19/22 CAR T cells and safety while response at Day 28 post-infusion was a secondary objective. Blood, bone marrow and cerebrospinal fluid samples were obtained at protocol defined intervals for correlative biology studies. Results: Nineteen patients have been enrolled (10 pediatric; 9 adult) with a median age of 23 years (range, 2-68) and median of 4 (range, 2-11) prior lines of leukemia-directed therapy. Ten patients received prior HCT, 9 were treated with prior Blinatumomab, 3 with prior CD19 directed CAR T cells and 4 with prior Inotuzumab. Fourteen patients (8 pediatric, 6 adult) have been infused to date with CD19/CD22 bispecific CAR T cells; 7 were treated at dose level 1 (DL1) and 7 at dose level 2 (DL2). Successful manufacturing of cells at target dose levels was achieved in all patients. Twelve patients have reached day 28 and are included in the safety and response analysis presented here. Nine of 12 (75%) experienced cytokine release syndrome (CRS) and 2/12 (17%) developed immune-effector cell neurotoxicity syndrome (ICANS). The CRS and ICANS were all grade 1 or 2 across both dose levels and across pediatric and adult patients except for one adult with high disease burden who experienced grade 4 CRS and grade 4 ICANS, both of which were reversible. No differences in toxicities were seen across the patient age spectrum and there were no cases of treatment-related mortality within 28 days following CAR T infusion. Eleven of 12 (92%) patients achieved a CR, 10 of whom achieved CR at day 28 and one with a PR of extramedullary disease at day 28 which improved to CR by day 180 without further leukemia-directed intervention. One patient had primary progressive disease prior to day 28. Peak CAR expansion as detected by peripheral blood flow cytometry reached a median level of 11.13% (DL1) and 29.1% (DL2) CAR T of CD3+ cells with a range of 0.7-22.54% and 3.8-86.96%, respectively. To date, 3 patients (1 pediatric and 2 adult patients) have relapsed, all with retention of CD19. Post-remission practice differed across pediatric and adult patients; Six pediatric patients reaching day 28 underwent consolidative hematopoietic cell transplantation (HCT) whereas no adult patients received subsequent HCT. One patient died from complications post HCT while in remission. Therefore, the overall survival for all infused patients was 92% with a median follow-up of 9.5 months from time of infusion (range, 1-20). Conclusion: The combined pediatric and adult phase I trials of bispecific CD19/CD22 targeting CAR T cells in relapsed/refractory ALL demonstrates safety and tolerability at two dose levels. Expanded accrual at dose level 2 is ongoing and clinical outcomes will be updated. This work additionally demonstrates feasibility of delivering unified B-ALL CAR T cell therapy across age boundaries. Multi-parametric CyTOF studies permitting CAR T cell phenotyping in conjunction with single cell TCR tracking, proteomics, epigenomics and cytokine profiling are ongoing and will be used to further characterize persisting CAR T cells and define inter-product and inter-patient variability. Disclosures Muffly: Pfizer: Consultancy; KITE: Consultancy; Adaptive: Research Funding. Majzner:Xyphos Inc.: Consultancy; Lyell Immunopharma: Consultancy. Feldman:Octane Biotech, Inc.: Employment; Personalized Medicine Initiative Science: Membership on an entity's Board of Directors or advisory committees. Miklos:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Becton Dickinson: Research Funding; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; AlloGene: Membership on an entity's Board of Directors or advisory committees. Mackall:Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board; Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Introduction: The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (Axi-cel) improved long-term survival of patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the pivotal ZUMA-1 trial indicates a 2-year PFS of ~40% (Locke, Lancet Oncology 2018). Early identification of patients with increased relapse risk may