Abstract: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders. Objective To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection. Design, Setting, and Participants This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023. Exposures Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment. Main Outcomes and Measures Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection. Results A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65] ; P   & amp;lt; .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32] ; P   & amp;lt; .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P   & amp;lt; .001), age 65 years or older (aHR vs age & amp;lt;65 years, 0.57 [95% CI, 0.50-0.64]; P   & amp;lt; .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P  = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20] ; P   & amp;lt; .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P  = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P  = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs & amp;lt;65 years, 1.75 [95% CI, 1.32-2.31]; P   & amp;lt; .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14] ; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P  = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P  = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P   & amp;lt; .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P   & amp;lt; .001). Conclusions and Relevance In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

Abstract: Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3] ), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Abstract: Background For patients who are less than 65 years with newly diagnosed AML, standard induction treatment is continuous infusion cytarabine for 7 days and an anthracycline for 3 days (7+3). Although a high percentage of patients achieve an initial CR by morphologic criteria, some requiring a 2nd induction, a significant number of patients are either primarily resistant to treatment or achieve a morphologic CR but with flow cytometric or molecular evidence of minimal residual disease (MRD). CD33, a cell surface antigen, is expressed in approximately 90% of AML, representing a promising target of therapy regardless of genetic or mutational heterogeneity. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Addition of 33A to 7+3 chemotherapy could result in enhanced and deeper (MRD negative) remissions, resulting in reduced relapse rates and improved overall survival. Methods This phase 1b study (NCT02326584) evaluated the safety and antileukemic activity of escalating doses of 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2). AML patients (ECOG status 0-1) must be eligible to receive induction therapy. 33A is given on Days 1 and 4 concomitantly with the combination treatment. Response assessments occur on Days 15 and 28; investigator assessment of response is per IWG criteria (Cheson 2003). A 2nd induction regimen and post-remission therapies were per investigator choice and did not include additional administration of 33A. MRD was assessed centrally by bone marrow examination using a multi-parametric flow cytometric assay at Days 15 and Day 28. Results To date, 42 patients (36% male) with a median age of 45.5 years (range, 18-65) have been treated with 10+10 (n=4) and 20+10 (n=38) mcg/kg of 33A. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by MRC criteria and 17% of patients had secondary AML. As expected, all patients experienced Grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from Day 1 of therapy was 33 days for neutrophils (≥1K) and 35 days for platelets (≥100K). Three DLTs (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred at the 20+10 mcg/kg dose level, which was determined to be the maximum tolerated dose (MTD) of 33A in combination with 7+3. No non-hematologic treatment emergent adverse events (AEs) ≥Grade 3 were reported in 〉 15% of patients; Grade 1 or 2 non-hematologic AEs occurring in 〉 15% of patients were nausea (55%), diarrhea (33%), constipation (31%), decreased appetite (19%), fatigue (19%), and vomiting (17%); no infusion-related reactions occurred. No veno-occlusive disease (VOD) or significant hepatotoxicity was observed. The 30- and 60-day mortality rates were 0% and 7%, respectively. Of the 40 efficacy evaluable patients, best responses include 24 CR (60%), 7 CRi (18%), and 4 morphologic leukemia-free state (10%) with a CR+CRi (CRc) rate of 78%; 94% of CR or CRi responses occurred with 1 cycle of induction therapy. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status. Median OS is not yet reached; 36 patients were alive at the time of this data cut with 6 patients (14%) still on treatment. Pharmacokinetic data demonstrate rapid elimination of 33A. Conclusions 33A can be safely combined with 7+3 with acceptable count recovery and the recommended phase 2 dose is 20+10 mcg/kg on Days 1 and 4. An alternate schedule of single-day dosing on Day 1 is under investigation and enrollment continues. Extramedullary AEs, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 alone in this AML population. A high remission rate within the 1st induction cycle was observed, the majority of which were MRD negative. Disclosures Erba: Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Jannsen: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Astellas: Research Funding; Juno: Research Funding. Levy:Millennium: Speakers Bureau; Amgen: Speakers Bureau; Jansen: Speakers Bureau; Seattle Genetics: Research Funding. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Bexalata: Other: Advisory Board participation. Advani:Seattle Genetics: Consultancy, Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Wood:Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement. Walter:Covagen AG: Consultancy; Astra-Zeneca: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Research Funding; Amgen: Research Funding; Celator Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Seattle Genetics: Research Funding; Emergent Biosolutions: Consultancy; Agios: Consultancy; Arog: Research Funding. Yang:Seattle Genetics: Research Funding. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding.