ALBERT

Description: Introduction: Despite the curative intent of the R-CHOP regimen in the first-line treatment of diffuse large B-cell lymphoma (DLBCL), 35-40% of patients who received R-CHOP will eventually succumb to their disease (Coiffier, et al. Blood 2010; Sarkozy and Sehn. Ann Lymphoma 2019). As such, improved treatments are needed. Mosunetuzumab (Mosun) is a T-cell-engaging bispecific antibody that redirects T cells to eliminate malignant B cells by binding to CD3 on T cells and CD20 on B cells. Mosun monotherapy has a manageable safety profile and promising efficacy, including durable complete responses (CR), in patients (pts) with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL) (Schuster, et al. ASH 2019). This is the first report describing the safety and efficacy of Mosun plus CHOP (M-CHOP) in pts with R/R NHL and newly diagnosed DLBCL in the ongoing GO40515 (NCT03677141) study. Methods: Pts with R/R NHL and with newly diagnosed DLBCL received six 21-day cycles of M-CHOP. In Cycle (C) 1, Mosun was administered in step-up doses on Day (D) 1 (1mg), D8 (2mg), and D15 (13.5mg and 30mg in R/R NHL; 30mg in newly diagnosed DLBCL) to mitigate cytokine release syndrome (CRS). Full dose Mosun (C1D15 dose) was given on D1 of subsequent cycles in addition to CHOP. Interim and primary response assessments were obtained after C4 and C6, respectively. Primary prophylaxis with granulocyte colony-stimulating factor was mandatory for all pts. Pts with a partial response or stable disease at the end of C6 could continue Mosun monotherapy for up to 11 additional cycles. Response rates were based on the Lugano criteria (Cheson, et al. J Clin Oncol 2014). Results: As of June 3, 2020, 43 pts had received M-CHOP: seven patients with R/R NHL, and 36 pts with newly diagnosed DLBCL. Pts with disease stage II-IV were enrolled, with a median IPI score of 3 (range: 2-4) and ECOG performance status between 0 and 2. Median age was 66 (range: 39-87) and 17 pts (42%) were female. In pts with R/R NHL treated with M-CHOP (n=7), the overall response rate (ORR) was 86%, with 71% of pts achieving a CR. Twenty-seven out of 36 pts with previously untreated DLBCL started treatment at least three months prior to data cut-off date; in these pts the ORR was 96%, with a CR rate of 85% (Table). Grade (Gr) ≥3 adverse events (AEs) occurred in 37 pts (86%) and serious AEs in 19 pts (44%). Two pts (29%) with R/R NHL experienced CRS (one with Gr 1 and one with Gr 2; ASTCT grading, Lee et al. Biol Blood Marrow Transplant 2019); one pt received tocilizumab. Nineteen pts (53%) with previously untreated DLBCL had CRS events (14 with Gr 1, five with Gr2); one pt received tocilizumab. No pts required vasopressors or high-flow oxygen. All CRS events occurred in C1, resolved without sequelae, and did not result in discontinuation or delay in treatment. No immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed. Neutropenia occurred in two pts with R/R NHL (29%; Gr 4 n=2) and 23 pts with newly diagnosed DLBCL (64%; Gr 3 n=3, Gr 4 n=20). Febrile neutropenia occurred in two pts (29%) with R/R NHL, and six pts (17%) with newly diagnosed DLBCL. Gr 5 AEs, excluding disease progression, were reported in two pts: one due to Pneumocystis jirovecii pneumonia in a pt with R/R NHL, and one due to pneumonia in a pt with newly diagnosed DLBCL. All pts with R/R NHL have completed treatment. Among pts with newly diagnosed DLBCL, four have completed treatment and 29 remain on treatment; one pt died on-study (Gr 5 pneumonia), and two withdrew from the study treatment due to AEs (one due to treatment-unrelated esophageal perforation; one due to treatment-related pneumonitis). Linear pharmacokinetics (PK) were observed for Mosun. No differences were seen in Mosun exposure for pts with R/R NHL and previously untreated DLBCL. Similar PK characteristics were seen with M-CHOP as with Mosun monotherapy, indicating no impact when co-administered with CHOP. Conclusions: Preliminary data show that Mosun, a novel CD20/CD3 bispecific antibody, when combined with CHOP confers high response rates and a manageable safety profile in pts with R/R NHL and previously untreated DLBCL. End of treatment response rate data for pts with previously untreated DLBCL, and correlative studies of T-cell response, will be presented. Disclosures Phillips: Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy; BMS: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy. Olszewski:TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding. Munoz:Alexion: Consultancy; Portola: Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Verastem: Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Incyte: Research Funding; Millenium: Research