allow for early intervention and improved outcomes. In a pilot study of 6 ZUMA-1 patients, minimal residual disease (MRD) evaluation via a next-generation sequencing MRD assay (Adaptive Biotechnologies, Seattle, WA) to assess for circulating tumor (ct)DNA, mirrored clinical outcome as assessed by PET-CT (Hossain et. al. Leukemia & Lymphoma 2019). Based on these promising results, a multi-institutional prospective study utilizing cell-free MRD assessments to predict outcomes in r/r DLBCL patients after Axi-cel therapy was initiated. Methods: To identify tumor clonotype(s), tumor DNA extracted from archival paraffin-embedded tissue underwent PCR amplification of IgH-VDJ, IgH-DJ and IgKappa/Lambda regions using universal consensus primers. CtDNA levels were measured pre-LD, 0, 7, 14, 21, 28, 56, 90, 180, 270, and 365 days following Axi-cel infusion. PET-CT scans were obtained at baseline, Day 28, Month 3, 6, and 12 with response assessed per Lugano criteria. Deauville 1-3 was considered PET-negative. The protocol prespecified that patients with less than Day 28 follow-up be excluded from analysis. Any detectable ctDNA was considered MRD positive. Results: Here we report on the pre-planned analysis of the first 50 study patients with at least a Day 28 MRD assessment and 3 months of follow up. An additional 4 patients with at least 3 months of follow-up but who did not have a Day 28 MRD assessment were also included. Baseline characteristics and clinical outcomes of patients were similar to ZUMA-1 and a real-world analysis of 295 patient who received Axi-cel (Nastoupil et al ASH 2018). The median age was 61 years old (range 19-76) (53.7% male, 46.3% female) and 59% of patients received 3 or more prior lines of therapy (range 1-6). After a median follow-up of 7.5 months, the best overall response rate was 87% (47 of 54) and complete response rate was 57% (31 of 54). The median OS was not reached and median PFS was 4.6 months (panel A). At Day 28, 56% (28 of 50) of patients were MRD negative (MRD-neg) and 44% (22 of 50) were MRD positive (MRD-pos). As compared to MRD-pos, MRD-neg correlated with improved median PFS (not reached vs. 2.96 months, p Conclusion: MRD monitoring using high-throughput sequencing of ctDNA has the potentially to make an impact on the clinical management of patients undergoing Axi-cel therapy. Furthermore, ctDNA is an informative tool to compare CAR19 therapies that vary by costimulatory domains or production methods. This technology potentially overcomes fundamental limitations of DLBCL imaging (cost, radiation exposure & limited repetition) and may minimize the need for surveillance PET-CT scans. These results provide a rationale for designing MRD-based risk-adaptive CAR T cell clinical trials. Figure Disclosures Kirsch: Adaptive Biotechnologies: Employment. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Mullins:Adaptive Biotechnologies: Employment. Lee:Adaptive Biotechnologies: Employment, Equity Ownership. Mackall:Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board; Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Miklos:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding.

Autologous CD19 directed CAR T-cell therapy has response rates of >70% in adult acute lymphoblastic leukemia (ALL) and >40% in adult diffuse large B cell lymphoma (DLBCL). Large trials (ZUMA-1/JULIET/TRANSCEND) have highlighted that many patients fail to achieve durable responses. Several groups have reported on the phenomenon of CD19 immune escape as a cause (Grupp et al, NEJM 2013, Neelapu et al, NEJM 2017) and the NIH Pediatric Oncology Branch has shown CD22 as an alternative target (Fry et al, Nat Med. 2018). We developed a bi-specific CAR construct targeting CD19 & CD22 with intracellular signaling domains incorporating 4-1BB and CD3ζ (CD19/CD22.BB.z) to overcome CD19 immune escape. Here, we present our Phase I experience with this bi-specific CAR in adults. This is a single institution phase I dose escalation study enrolling patients Age ≥ 18 years with relapsed/refractory B-ALL or DLBCL after standard therapies. Primary