Phase 1/2 Study of Agent-797, an Allogeneic Invariant Natural Killer T (Inkt) Cell Therapy, in Subjects with Moderate to Severe Acute Respiratory Distress Syndrome (Ards) Secondary to Sars-Cov-2 (Covid-19)

Background AgenT-797 is a novel allogeneic iNKT cell therapy demonstrating activity in malignances and serious viral infections (i.e., SARS-CoV-2). In response to inflammatory injury, iNKTs home to critical organs, including lungs, dampen proinflammatory cytokines and protect epithelial tissues. INKTs drive response through activation of innate and adaptive immunity, recruitment/trans-activation of NK, B, and T cells, and myeloid cells via contact and soluble mediators. iNKTs represent a novel and attractive potential immunotherapy for viral ARDS. This analysis presents results from an ongoing phase 1/2 study of agenT-797 in mechanically ventilated patients with moderate to severe ARDS secondary to COVID- 19;NCT04582201. Methods As of February 2022, patients on mechanical ventilation with confirmed moderate to severe (Berlin Definition) ARDS, secondary to COVID-19 were treated with a single infusion of agenT-797 at 100, 300, or 1000 x 106 iNKT cells. Primary endpoint was safety and secondarily, time to extubation, prevention of secondary infections, persistence and alloimmunity were evaluated. Clinical benefit was defined as improvement/resolution of viral ARDS evaluated as time to extubation and survival at 30 days post-infusion. Results Twenty evaluable patients were treated with agenT-797 with a median age of 66 years (range 26-77;85% >=65y). Patients enrolled early in pandemic (pre-vaccines) and were heavily pre-treated with remdesivir, steroids and/or tocilizumab. No dose-limiting toxicities were observed. Tolerability was favorable with no cytokine release syndrome (CRS), neurotoxicity, or severe immune-related AEs. One SAE was deemed possibly related to agenT-797 (Dyspnea, Grade 4). The most frequent AEs deemed possibly related was pyrexia (grade 1;n=6). Survival was 70% (14/20) in this predominantly elderly, mechanically ventilated population. Early signals of reduction in ARDS symptoms, rapid extubation, and reduction in secondary infections were observed. AgenT-797 was detected in peripheral blood up to day 6 post-infusion, consistent with a rapid translocation from blood to tissue. Spikes in the blood during D1 and D2 showed a dose-proportional relationship, however, increased dose did not lead to prolonged peripheral persistence. Additional translational and biomarker evaluation is underway. Conclusions In patients with severe viral ARDS secondary to SARS-COV-2, agenT-797 demonstrated encouraging survival and disease mitigating benefit with a favorable tolerability profile. The deep and broad activity observed is likely attributed to iNKT cells' ability to promote viral clearance, home to the lungs, and reduce inflammation. These findings support the potential for a variant-agnostic therapy for patients with viral ARDS, a condition for which there are currently no effective therapies.