Funding. Kim:AstraZeneca: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Greil:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Westin:Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Infinity: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; True North: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding; Karyopharm: Honoraria; Gilead: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding. Canales:Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, F. Hoffmann-La Roche, Sandoz: Honoraria; Janssen, F. Hoffmann-La Roche, Sandoz, Takeda: Speakers Bureau. Chen:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol-Myer Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Janssen Pharmaceuticals: Current equity holder in publicly-traded company. Althaus:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Negricea:F. Hoffmann-La Roche: Current Employment. Xie:F. Hoffmann-La Roche: Current Employment. McCord:Genentech, Inc.: Current Employment; F. Hoffman-La Roche: Current equity holder in publicly-traded company. Purev:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Vallurupalli:Received Research funding to University of Kansas to conduct the ongoing GO40515 clinical trial for which the abstract is being submitted.: Research Funding; On Kite speaker Bureau but do not receive any honorarium.: Speakers Bureau. OffLabel Disclosure: Mosunetuzumab (RG7828; CD20-TDB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Description: Introduction The prognosis of patients with recurrent or refractory acute myeloid leukemia (AML-RR) is very poor, especially if they are not candidates for allogeneic transplantation (allo-SCT) after a second complete response (CR). Venetoclax, a potent and selective inhibitor of the antiapoptotic protein BCL-2, was approved by the FDA in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) in patients with newly diagnosed AML of age ≥ 75 years, or who have comorbidities that preclude the use of intensive chemotherapy. However, the evidence in AML-RR patients is still scarce. For this reason, the objective of our study is to retrospectively analyze the efficacy of the off-label use of venetoclax in patients with AML-RR. Methods We conducted a retrospective, multicenter, observational study of a cohort of patients with AML-RR who were treated with venetoclax in the hospitals of the PETHEMA group. We evaluated efficacy, CR/CRi rate and overall survival (OS). We performed a descriptive analysis. Overall survival (OS) was calculated using the Kaplan-Meier method. Results A total of 41 patients were included, 25 men and 16 women, with a median age of 68 years (25 - 82 years) and an ECOG ≥ 2 at the beginning of the venetoclax treatment in 52% of the cases. Seventy-five percent of patients had AML with myelodysplasia-related changes. 25 patients (61%) were at high risk according to the European Leukemia Net 2017. Sixty-six percent of patients received ≥2 previous lines (range, 1-4), 29 patients (71%) received intensive first line chemotherapy, 10 (25%) received a previous transplant and 18 (44%) received previous treatment with HMA. Venetoclax median treatment duration was 40 days, and it was administered in 54% with azacitidine, 34% with decitabine and 12% with LDAC. In all, 11% of patients achieved CR/CRi. Only 10% of patients received subsequent salvage treatment. With a median follow-up time of 166 days (range, 21 - 311), 65% of the patients died. The median OS from diagnosis was 15 months (1 - 67 months) and the median from venetoclax initiation was 78 days (2 - 311 days). Those patients who achieved CR/CRi had higher OS (median not reached vs. 78 days, p= 0.048). Regarding toxicity, it was the expected in these patients. Twenty-eight percent of the patients required discontinuation of treatment due to toxicity. Sixty percent of the patients were admitted at some time during treatment with venetoclax, mainly because of infections (53%), 12% because of bleeding and other causes in 15%. Conclusions Our real-life series depicts a marginal probability of CR/CRi and poor OS after venetoclax-based salvage. Patients treated with this regimen had very poor-risk features, and were heavily pre-treated, which could explain in part the observed poor outcomes. Although follow-up is still short, the small proportion of responders did not reach the median overall survival. Further studies will help to identify those patients potentially benefiting from venetoclax-based salvage regimens. Disclosures Sanchez: Amgem: Other: travel grants; Janssen: Other: travel grants; Roche: Other: travel grants; Abbvie: Other: travel grants; Celgene: Other: travel grants. Tormo:Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: The objective of our study is to retrospectively analyze the efficacy of the off-label use of venetoclax in patients with recurrent or refractory acute myeloid leukemia