aim is to determine feasibility of manufacturing the bi-specific CAR and safety at three dose levels (1 x 106 CAR T cells/kg, 3 x 106 CAR T cells/kg, 1 x 107 CAR T cells/kg). Clinical response was evaluated as a secondary endpoint utilizing standard response criteria for ALL and DLBCL. All patients underwent lymphodepletion with cyclophosphamide (500mg/m2 daily x3 doses) and fludarabine (30mg/m2 daily x 3 doses) followed by CAR infusion two days later. Patients were assessed at pre-defined time-points (Day 28, Month 3, 6, 9, 12 then every 6-12 months) with correlative assessments including immunophenotyping, single cell RNAseq, CAR qtPCR, serum and single cell cytokine analysis. Seven adult patients (5 DLBCL, 2 ALL), aged 35 - 75 years have been enrolled and 6 treated, all at dose Level 1 [Table 1]. The first 3 patients received freshly harvested cells and the remaining received cryopreserved cells (1 patient treated twice received initial fresh then cryopreserved product). None received systemic bridging therapy before CAR T infusion. Six patients developed reversible cytokine release syndrome (CRS,4 with Grade 1, 2 with Grade 2), onset between Day 1 to 13, and 2 patients received tocilizumab & systemic steroids. Three patients developed neurotoxicity (1 with grade 2, Day 8-11 and the others grade 1) with grade 2 neurotoxicity managed with steroids. Four patients required growth factor support beyond Day 28 and all treated patients show persistent B-cell aplasia. Two patients achieved CR: an ALL patient with disease in bone marrow/blood/CNS was MRD negative at day 28 & 60; a 75yo DLBCL patient achieved PR at day 28 and CR at month 3. Three others have ongoing PR and one died of progressive disease after initial PR at Day 28. A patient with PD at Day 28 subsequently treated with radiation and 2-months of revlimid/rituximab, now has no detectable disease 6 months post CAR-T. One patient with initial 6-month PR received a second infusion due to PD, did not develop CRS or CRES with 2nd infusion and has SD at Day 28 Notably, the patient experienced a lack of CAR-T expansion with the second infusion, raising the possibility of an immunogenic response to the CAR-T cell infusion. Flow analysis of all patients' peripheral blood showed CAR expansion peaked at median Day 13 (range Day 10-20) and CARs remained detectable [Figure 1]. Multi-parametric CyTOF phenotyping of the CAR19-22 products showed significant numbers of transduced CAR-T memory stem cells (phenotype: CD3+CD8+CD45RA+CD127+CD27+CCR7+). Single cell cytokine secretion analysis (Isoplexis,Rossi et al Blood 2018) revealed high polyfunctional strength index (PSI) in both CD4+ and CD8+ cell subsets in each patient's pre-infusion CAR product that reflected phenotypic expansion in patients. Additional correlative studies, including cytokine analysis, qtPCR based CAR quantification and CyTOF phenotypic analysis of the CAR-T cells will be presented. This first adult phase I trial of bi-specific CAR targeting CD19 & CD22 shows low toxicity with promising efficacy including achievement of CR in adult DLBCL and ALL patients. We have escalated dose to 3x 106 CAR T cells/kg and an expansion study of 60 patients will follow. CAR-T cells expanded within the first 20 days and continue to be detectable through 6 months. Disclosures Muffly: Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding. Miklos:Janssen: Consultancy, Research Funding; Genentech: Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Kite - Gilead: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Background: Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR-T), showed significant clinical responses in patients with relapsed-refractory large-B cell lymphomas in the Zuma-1 trial (Neelapu et al, NEJM 2017). Zuma-1 analysis showed blood CAR-T cell expansion was associated with clinical response and toxicity. Herein, we report on 25 patients treated with commercial axi-cel and describe CAR-T expansion by immunophenotyping and its correlation with clinical outcomes. Methods: Twenty-five patients with aggressive