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is require to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. [Formula presented] Disclosures: Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding;Celgene/BMS: Research Funding;BeiGene: Research Funding;Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy;BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Takeda: Research Funding;Genentech: Consultancy;AstraZeneca: Speakers Bureau;Roche: Consultancy;Karyopharm: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding;AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharma: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Research Funding;Incyte: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Genmab: Consultancy, Honoraria;Epizyme: Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau;Servier Pharmaceuticals: Consultancy;Seattle Genetics: Speakers Bureau;Sanofi: Speakers Bureau;Pharmacyclics: Consultancy;MorphoSys: Consultancy;Kite (Gilead): Speakers Bureau;KaryoPharm: Consultancy;CSL Therapeutics: Consultancy;Bristol-Myers Squibb: Speakers Bureau;Biogen: Consultancy;Beigene: Consultancy;AstraZeneca: Speakers Bureau;ADC Therapeutics: Consultancy;Adaptive Biotechnologies: Consultancy;AbbVie: Consultancy. Grover: Genentech: Research Funding;Novartis: Consultancy;ADC: Other: Advisory Board;Kite: Other: Advisory Board;Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months;BMS: Divested equity in a private or publicly-traded company in the past 24 months;Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months;Novatis: Divested equity in a private or publicly-traded company in the past 24 months;Janssen: Divested equity in a private or publicly-traded company in the past 24 months;Morphosys: Divested equity in a private or publicly-traded company in the past 24 months;ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months;Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months;Beigene: Divested equity in a private or publicly-traded company in the past 24 months;Merck: Divested equity in a private or publicly-traded company in the past 24 months;KITE: Divested equity in a private or publicly-traded company in the past 24 months;Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support;Humanigen: Consultancy, Honoraria, Other: Travel support;Celgene: Consultancy, Honoraria, Other: Travel support;Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding;Lonza: Consultancy, Honoraria, Other: Travel support;AbbVie: Consultancy, Honoraria;Precision Biosciences: Consultancy, Honoraria, Other: Travel support;Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support;Nkarta: Consultancy, Honoraria;Axis: Speakers Bureau;Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy;Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)

INTRODUCTION: Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma (AITL), is characterized by recurrent mutations affecting epigenetic regulators such as TET2, DNMT3A, IDH2 and RHOA. The association of aberrant DNA methylation with lymphomagenesis provides rationale for clinical application of hypomethylating agents. Azacitidine, an epigenetic modifier which inhibits DNA methyltransferase, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the findings of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). METHODS: This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Priming with oral azacitidine (CC-486) at 300 mg daily was administered for 7 days prior to cycle 1 of CHOP, and for 14 days before CHOP cycles 2-6. Supportive care included mandatory G-CSF. The primary endpoint is CR per 2014 IWG criteria. Secondary endpoints include ORR, safety and survival. Correlative biomarker studies are planned to assess genomic mutations by next-generation-sequencing (NGS), in addition to methylation and transcription profiles. Using a Simon two-stage design comparing an CR of ≥60% with treatment to an unacceptable CR of ≤35% (alpha=10%, power=80%), 9 or more CR out of 17 enrolled patients were required to declare the treatment worthy of further study. RESULTS: From 6/2018 to 3/2020, 21 subjects with previously untreated PTCL were enrolled at 4 centers, and the study met its accrual. At study entry, 17 patients (81%) had