Description: Background: Phase I clinical trial for oncology drugs have the highest clinical failure rate. Drug candidates may be discarded if they don´t show activity. Yet these drugs may have valuable activity in patient subgroups. Biomarkers attempt to identify these sensitive subpopulations, but are normally evaluated and validated in Phase II when good drugs may have been discarded. OPB-111077 is a novel, oral, low-molecular-weight compound that inhibits STAT3 and mitochondrial electron transport. A prior Phase I trial on 145 patients from all tumor types gave only 1 partial response (PR). A strong anti-proliferative activity was identified in Acute Myeloid Leukemia (AML) samples ex vivo. This new biomarker was used for patient selection in this trial. We present a novel design of a Phase Ib trial directly selecting patients with a potential biomarker, that can benefit the patient without increasing toxicity risks, in Relapsed/Refractory (RR) AML patients. Method: This is an open-label, phase Ib dose-escalation clinical trial to evaluate the safety profile, maximum tolerated dose (MTD) and preliminary efficacy of oral OPB-111077 in AML relapsed or refractory to chemotherapy patients. Patients 〉 18 years old with high risk AML, ECOG ≤2 and adequate organ functions were selected for biomarker screening. Biomarker consisted on a dose response curve for antiproliferative activity of agent in a bone marrow sample of patients incubated 72-96-120h (Figure), quantified as the Area Under the Curve (AUC). Patient samples whose ex vivo biomarker showed low sensitivity (70% worst) we excluded, since they were potentially predicted as resistant to the agent. The remaining 30% with higher sensitivity were included. OPB-111077 was administered orally on a once daily dose schedule in 28-day cycles until intolerable toxicity or disease progression. Two dose schemas were evaluated: 200 (DL1) and 250 mg/day (DL2). Dose limiting toxicities were any Grade ≥ 3 non-hematologic toxicity and any unexpected non-tolerable grade II that requires delay beyond 1 week until recovery and evaluated during the first 28 days of treatment. Adverse events were graded according to NCI-CTCAE vs 4.03 and response criteria was based on those given by Cheson et al. IC50 and area under the curve (AUC) determined by the Vivia ex vivo biomarker were correlated with clinical response. Results: We screened 47 RR AML patients, twelve patients were included and selected by personalized medicine test (5 in DL1 and 7 in DL2), median age 76 years, 92% men, 42% ECOG 0 were included in the study. AML patients were refractory in 41.7% and patients were in median of relapses 2 (range 1-6). No DLT was reported. Adverse events related to study treatment were reported in three patients, all G 1-2: in DL1 one patient had vomiting; in DL2 one patient had extrasystoles and other had anorexia, diarrhoea, epigastric discomfort, nausea and vomiting. Two patients died during study treatment due to disease progression and respiratory infection. Half of the patients discontinued study treatment due to disease progression and 25% due to adverse events (respiratory failure G5, respiratory infection G5 and extrasystoles G2). Over the 6 patients evaluable for efficacy, 3 of them achieved PR and 3 treatment failure as best response. Progression free survival and overall survival were 57 days (95% CI: 37 - 77) and 95 days (95% CI: 27 - 163) respectively. The biomarker AUC and IC50 values stratified patients consistent with their clinical response, although without enough sampling potency for statistical significance. Figure shows the relative position of patients included in the study in the context of the overall population of samples considered to build up the mixed effect population pharmacodynamic model used to analyze samples results and define inclusion criteria. In green those that correspond to patients who showed a positive response; in orange those who failed. Conclusions: OPB-111077 is generally well tolerated and has a manageable toxicity profile. The MTD was not reached. The 50% PR rate achieved by OPB-111077, albeit in a few patients, is substantially higher that the 0.7% (1/145) PR rate achieved in a prior phase I trial on all tumor types1. This innovative Phase Ib design selecting patients using a biomarker may enable to rescue drug failures in the future. References: 1. Tolcher A, Flaherty K, Shapiro GI et al. Oncologist. 2018, 23(6):658-e72 Figure Disclosures Martinez-Lopez: Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Vivia Biotech: Honoraria; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novartis: Research Funding; Takeda: Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Gorrochategui:VIVIA BIOTECH: Current Employment. Rojas:VIVIA BIOTECH, S.L.: Current Employment. Primo:Vivia Biotech: Current Employment. Perez De Oteyza:MACROGENICS: Research Funding. Ballesteros:Vivia Biotech: Current Employment.