lymphoma consecutively apheresed at Stanford University prior to June 30, 2018 were studied on an IRB approved biorepository-clinical outcome protocol. Cytokine release syndrome (CRS) was graded by Lee criteria (Blood 2014) and neurotoxicity according to Neelapu et. al (Nat. Rev. Clin. Onc. 2017). CAR-T cell immunophenotyping was assessed by peripheral blood flow cytometry on days 7, 14, 21 and 28 and then monthly. CAR-T cells were identified by gating on singlet+, live+, CD45+, CD14-, CD3+, anti-CD19-specific CAR mAb (clone 136.20.1; Jena et. al Plos 2013) and characterized as either CD4+ or CD8+. Results: Of 25 apheresed patients, 3 patients died prior to axi-cel infusion due to progressive lymphoma. Of 22 infused patients, 14 (64%) would have been eligible for the Zuma-1 trial. Reasons for ineligibility included symptomatic DVT (n=2), renal insufficiency (n=1), transaminitis (n=1), thrombocytopenia (n=1), MDS (n=1), pleural effusion (n=1) and 1 was ineligible by multiple criteria. Median time from initial clinic visit to infusion was 47 days (range 34-117); median time from apheresis to infusion was 22 days (range 19-38). Nine patients received bridging therapy prior to lymphodepletion chemotherapy (chemo = 4, radiation = 2, high dose dexamethasone = 3). Axi-cel infusion occurred in hospital and patients were followed expectantly for a minimum of 7 days or until adverse events resolved to Ninety-five percent of patients developed CRS (Grade 2 = 73%, none ≥Grade 3). Median number of tocilizumab doses was 1 (range 0-4). Neurotoxicity occurred in 64%, Grade 3 or 4 in 27%. Corticosteroid therapy was required in 82% (77% received both tocilizumab and steroids). Median duration of steroids was 8.5 days (range 1-30); 12 patients required at least 1 week and 4 patients ≥2 weeks. Of patients infused, complete response (CR) at day 28 was 45% (ORR 86%). Of 15 patients evaluable at 3 months, ORR was 53% (CR = 7, PR = 1) and 47% progressed, similar to Zuma-1. Ineligibility for Zuma-1 was not associated with inferior outcomes. Overall, median day 7 peak in vivo axi-cel expansion using anti-CAR19 flow cytometry was 38 CAR-T/ul (Fig. 1A), matching RT-PCR measured levels reported in Zuma-1. As shown in Fig. 1A, the majority of CAR-T cells were CD8+. Patients with Grade 2 CRS had significantly higher peak expansion of CAR-T cells (both CD4+ and CD8+) as compared to those with either Grade 0 or 1 CRS (Fig. 1B). Grades 2-4 neurotoxicity were significantly associated with peak total and CD8+ CAR-T but not CD4+ (Fig. 1B). Illustratively, 2 patients with the most robust CAR-T expansion (▪, ▼ Fig. 1A) experienced Grade 4 neurotoxicity including status epilepticus requiring multiple anti-epileptics and intubation. Peak CAR-T expansion in blood did not correlate with CR or ORR at day 28; expansion did not differ between patients who did or did not require steroids. Fine needle aspirates (FNA) on a subset of patients with FDG-avid lymph nodes 2-3 days post axi-cel showed significant CAR-T expansion within the node despite low detectable circulating CAR-T. Figure 1C depicts a 76-year-old male with double expressor DLBCL who attained a CR at day 28; day 14 blood CAR-T expansion was below average (6 CAR-T/ul), while his day 2 FNA showed >35% of CD3+ T-cells expressed CAR19. As of submission, 34 patients were apheresed and updated blood and FNA results will be presented. Conclusion: Our analysis of 22 infused axi-cel patients showed an ORR of 86% and CR of 45%, despite 36% Zuma-1 ineligibilities and steroid use in 82%. Blood CAR-T expansion was associated with both CRS and neurotoxicity but not clinical response. Detection of high concentration of CAR-T cells in affected lymph nodes 2 days post infusion suggests quantification of CAR-T cells at disease sites could be predictive of clinical responses. J.Y.S and B.S are co-first authors Disclosures Latchford: Kite a Gilead Company: Speakers Bureau. Muffly:Adaptive Biotechnologies: Research Funding; Shire Pharmaceuticals: Research Funding. Miklos:Kite - Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding.