PTCL-TFH (16 AITL and 1 TFH), 3 with PTCL-NOS, 1 with ATLL, including 5 (24%) with CD30+ disease. The median age was 66 years (range 22-77), and the M:F ratio was 1.6:1. Nineteen (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (33%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (71.4%), thrombocytopenia (9.5%) and anemia (14.3%), with febrile neutropenia uncommon (14.3%). Grade 3-4 non-hematologic toxicities included fatigue (14.3%), hyponatremia (14.3%), diarrhea (4.8%), vomiting (4.8%), rash (4.8%), and elevated ALT (4.8%). One incidence each of influenza A, COVID-19 pneumonia, C.diff and strongyloides hyperinfection were observed and treated. There was no study treatment-related mortality to date. As of July 2020 at a median follow-up of 7 months (range 4-25 months), one subject withdrew consent after cycle 1 (patient preference), and 20 subjects had at least one response assessment, including 15 completed treatment, 2 progressed during treatment, and 3 nearing completion of therapy. At interim assessment after cycle 3 (n=20), the ORR was 85% with CR at 55% (90%CI of 34.7%-74.1%). To date, the preliminary end-of-treatment (EOT, n=17) CR was 76.5% (90%CI of 53.9%-91.5%) for all evaluable patients and was 86.7% for 15 PTCL-TFH, exceeding primary endpoint threshold. CR did not correlate with CD30 expression. The estimated 1-yr PFS for all patients was 56.8% (95%CI of 26.3%-87.3%), with 1-yrs PFS for PTCL-TFH at 61.1% (95%CI of 29.5%-92.7%), and the estimated 1-yr OS for all patients was 74.4% (95%CI of 48.8%-100.0%), with 1-yr OS for PTCL-TFH at 88.9% (95%CI of 68.4%-100.0%). Mutational status by NGS was determined in 15 patients to date. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 73%, 40%, 13% and 13%, respectively. TET2 mutations were significantly associated with CR (p=0.014), favorable PFS (p-0.012) and OS (p=0.042). In contrast, DNMT3A mutations were associated with adverse OS (p=0.028). CONCLUSIONS: This study provides the first demonstration that addition of hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is feasible, safe, and induces high CR rate in PTCL-TFH subtype, with expected side effects. Although preliminary, the EOT CR to date exceeds the threshold of meeting study primary endpoint. Final efficacy data as well as response according to subtype and mutational profiling will be updated at ASH. This active combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL. [Formula presented] Disclosures: Ruan: Seattle Genetics: Research Funding;AstraZeneca: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Juno: Consultancy;BMS: Consultancy, Research Funding;Pharmacyclics: Research Funding;Kite Pharma: Consultancy. Moskowitz: Seattle Genetics: Research Funding;Incyte: Research Funding;Merck: Consultancy;Seattle Genetics: Consultancy;Bristol-Myers Squibb: Research Funding;Merck: Research Funding;Imbrium Therapeutics, L.P.: Consultancy;Miragen Therapeutics: Consultancy. Mehta-Shah: Bristol Myers-Squibb: Research Funding;Genetech: Research Funding;Innate Pharmaceuticals: Research Funding;Kyowa Kirin: Consultancy;Verastem: Research Funding;Karyopharm Therapeutics: Consultancy;Celgene: Research Funding;C4 Therapeutics: Consultancy. Sokol: EUSA Pharma: Consultancy, Honoraria, Speakers Bureau;Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees;Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees. Horwitz: Portola: Consultancy, Research Funding;Aileron: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Beigene: Consultancy;Daiichi Sankyo: Research Funding;C4 Therapeutics: Consultancy;ADCT Therapeutics: Consultancy, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Innate Pharma: Consultancy;Corvus: Consultancy;Trillium: Consultancy, Research Funding;Kyowa Hakka Kirin: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Mundipharma: Consultancy;Infinity/Verastem: Research Funding;Forty Seven: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Miragen: Consultancy;Myeloid Therapeutics: Consultancy;Verastem: Consultancy, Research Funding;Vividion Therapeutics: Consultancy;Affirmed: Consultancy;ASTEX: Consultancy;Janssen: Consultancy;Kura Oncology: Consultancy. Rutherford: LAM Therapeutics: Research Funding;Juno: Consultancy;AstraZeneca: Consultancy;Seattle Genetics: Consultancy;Genentech/Roche: Research Funding;Regeneron: Research Funding;Celgene: Consultancy;Heron: Consultancy;Karyopharm: Consultancy, Research Funding;Dova: Consultancy;Kite: Consultancy. Coleman: Novartis Pharmaceuticals: Research Funding;Innocare: Research Funding;Merck Sharp & Dohme Corp.: Research Funding;BeiGene: Research Funding;Acerta: Research Funding;Ipsen Group: Research Funding;BMS (Celgene Corporation): Research Funding;AstraZeneca Pharmaceuticals, LP: Research Funding;Karyopharma Therapeutics, Inc.: Research Funding;ARCUS Biosciences: Research Funding;AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding;Incyte Corporation: Research Funding;Eli Lilly and Company: Research Funding;EMD Serono Research and Development Institute Inc.: Research Funding;Genetech (F. Hoffman-LaRoche Ltd): Research Funding;Hutchinson MediPharma, LTD: Research Funding;Klus Pharma, Inc.: Research Funding;MeiPharma, Inc.: Research Funding;Seattle Genetics: Research Funding;Boston BIoMedical, Inc.: Research Funding. Melnick: Jubilant: Consultancy;Epizyme: Consultancy;Constellation: Consultancy;Janssen: Research Funding;Daiichi Sankyo: Research Funding. Cerchietti: BMS: Research Funding. Leonard: ADC Therapeutics: Consultancy;MEI Pharma: Consultancy;Bayer: Consultancy;Gilead/Kite: Consultancy;Karyopharm: Consultancy;GenMab: Consultancy;Regeneron: Consultancy;Sutro: Consultancy;AstraZeneca: Consultancy;Roche/Genentech: Consultancy;BMS/Celgene: Consultancy;Epizyme: Consultancy;Miltenyi: Consultancy. Martin: Regeneron: Consultancy;I-MAB: Consultancy;Sandoz: Consultancy;Janssen: Consultancy;Karyopharm: Consultancy, Research Funding;Teneobio: Consultancy;Bayer: Consultan y;Beigene: Consultancy;Cellectar: Consultancy;Incyte: Consultancy;Kite: Consultancy;Morphosys: Consultancy;Celgene: Consultancy. OffLabel Disclosure: Oral azacitidine (CC-486) as hypomethylating agent for the treatment of peripheral T-cell lymphoma

COVID-19 pneumonia in patients with hematologic malignancies-a report from the us epicenter

Background: Limited data are available for risk assessment and outcome of COVID-19 in patients with hematologic malignancies (HM). We present a single center study of COVID-19 pneumonia in a cohort of 31 patients with HM. Methods: Data were abstracted from electronic medical records for patients admitted to NYPH between 3/5/20 and 4/17/20 and entered into a REDCap database. Results: Twenty (64.5%) were male;median age was 71 years. There were 8 patients with Multiple Myeloma (MM), 8 with Chronic Lymphocytic Leukemia (CLL), 6 (19.4%) had AML, 5 (16.1%) NHL, 2 (3.2%) ALL;CML, MDS and Polycythemia Vera occurred in 1 patient each. Twenty-four (77.4%) had active HM;6 (19.4%) were in remission;and 1 relapsed. Nineteen patients (61.3%) received recent chemotherapy and 11 (35.5%) immunosuppressive therapies. There were 7 (22.6%) hematopoietic stem cell transplant (HSCT) recipients (4 allogeneic and 3 autologous). Comorbidities were evenly distributed among all malignancies: 18 (58.1%) had hypertension, 9 (38.7%) obesity, 7 (22.6%) diabetes mellitus, and 11 (35.5%) were former smokers. The most common symptoms included cough (90.3%), fever (83.9%) and dyspnea (61.3%);7 (22.6%) had nausea and vomiting;7 (22.6%) had diarrhea. On presentation, hypoxia (O2 sat ≤94% on room air) occurred in 64.5%;median ALC was 330/ml;23 (74.2%) had ALC< 1000/ml;median CRP was 15.9 mg/dl (2.5-40.4), ferritin 1162 ng/ml (264 - > 16500), and D-dimers 456 ng/ml (< 150-2418). Thirteen patients (41.9%) required ICU admission and were intubated;among those 9 (69.2%) had either MM or CLL. Co-infections were uncommon;two patients developed HSV1 pneumonitis and one of these also had CMV pneumonitis. Twenty-eight (90.3%) were treated with hydroxychloroquine, 5 (16.1%) remdesivir, 2 (6.5%) tocilizumab, 1 (3.2%) sarilumab, and 4 (12.9%) with methylprednisolone 0.5mg/kg Q12h. Seventeen patients (54.8%) recovered and were discharged, 12 (38.7%) died;2 (6.5%) were still hospitalized but left the ICU. Conclusion: In our cohort, there were predominantly more patients with MM and CLL and 56% of these were intubated;larger cohort studies will further define the risk and outcome for COVID-19 in patients with HM.