Description: Background: KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is currently being evaluated in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who received 1 - 5 prior therapies (including a Bruton tyrosine kinase inhibitor) in the Phase 2, registrational, multicenter ZUMA-2 study. With a median follow-up of 12.3 months, we previously reported an objective response rate (ORR) of 93% (67% complete response [CR] rate) with KTE-X19 treatment in the 60 efficacy-evaluable patients in ZUMA-2 (Wang et al. N Engl J Med. 2020;382:1331). Here, we present an updated analysis of efficacy, safety, and pharmacology for all patients with a minimum follow-up of 1 year. Methods: Eligible patients with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19 (2 × 106 CAR T cells/kg; Wang et al. N Engl J Med. 2020;382:1331). The primary endpoint was ORR (CR + partial response) as assessed by an Independent Review Committee according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014;32:3059). Efficacy data are reported for the 60 treated patients with ≥ 1 year of follow-up; safety data are presented for all 68 treated patients. Results: As of December 31, 2019, the median follow-up was 17.5 months (range, 12.3 - 37.6). The ORR was 92% (95% CI, 81.6 - 97.2), with a CR rate of 67% (95% CI, 53.3 - 78.3). Of all efficacy-evaluable patients, 48% had ongoing responses at the data cutoff. Medians were not reached for duration of response, progression-free survival (PFS), or overall survival; 15-month estimates were 58.6% (95% CI, 42.5 - 71.7), 59.2% (95% CI, 44.6 - 71.2), or 76.0% (95% CI, 62.8 - 85.1), respectively. In patients who achieved a CR, the median PFS was not reached (15-month rate, 75.1% [95% CI, 56.8 - 86.5]); in those who achieved a partial response, the median PFS was 3.1 months (95% CI, 2.3 - 5.2). Median PFS was 1.1 months (95% CI, 0.9 - 3.0) in nonresponding patients. The first 28 patients treated had a median follow-up of 32.3 months (range, 30.6 - 37.6); 39.3% of these patients remain in remission with no further therapy. Common grade ≥ 3 adverse events were neutropenia (85%), thrombocytopenia (53%), anemia (53%), and infections (34%). Grade ≥ 3 cytopenias were reported in 60% of patients ≥ 30 days post-infusion. Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al. [Blood. 2014;124:188]) occurred in 15% of patients; 59% received tocilizumab for management of CRS. Grade ≥ 3 neurologic events (NEs) were reported in 31% of patients, and 38% received steroids for NE management. All CRS events and most NEs (37/43) resolved, as previously reported. There were no Grade 5 CRS events or NEs, and no new Grade 5 events occurred with additional follow-up. As previously reported, there were 2 cases of Grade 2 cytomegalovirus infection, 1 case each of Grade ≥ 3 hypogammaglobulinemia and Grade ≥ 3 tumor lysis syndrome, and no cases of Epstein-Barr virus-associated lymphoproliferation, replication-competent retrovirus, hemophagocytic lymphohistiocytosis, or KTE-X19-related secondary cancers. Median peak CAR T cell levels and median area under the curve (Days 0 - 28) were 98.9 cells/µL (range, 0.2 - 2565.8) and 1394.9 cells/µL (range, 3.8 - 27,700) in patients with ongoing responses at 12 months, 202.6 cells/µL (range, 1.6 - 2589.5) and 2312.3 cells/µL (range, 19.0 - 27,200) in patients who were relapsed at 12 months, and 0.4 cells/µL (range, 0.2 - 95.9) and 5.5 cells/µL (range, 1.8 - 1089.1) in nonresponders. Of the 57 efficacy-evaluable patients with data available, 84% had B cells detectable by flow cytometry at baseline. Of those in ongoing responses at 12 months, 10 of 26 patients (38%) with evaluable samples had B cells detectable at 3 months, and 10 of 18 (56%) had detectable B cells at 12 months; gene-marked CAR T cells were no longer detectable at 12 months in 5 of 28 evaluable patients (17%). Conclusions: The ZUMA-2 study continues to demonstrate substantial and durable clinical benefit of KTE-X19 therapy with manageable safety in patients with R/R MCL. Within this patient population, which lacks curative treatment options, most patients achieved durable CR, and no new safety signals were reported. Although early CAR T cell expansion was higher in patients who achieved an objective response, those who later relapsed showed elevated CAR T cell levels pointing to alternate mechanisms of secondary treatment failure in MCL. Disclosures Wang: Verastem: Research Funding; Molecular Templates: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; Targeted Oncology: Honoraria; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Guidepoint Global: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Acerta Pharma: Research Funding; Oncternal: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; InnoCare: Consultancy; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria. Munoz:Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau; Innovent: Consultancy; Fosunkite: Consultancy; Beigene: Consultancy, Speakers Bureau; Alexion: Consultancy; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Millenium: Research Funding. Goy:MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Xcenda: Consultancy; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity Verastem: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment. Locke:Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options. Hill:Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Timmerman:Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Merck: Research Funding; Valor: Research Funding; Genmab: Current equity holder in publicly-traded company. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Flinn:Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Agios: Research Funding; ArQule: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Great Point Partners: Consultancy; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; Nurix Therapeutics: Consultancy; Curis: Research Funding; MorphoSys: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Merck: Research Funding; Celgene: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Curio Science: Consultancy. McSweeney:Fred Hutchinson: Patents & Royalties; Colorado Blood Cancer Institute: Current Employment; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Miltenyi Biotec: Research Funding. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy. Kersten:Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Celgene: Research Funding; Roche: Research Funding; Takeda: Research Funding; Miltenyi: Consultancy, Honoraria, Other: travel support. Milpied:Celgene: Other: Travel support; Gilead Sciences: Other: consultancy or advisory role; Janssen: Honoraria; Sandoz: Honoraria, Other: consultancy or advisory role; Astellas: Honoraria; Roche: Honoraria, Other: Travel support. Fung:Takeda: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Houot:Janssen: Honoraria; Gilead: Other: Personal fees; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Beitinjaneh:Jazz: Other: speaker's bureau; Kite, a Gilead Company: Honoraria, Other: consulting or advisory role, speaker's bureau, ; ATARA: Research Funding; Gilead: Research Funding. Peng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Murugappan:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kloos:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Reagan:Curis: Consultancy; Seattle Genetics: Research Funding; Kite, a Gilead Company: Consultancy.