Introduction: Autologous anti-CD19 chimeric antigen receptor T cells (CAR19) have shown dramatic clinical responses in relapsed-refractory large B cell lymphomas, but more than 50% of patients will have disease progression. Here we characterize the observed mechanisms of treatment failure following Axicabtagene Ciloleucel (Axi-cel) therapy. Methods: Sixty-nine patients with refractory large B cell lymphoma were referred for CAR19 therapy from October 2017 to June 2018. The WHO diagnosis and B cell antigen expression on lymphoma cells were assessed by immunohistochemistry and/or flow cytometry before and at the time of progression. We assessed peripheral blood CAR-T cell numbers at Days 7, 14, 21, and 28 by flow cytometry immunophenotyping and monitored disease response with PET-CT at Day 28, 3 months, and 6 months post-infusion. Results: Twenty-two patients who received CAR19 therapy, including patients with transformed large B cell lymphoma (N =5), diffuse large B cell lymphoma, not otherwise specified (N =11), high grade B cell lymphoma, not otherwise specified (N = 2), primary mediastinal large B cell lymphoma (N = 2), and high grade B cell lymphoma with rearrangement of MYC and BCL2 or BCL6 (N =2). The Day 28 ORR was 86%: 10 patients had complete response, 9 had a partial response, 1 had stable disease, and 2 had progressive disease. There was no statistically significant difference in age, gender, underlying disease, or number of prior treatment regimens between patients who achieved a clinical response versus those who failed therapy. Both patients (2 of 2) with progressive disease at Day 28 showed dim or partial CD19 expression prior to CAR-T infusion but nonetheless demonstrated robust Axi-cel expansion. In contrast, one patient with Day 28 stable disease showed no CAR-T cell expansion despite intact CD19 expression. Overall, there was no statistical difference in relative or absolute CAR+ T cells in patients who responded versus those who did not at Day 28 (Figure 1). Day 90 response was available for 12 patients with either CR or PR at Day 28. Five patients (26%) developed progressive disease, and 4 of 5 underwent repeat biopsy. Of these patients, 2 had complete loss of tumor CD19 (Figure 2) and another had downregulation of CD19 with variable expression of other B cell antigens. Conclusion: Eight of 22 (36%) of patients who underwent CAR19 infusion did not respond or relapsed after Day 28 response. Five patients (62%) who failed therapy had loss or downregulation of CD19, which emphasizes that single target antigen loss is a common mechanism of CAR-T failure. However, lack of CAR-T cell expansion was noted in multiple patients, suggesting that there may be T cell intrinsic causes of treatment failure. Further studies are necessary to help identify and predict which patients will benefit from targeted immunotherapy. Disclosures No relevant conflicts of interest to declare.

Introduction: Most patients (pts) with diffuse large B cell lymphomas (DLBCL) are cured with first line chemoimmunotherapy including an anthracycline and rituximab. Pts who obtain complete remission (CR) but latter relapse often can be cured with salvage therapy and autologous hematopoietic cell transplantation (auto-HCT). This management paradigm often is applied to pts with primary treatment failure (PTF). However, this group is heterogeneous and detailed data on outcomes in current era is needed to identify the DLBCL pts for whom novel therapeutic strategies should be designed. Methods: Fifteen US academic medical centers contributed pts to the REgistry of diFfuse large B cell lymphoma with prImary treatmeNt failurE (REFINE) collaboration. REFINE retrospectively captured patient, disease and treatment characteristics and treatment response as assessed by treating physician. Eligible pts were ≥ 18 years diagnosed with DLBCL during 2008-2015, who received upfront cheomoimmunotherapy including anthracycline and CD20-directed antibody and developed one of 3 patterns of PTF: relapse < 6 months following CR (early relapse- ER); only partial remission (PR) or stable disease (SD) with upfront therapy (residual disease-RD); progressive disease (PD) while receiving upfront therapy (primary progression-PP). Pts with HIV infection, primary CNS lymphoma or lymphoma transforming from a more indolent histology were excluded. Results: Patient characteristics for the 331 cases are summarized in Table 1. Median follow up of survivors was 18.9 months. R-CHOP was the upfront treatment for 87.6% of pts. Nearly all pts (94.6%) received salvage therapy after PTF and prior to any HCT, with a median of 1 and range 0 to 5 regimens. Response to first salvage regimen was CR in 19.9%, PR in 21.8%, SD in 9.0% and PD in 40.8%. Only 15.1% of pts were enrolled in clinical trials. One hundred and thirty-two pts (39.9%) underwent auto-HCT and 33 (10.0%) allogeneic-HCT (8 after failure of auto-HCT). Two-year overall survival (OS) from time of PTF was 45.5% (95% C.I. 34.5-56.5%) for ER, 30.6% (95% C.I. 20.0-41.2%) for RD and 18.5% (95% C.I. 11.4-25.6%) for PP (P Conclusions: Pts with DLBCL experiencing PTF have poor prognosis but low clinical trial participation even when treated in academic centers. Pts with PP disease, intermediate-high/high NCCN-IPI at time of PTF or with c-myc(+) tumors constitute a UHR category with dismal outcomes on existing therapies. REFINE provides benchmarking for future experimental agents targeting this population. UHR pts represent an unmet medical need and should receive high priority for development of new drugs and cellular therapies. Table 1. Table 1. Figure 1. Figure 1. Disclosures Chavez: Janssen: Speakers Bureau. Reddy:INFINITY: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Karmali:Celgene: Speakers Bureau. Calzada:Seattle Genetics: Research Funding. Barta:Janssen: Honoraria, Speakers Bureau; Celgene, Merck, Seattle Genetics: Research Funding. Lansigan:Spectrum: Consultancy, Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Teva: Research Funding. Flowers:Roche: Consultancy, Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; NIH: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Infinity: Research Funding; Gilead: Consultancy, Research Funding; Millenium/Takeda: Research Funding; ECOG: Research Funding; AbbVie: Research Funding; Mayo Clinic: Research Funding; Genentech: Consultancy, Research Funding. Fenske:Seatle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria; Pharmacyclics: Honoraria. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hamadani:Takeda: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

Introduction: Modern chemoimmunotherapy cures the majority of patients (pts) with newly diagnosed diffuse large B cell lymphomas (DLBCL). The paradigm for pts who relapse has been salvage chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) when chemosensitive disease. This approach is often also applied to pts with primary treatment failure (PTF), although this group is heterogeneous and outcomes of HCT in this population have not been well described. Methods: Fifteen US academic medical centers contributed pts to the REgistry of diFfuse large B cell lymphoma with prImary treatmeNt failurE (REFINE) collaboration. REFINE retrospectively captured patient, disease and treatment characteristics and response as assessed by treating center. Eligible pts were ≥ 18 years diagnosed with DLBCL during 2008-2015, who received upfront therapy including anthracycline and CD20-directed antibody and developed one of 3 patterns of PTF: relapse < 6 months following CR (early relapse- ER); only partial remission (PR) or stable disease (SD) with upfront therapy (residual disease-RD); progressive disease (PD) while receiving upfront therapy (primary progression-PP). Pts with HIV infection, primary CNS lymphoma or lymphoma transforming from a more indolent histology were excluded. Results: Among 331 cases included in REFINE, patterns of PTF were ER in 95 (28.7%), RD in 92 (27.8%) and PP in 144 (43.5%) pts. Salvage therapy was administered to 94.6% of pts. We analyzed the 157 (47.4%) PTF pts who subsequently underwent HCT, 132 auto-HCT and 33 allo-HCT (8 after failure of auto-HCT) (Table). Nearly half of pts were in CR at transplant, after 1-2 lines of salvage therapy. Among all pts receiving auto-HCT, 2-year progression-free survival (PFS) from time of transplant was 38.4% (95% C.I. 29.6-47.2%) and overall survival (OS) 54.9% (95% C.I. 44.9-64.9%). Two-year OS from auto-HCT was affected by pattern of PTF: 71.3% for ER, 55.0% for RD and 41.7% for PP (P=0.05). OS at 2-years was 23.7% for auto-HCT pts with germinal center B (GCB)type,c-myc(+) (by FISH) tumors vs. 66.7% for GCB, c-myc (-), vs. 67.8% for non-germinal center (NGC) (P=0.01). Auto-HCT pts with intermediate-high/high NCCN-IPI at time of PTF had 2-year OS of 28.6% vs. 66.0% for intermediate-low and 80.9% for low risk (P Conclusions: Pts with DLBCL experiencing PTF and 2 or more UHF features have dismal outcome after auto-HCT and should be targeted for experimental modalities of cellular therapy. Outcomes of allo-HCT in DLBCL with PTF are poor, due to rapid and fatal relapses. Table. Table. Figure. Figure. Disclosures Costa: Sanofi: Honoraria, Research Funding. Reddy:INFINITY: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Karmali:Celgene: Speakers Bureau. Chavez:Janssen: Speakers Bureau. Calzada:Seattle Genetics: Research Funding. Barta:Janssen: Honoraria, Speakers Bureau; Celgene, Merck, Seattle Genetics: Research Funding. Flowers:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Mayo Clinic: Research Funding; Acerta: Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Research Funding; ECOG: Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; NIH: Research Funding; Infinity: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding. Fenske:Seatle Genetics: Honoraria; Pharmacyclics: Honoraria; Celgene: Honoraria; Millennium/Takeda: Research Funding. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Hamadani:Takeda: Research Funding.