Description: Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of patients (pts) with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies. ZUMA-1 is the multicenter, single-arm, registrational Phase 1/2 study of axi-cel in pts with refractory LBCL. In a 2-year analysis of ZUMA-1 (median follow-up, 27.1 months; N=101), axi-cel demonstrated objective response, complete response (CR), and ongoing response rates of 83%, 58%, and 39%, respectively (Locke et al. Lancet Oncol. 2019). Here, we present additional survival follow up and recovery of normal, polyclonal B cells from ongoing responders in ZUMA-1. Methods: Eligible pts with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis at enrollment and subsequently received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu et al. NEJM. 2017; NCT02348216). The primary endpoint was objective response rate (ORR), and the first response assessment was 4 weeks post infusion. Response assessments were performed per protocol up to 24 months or disease progression, whichever occurred first. For pts in ongoing response beyond Month 24, response assessments continued per institutional standard-of-care (SOC). Blood levels of CAR T cells were quantified using polymerase chain reaction and B cells were characterized using flow cytometry in pts with ongoing responses and evaluable samples. Results: A total of 111 pts were enrolled, and axi-cel was administered to 101 pts. As previously reported in the ZUMA-1 2-year analysis, among pts who received axi-cel, the median time from axi-cel infusion to both objective response and CR was 1.0 month (range, 1 - 12 months; Locke et al. Lancet Oncol 2019). When the entire enrolled population (N = 111) was included on an intent-to-treat basis, the median manufacturing time was 17 days (range, 14 - 51; n = 110 as manufacturing was not feasible for 1 pt). Additionally, among the 111 pts, the median time from enrollment/leukapheresis to objective response and CR was 1.7 months (range, 0.7 - 12.9) and 1.9 months (range, 0.7 - 13.3), respectively. Responses have been durable, and with a minimum of 3 years of follow-up (median, 39.1 months), the median overall survival (OS) was 25.8 months, and the 3-year OS rate was 47%. Importantly, no axi-cel-related secondary malignancies have been reported. As previously reported, pts in ongoing response after 2 years had significantly greater peak CAR T cell expansion in blood 7 - 14 days after axi-cel infusion than did those with relapse (P = 0.014) or no response (P = 0.0003; Locke et al. Lancet Oncol 2019). Blood samples from 22 pts in ongoing response (per institutional SOC) at ≥ 3 years were available for analysis of CAR T cells and evaluation of B cell recovery. All evaluable pts had detectable B cells in blood at 3 years post axi-cel. Notably, 91% of pts in ongoing response at 3-year follow-up demonstrated recovery of polyclonal B cells measured by presence of both kappa and lambda light chains on non-malignant CD19+CD20+ B cells. The median kappa-lambda ratio of 1.6 and relative levels of key B cell subsets, including memory and naive B cell immunophenotypes, suggested reconstitution of B cell repertoire, consistent with published data from healthy individuals (Deneys et al. J Immunol Methods 2001; Scott et al. J Clin Pathol 2018). Additionally, 15/22 (68%) had both minimal levels of detectable CAR gene-marked cells and detectable polyclonal B cells in blood. Altogether, these findings support the hypothesis that persistence of functional CAR T cells is not necessary for durable remissions of LBCL. Overall survival and translational findings with ≥ 4 years of follow-up will be presented. Conclusions: Axi-cel produced rapid responses and longterm disease control in pts with refractory LBCL. Most responses occurred by the first assessment, and the brief time elapsed between enrollment and response supports both the speed and success of manufacturing. Furthermore, axi-cel-treated pts with ongoing responses at ≥ 3 years showed evidence of restoration of a normal B cell compartment and clearance of functional CAR T cells, a critical component of the long-term safety of CD19-directed CAR T cell therapies. Disclosures Locke: Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ghobadi:Celegene: Consultancy; Wugen: Consultancy; Atara: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Oluwole:Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy. Lin:Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Hill:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Timmerman:Merck: Research Funding; Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Valor: Research Funding. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Reagan:Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Flinn:Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; BeiGene: Consultancy, Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Calithera Biosciences: Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Gilead Sciences: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Curis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Goy:COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Colorado Blood Cancer Institute: Current Employment; Fred Hutchinson: Patents & Royalties. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siddiqi:Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Bot:Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support . Zheng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Vezan:Merck: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. Bashir:Kite, a Gilead Company: Current Employment; OmniacPharmConsult Ltd: Current Employment, Current equity holder in private company. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Chu:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Kite, a Gilead Company: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Novartis: Other: personal fees; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees.

Description: Introduction: Trauma-induced coagulopathy (TIC) is a multifactorial condition secondary to severe trauma. In TIC, early fibrinogen (FI) replacement and low dose of recombinant activated factor VII (rFVIIa) may positively impact outcome. Factor XIII (FXIII), on the other hand, may stimulate in vitro clot formation and clot stability. We hypothesized that combination of FI, rFVIIa and FXIII might normalize clot formation more effectively than the isolated use of each concentrate in a model of TIC. Aim: Evaluation of the procoagulant effect of isolated or combined use of FI, rFVIIa and FXIII in a model of TIC. Methods: TIC in vitro model was obtained by dilution of whole blood from seven healthy controls with isotonic saline (NaCl 0.9%) (2:3 whole blood:saline ratio). FI, rFVIIa and FXIII were spiked in combination or alone until obtaining final levels of 2 g/L, 1 μg/mL and 100 IU/dL respectively. Procoagulant effects of the different concentrates or their mixtures were evaluated by Rotational Thromboelastometry (ROTEM®, Werfen) triggered using starTEM® (calcium chloride 0,2 M) and exTEM® reagent (source of tissue factor) diluted with saline up to 1:100.000 (final dilution) for a better evaluation of both the extrinsic and intrinsic pathways of coagulation. The values of clotting time (CT: time until 2 mm of amplitude, in seconds), amplitude (parameter proportional to the clot strength) at 5 minutes (A5, in mm) and clot formation time (CFT: time from CT to 20 mm of amplitude, in seconds) were evaluated. Statistical analysis of differences was performed by One-Way ANOVA test assuming no paring of data and using the Holm-Sidak's correction for multiple comparisons with a family-wise significance and confidence level of 0.01. Statistical significance was set at p〈 0.05. Results/Discussion: Data are summarized in Table I and Figure 1. CT needed the combination of two of more concentrates to reach the normal range suggesting that the administration of FI alone in TIC may not be enough to restore the patients' hemostatic potential. In regard to the clot strength evaluated by A5, the addition of FXIII or rFVIIa alone or in combination did not improve the value of A5 that was only normalized by the addition of FI. This effect of FI was increased in the presence of FXIII or rFVIIa which indicated that normal levels of FI might be required for rFVIIa or FXIII to be effective emphasising the possible benefit of the combinatory therapy. Like observed in A5, the velocity of clot formation evaluated by the CFT was normalised only by the addition of FI. However, the combination of FI plus FXIII + rFVIIa had a stronger effect on CFT compared with the combination of FI + FXIII or FI + rFVIIa, indicating that the improvement of thrombin generation due to rFVIIa plus an increment of fibrin formation and net stabilization through the contribution of higher levels of FI and FXIII respectively, might provide a beneficial synergistic procoagulant effect in TIC. Conclusion: The use of FI in TIC may contribute to increase the patient's hemostatic potential but might not be enough. Combinatory therapies based on the administration of FI, rFVIIa and FXIII might be of better benefit in this setting. Ex-vivo studies using blood of patients with stablished TIC might bring new insights on the possible advantages of this combinatory therapy to design more effective protocols to treat this frequent and life-threatening acquired condition. Disclosures Canales: Sandoz: Honoraria; iQone: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Karyopharm: Honoraria; Sandoz: Speakers Bureau; Novartis: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Roche: Honoraria; Gilead: Honoraria. Butta:NovoNordisk: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; SOBI: Speakers Bureau; Pfizer: Speakers Bureau; ROCHE: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Grifols: Research Funding. Alvarez Román:NovoNordisk,: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; SOBI,: Consultancy, Research Funding, Speakers Bureau; Pfizer,: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy; Grifols: Research Funding. Jiménez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer: Consultancy; Grifols, Novo Nordisk, Takeda, Sobi, Pfizer: Research Funding; F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer: Honoraria.