Background: Mantle Cell Lymphoma (MCL) is a rare sub-type of Non-Hodgkin's Lymphoma (NHL). Outcomes of secondary MCL (sMCL) in patients with a prior diagnosis of a solid malignancy as compared to de novo MCL are not well understood. Differences may be attributable to age, gender, race/ethnicity, extra-nodal involvement, and stage at initial diagnosis. We sought to determine differences in outcome by analyzing data from a large nationwide cancer registry. Methods: The Surveillance Epidemiology and End Results (SEER) database (1973-2012) was used to detect MCL (ICD-O-3 code: 9673/3) adult (>18 years) cases. The variable "First Malignant Primary Indicator" was used to differentiate between de novo and sMCL cases. Primary solid malignancy subtypes categorized included prostate, breast, colorectal, lung bladder, renal, head and neck, thyroid, testicular, and endometrial cancer. Selected sMCL cases included patients with a diagnosis of a primary solid malignancy with a latency period ≥ 2 months. Overall survival (OS) was calculated using the cox regression model to determine the impact of sMCL on survival, adjusting for age at diagnosis, race/ethnicity, primary solid malignancy subtype type and latency period. Chi square test was utilized to ascertain for any significant difference between de novo MCL and sMCL cases. Results: Overall, 8,889 patients were included: 875 (9.8%) sMCL and 8,014 (90.2%) de novo MCL cases. For de novo MCL, 67.1% were males. Race/ethnicity in descending frequency consisted of Non-Hispanic Whites (NHW) (81.8%), Hispanics (8.4%), Blacks (4.4%), Asian and Pacific Islanders(API)(4.1%) and American Indian/Native Indian (AI) (0.4%). The most frequent stage at initial diagnosis for de novo MCL was stage IV (57.9%) followed by stage III (13.4%), stage II (8.1%) and stage I (10.0%). Males consisted of 75.4% of sMCL cases. Cases of sMCL categorized by race/ethnicity in descending frequency were NHW (87.3%), Hispanics (5.1%), Blacks (4.2%), API (3.2%) and AI (0.1%). Stage at diagnosis for sMCL was most frequently stage IV (54.6%), followed by stage III (15.8%), stage II (10.9%) and stage I (11.7%). Compared to de novo MCL, sMCL cases were more likely to occur in patient's ≥75 years (48.3% vs. 28.7%, p Conclusion: Our analysis demonstrates that elderly age appears to be significantly more common in sMCL cases as compared to de novo MCL. By contrast, race/ethnicity, and extra-nodal involvement were similar between the two groups. Survival was worse in sMCL compared to de novo MCL. This may be due to differences in treatment preferences. Further studies are necessary to elucidate the etiology for such differences in outcomes. Disclosures Kropf: Teva Pharmaceuticals: Consultancy.

Background: Nodular Lymphocyte Predominant Hodgkin’s Lymphoma (NLPHL) is an uncommon subtype of Hodgkin’s Lymphoma. The risk for secondary primary cancers is not well understood. Methods: The Surveillance Epidemiology and End Results (SEER) database was used to identify cases of NLPHL diagnosed up to 12/31/2011. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cases of secondary primary malignancies based on incidence data in the general United States population. The latency exclusion period from the date of diagnosis was 60 months. We also investigated for possible modifying effects of gender, age at diagnosis (20-39 years of age and ≥ 40 years of age), use of radiation therapy, and latency periods (5-10 years and >10 years) after initial diagnosis of NLPHL. Results: A total 947 cases of NLPHL were present in the database. Secondary primary cancer cases occurred in 64 cases with 36 (56.3%) solid tumors and 28 (43.8%) hematological malignancy cases. Radiation was administered in 38 (59.4%) of secondary primary cancer cases. Females had an increased risk of Non-Hodgkin’s Lymphoma (NHL) (SIR: 13.86, p10 years, after the initial diagnosis, was associated with increased risk of “All Solid Tumors” (SIR: 2.62, p Conclusion: NLPHL is associated with an increased risk of secondary primary cancers, both solid and hematological malignancies. Thyroid cancer and NHL were the most frequent tumors observed in patients ten years after initial NLPHL diagnosis. Radiation treatment for NLPHL increased the risk for solid tumors, including colorectal cancer. Further research is necessary to clarify optimal surveillance technique in patients after treatment of NLPHL. Disclosures No relevant conflicts of interest to declare.