Description: Background: Patient (pts) with MCL who progress after BTKi therapy have a median overall survival of only 5.8 mo with salvage therapies (Martin, et al. Blood 2016). KTE-X19 is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy being evaluated in the Phase 2, registrational, multicenter ZUMA-2 study of pts with R/R MCL after 1 - 5 prior therapies, including a BTKi. In the primary analysis of ZUMA-2 (N = 60), the objective response rate (ORR) with KTE-X19 treatment (median follow-up 12.3 mo) was 93% (67% complete response [CR] rate; Wang et al. N Engl J Med 2020). Here, we describe a comparative analysis of KTE-X19 pharmacology profile and outcomes by MCL morphology and prior BTKi exposure (ibrutinib [Ibr] and/or acalabrutinib [Acala]), accompanied by basic product attribute characterization. Methods: Eligible pts with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of 2 × 106 anti-CD19 CAR T cells/kg (Wang et al. N Engl J Med 2020). Product attributes, CAR T cell levels in blood, and cytokine levels in serum were assessed using methods previously described (Locke et al. Mol Ther 2017). Clinical outcomes are reported in the 60 efficacy-evaluable pts; product attributes and pharmacology data are reported for all 68 treated pts (data cutoff 7/24/2019). Additional pharmacodynamic and cytogenetic data were generated and will be presented. Results: At baseline, 40 pts (59%) had classical MCL, 17 (25%) had blastoid MCL, and 4 (6%) had pleomorphic MCL as assessed by investigator. Before study entry, 52 pts (76%) had prior Ibr, 10 (15%) had prior Acala, and 6 (9%) had both; 88% had BTKi-refractory disease. In manufactured KTE-X19 products, median (range) CD4/CD8 ratios for pts with classical, blastoid, or pleomorphic MCL were 0.7 (0.04 - 2.8), 0.6 (0.2 - 1.1), or 0.7 (0.5 - 2.0), respectively. Product T cell phenotypes (median [range]) included less differentiated CCR7+ T cells (classical 40.0% [2.6 - 88.8]; blastoid 35.3% [14.3 - 73.4]; pleomorphic 80.8% [57.3 - 88.8]) and effector + effector memory CCR7- T cells (classical 59.9% [11.1 - 97.4]; blastoid 64.8% [26.6 - 85.7]; pleomorphic 19.2% [11.1 - 42.7]). Median (range) interferon (IFN)-γ levels by coculture in pts with classical, blastoid, or pleomorphic MCL were 6309.5 pg/mL (424.0 - 20,000), 6510.0 pg/mL (2709.0 - 18,000), or 7687.5 pg/mL (424.0 - 12,000), respectively. In pts with classical, blastoid, or pleomorphic MCL, median (range) peak CAR T cell levels were 77.6 cells/µL (0.2 - 2241.6), 35.0 cells/µL (0.2 - 2589.5), or 144.9 cells/µL (39.2 - 431.3), respectively. ORR/CR rates were 93%/65% in pts with classical MCL, 88%/53% in those with blastoid MCL, and 100%/75% in those with pleomorphic MCL. The 12-mo survival rates in pts with classical, blastoid, or pleomorphic MCL were 86.7%, 67.9%, or 100%, respectively. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events occurred in 15% and 38% of pts with classical MCL, 6% and 8% of pts with blastoid MCL, and 25% and 50% of pts with pleomorphic MCL. For pts who received prior Ibr, Acala, or both, median CD4/CD8 ratios in manufactured KTE-X19 products were 0.7 (range, 0.04 - 3.7), 0.6 (range, 0.3 - 1.2), or 1.0 (range, 0.7 - 1.9), respectively. Product T cell phenotypes (median [range]) included less differentiated CCR7+ T cells (Ibr 39.3% [2.6 - 86.4]; Acala 42.7% [16.3 - 88.8]; both 49.5% [14.3 - 83.0]) and CCR7- effector + effector memory T cells (Ibr 60.6 [13.7 - 97.4]; Acala 57.3% [11.1 - 83.8]; both 50.6% [17.0 - 85.7]). Median (range) levels of IFN-γ by coculture in pts with prior Ibr, Acala, or both was 6496.0 pg/mL (424.0 - 20,000), 5972.5 pg/mL (2502.0 - 18,000), or 7985.5 pg/mL (2709.0 - 12,000), respectively. For pts with prior Ibr, Acala, or both, median (range) peak CAR T cell levels were 95.9 (0.4 - 2589.5), 13.7 (0.2 - 182.4), or 115.9 (17.2 - 1753.6), respectively. ORR/CR rates were 94%/65% in pts with prior Ibr, 80%/40% in pts with prior Acala, and 100%/100% in pts with both BTKis. The 12-mo survival rates in pts with prior Ibr, Acala, or both were 81%, 80%, or 100%, respectively. Grade ≥ 3 CRS and neurologic events occurred in 17% and 31% of pts with prior Ibr, 10% and 10% of pts with Acala, and 0 and 67% of pts with both BTKis. Conclusions: All subgroups defined by MCL morphology or prior BTKi drew clinical benefit from KTE-X19 treatment, with lower post-treatment CAR T cell levels in pts with blastoid morphology or previously treated with Acala alone. Disclosures Wang: OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Loxo Oncology: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; VelosBio: Research Funding; Nobel Insights: Consultancy; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Lu Daopei Medical Group: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; Verastem: Research Funding; InnoCare: Consultancy; OncLive: Honoraria; Acerta Pharma: Research Funding; Beijing Medical Award Foundation: Honoraria; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding. Rossi:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Munoz:Millenium: Research Funding; Incyte: Research Funding; Portola: Research Funding; Merck: Research Funding; AbbVie: Consultancy, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau; Innovent: Consultancy; Fosunkite: Consultancy; Beigene: Consultancy, Speakers Bureau; Alexion: Consultancy; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Goy:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Karyopharm: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; Infinity: Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; Genentech/Roche: Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Celgene: Honoraria, Research Funding; PracticeUpdate Oncology: Consultancy; Bayer: Research Funding; RCCA/OMI: Current Employment; Hackensack UMC and University of Nebraska: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Morphosys: Research Funding; CALBG: Research Funding. Locke:Kite, a Gilead Company: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; GammaDelta Therapeutics: Consultancy; Wugen: Consultancy. Reagan:Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Jacobson:Celgene/BMS: Consultancy, Honoraria, Other: travel support; Precision Biosciences: Consultancy, Honoraria, Other: travel support; Nkarta: Consultancy, Honoraria, Other: travel support; AXIS: Speakers Bureau; Clinical Care Options: Speakers Bureau; Pfizer: Research Funding; Lonza: Consultancy, Honoraria, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Hill:Genentech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Peng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Fang:Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Xue:Kite, a Gilead Company: Current Employment; Kite, a Gilead Company: Current equity holder in private company. Kloos:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Bot:Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support .

Description: Introduction: COVID-19 has transformed stem cell transplantation (HSCT) dynamics throughout the world. Bone Marrow Transplantation units are facing many challenges complicating admission; deferrals in transplant schedules and even temporary closure. Delay in treatment may have a negative impact in outcomes. Outpatient care has been an alternative to hospital care in patients undergoing HSCT since the 1990s. Potential advantages include improved patient independence and satisfaction, improved quality of life, and less hospital resource utilization, which is of particular importance during this epidemic. In this prospective cohort study, we investigated the impact of the pandemic in our outpatient HSCT program. Objective: To describe the outcomes of patients undergoing ambulatory HSCT during the COVID-19 pandemic. Methods: Adults and children with any hematological disease undergoing any type of HSCT with an outpatient intent from March to July 2020 were included. All were required to have a Karnofsky score 〉70%, serum creatinine

Description: Although chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genomic discovery, complete characterization of its genomic landscape has been limited by sample size and cohort diversity. To address this challenge, we assembled and generated new genomic data from CLL samples from ~1100 patients ('CLL-1100'). In total, we analyzed 984 whole-exome sequences (WES), 177 whole-genome sequences (WGS), RNA-sequencing of 717 cases, and 758 methylome profiles. With our large dataset, we had increased sensitivity to detect candidate drivers even with frequency less than 1%. By applying MutSig2CV to the WES data, we identified 89 putative cancer driver genes (q92% of CLL samples within the cohort. The gain in power was most evident in our characterization of the two major molecular subtypes of CLL, those with mutated (M-CLL) or unmutated (U-CLL) IGHV. Separate WES analyses of 513 M-CLLs and 459 U-CLLs revealed numerous differences between these two subtypes: (i) Mutation analysis revealed 24 and 59 candidate driver genes in M-CLL and U-CLL, respectively (q