Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy;An Open-Label, Multicenter, Phase 1b Study

Background: Acute myeloid leukemia (AML) is driven by aberrant leukemic stem cells (LSCs) that initiate and sustain malignancy. To circumvent resistance to therapy, combination therapies with additive mechanisms of action are needed. CD70, a tumor necrosis factor receptor ligand, and its receptor CD27 are expressed on LSCs and AML blasts, but not on hematopoietic stem cells. Cusatuzumab, a high-affinity humanized monoclonal anti-CD70 antibody, kills CD70-expressing cells by Fc domain-mediated effector functions and is a potent inhibitor of CD70-CD27 signaling. Here we report initial results of a study of cusatuzumab in combination with the current standard of care therapy, venetoclax plus azacitidine (CVA), in patients with untreated AML (de novo or secondary) ineligible for intensive chemotherapy due to age ≥75 years or medical comorbidities. Methods: The primary objective of this open label, multicenter, phase 1b study was to assess safety and tolerability of CVA. Key secondary objectives included response rate per ELN 2017 criteria and time to response. Patients received cusatuzumab 10 or 20 mg/kg IV on Day 3 and Day 17, a 3-day ramp-up of venetoclax (100, 200, and 400 mg PO) followed by 400 mg daily dosing, and azacitidine 75 mg/m 2 SC or IV on Days 1-7 of each 28-day cycle. Results: Based on data through Jul 9, 2021, 44 patients enrolled with median age 75 years (range 32-89), 36.4% had secondary AML, 40.9% had an ECOG performance status of 2, and ELN risk was favorable, intermediate and adverse in 18.2%, 20.5% and 61.4%, respectively. All patients received 20 mg/kg cusatuzumab except for 3 patients who received a starting dose of 10 mg/kg with the option to escalate to 20 mg/kg. Of these 3 patients, 1 escalated to 20 mg/kg. At a median follow-up of 29.1 weeks, the median number of treatment cycles was 4.0 (range 1.0-11.0). Grade 3 or above TEAEs were reported in 97.7% of patients;the most common (reported in ≥10%) were neutropenia (68.2%), thrombocytopenia (65.9%), febrile neutropenia (36.4%), anemia (34.1%), leukopenia (29.5%), sepsis (27.3%), and lymphopenia (15.9%). Treatment-emergent serious adverse events (SAEs) were reported in 75% of patients;the most common (reported in at least ≥5%) were febrile neutropenia (27.3%), sepsis (22.7%), COVID-19 (6.8%), and thrombocytopenia (6.8%). Treatment-emergent SAEs of grade ≥3 were reported in 72.7% of the patients. Infusion-related reactions (IRRs) were reported for 11.4% of patients with 2.3% at grade ≥3. Six (13.6%) patients discontinued treatment due to AEs, and 5 (11.4%) TEAEs resulted in death. The mortality rate within 30 days from start of treatment was 4.5%. Table 1 summarizes best response to study treatment. In the intent-to-treat analysis set (n=44) complete remission (CR) rate was 45.5%, while CR + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi) was 77.3%;MLFS was observed in 11.4% of patients. Of 34 responders (defined as CR, CRi or CRh), 47% were MRD negative by flow cytometry at or after achievement of response. Median time to first response for patients who achieved CR, CRh or CRi was 4.21 (3.0-25.0) weeks. Best response rates in the post-hoc response evaluable analysis set (n=42) that excluded two patients who died before the first disease evaluation were: CR in 47.6%, CR + CRh + CRi in 81.0% and MLFS in 11.9% of patients (Table 1). The majority (97.1%) of responders experienced at least one cycle delay in administration of CVA post response. Conclusions: Cusatuzumab administered in combination with venetoclax and azacitidine to elderly patients with untreated AML was generally well tolerated and demonstrated a safety profile consistent with that previously reported with venetoclax-azacitidine, with the addition of generally manageable IRRs. Response rates support an additive effect of cusatuzumab to the standard of care with potential for improved clinical outcomes. However, further clinical trials are needed for validation of these initial results. HK and GB contributed equally to this publ cation. [Formula presented] Disclosures: Roboz: AstraZeneca: Consultancy;Janssen: Research Funding;Bristol Myers Squibb: Consultancy;Jasper Therapeutics: Consultancy;Agios: Consultancy;Novartis: Consultancy;Amgen: Consultancy;Blueprint Medicines: Consultancy;Janssen: Consultancy;Helsinn: Consultancy;Daiichi Sankyo: Consultancy;Glaxo SmithKline: Consultancy;Celgene: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Mesoblast: Consultancy;Actinium: Consultancy;AbbVie: Consultancy;Astex: Consultancy;Bayer: Consultancy;Astellas: Consultancy;Roche/Genentech: Consultancy;Pfizer: Consultancy;Otsuka: Consultancy. Aribi: Seagen: Consultancy. Brandwein: Astellas: Honoraria;Jazz: Honoraria;Amgen: Honoraria;Taiho: Honoraria;BMS/Celgene: Honoraria;Pfizer: Honoraria;Abbvie: Honoraria;University of Alberta: Current Employment. Döhner: Astellas: Consultancy, Honoraria, Research Funding;AstraZeneca: Consultancy, Honoraria;Berlin-Chemie: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria, Research Funding;Agios: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;GEMoaB: Consultancy, Honoraria;Helsinn: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Jazz: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Oxford Biomedicals: Consultancy, Honoraria;Pfizer: Research Funding;Roche: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding;Astex: Consultancy, Honoraria;Ulm University Hospital: Current Employment. Fiedler: Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance;Abbvie: Consultancy, Honoraria;Morphosys: Consultancy;Celgene: Consultancy;Pfizer: Consultancy, Research Funding;Novartis: Consultancy;ARIAD/Incyte: Consultancy;Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding;Servier: Consultancy, Other: support for meeting attendance;Daiichi Sankyo: Consultancy, Other: support for meeting attendance;Stemline: Consultancy. Gandini: argenx: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Geddes: University of Calgary: Current Employment;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy;Paladin: Consultancy;Janssen: Research Funding;Geron: Research Funding;Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hou: University of Pittsburgh Medical Center Hillman Cancer Centers: Current Employment;AbbVie: Honoraria;AstraZeneca: Honoraria;Karyopharm: Honoraria;Chinese American Hematology Oncology Network: Membership on an entity's Board of Directors or advisory committees. Howes: Janssen R&D, part of Johnson & Johnson: Current Employment;Johnson & Johnson: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hultberg: argenx: Current Employment, Patents & Royalties. Huselton: University of Rochester: Current Employment. Jacobs: Argenx BV: Current Employment, Current equity holder in publicly-traded company;University of Antwerp: Ended employment in the past 24 months. Kane: Janssen R&D, part of Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Lech-Marańda: Takeda: Membership on an entity's Board of Directors or advisory committees;AbbVie: Membership on an entity's Board of Directors r advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Roche: Membership on an entity's Board of Directors or advisory committees;Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Louwers: argenx: Current Employment, Patents & Royalties: Patents (no royalties). Nottage: Janssen R&D, part of Johnson & Johnson: Current Employment;Johnson & Johnson: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Platzbecker: Novartis: Honoraria;AbbVie: Honoraria;Janssen: Honoraria;Celgene/BMS: Honoraria;Geron: Honoraria;Takeda: Honoraria. Rampal: Pharmaessentia: Consultancy;BMS/Celgene: Consultancy;Abbvie: Consultancy;Sierra Oncology: Consultancy;Incyte: Consultancy, Research Funding;Blueprint: Consultancy;Disc Medicine: Consultancy;Jazz Pharmaceuticals: Consultancy;Constellation: Research Funding;Kartos: Consultancy;Stemline: Consultancy, Research Funding;CTI: Consultancy;Novartis: Consultancy;Memorial Sloan Kettering: Current Employment. Salman: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shah: Janssen R&D, part of Johnson & Johnson: Current Employment. Stuart: Clinical Drug Development Consultants LLC: Current Employment;Argenx: Consultancy;Cleave Therapeutics: Consultancy;Triphase Accelerator Corp: Consultancy;IgM Biosciences: Consultancy;Revolution Medicines: Consultancy;Jiya Corp:Consultancy;Geron Corp: Current holder of individual stocks in a privately-held company. Subklewe: Janssen: Consultancy;Pfizer: Consultancy, Speakers Bureau;Takeda: Speakers Bureau;Klinikum der Universität München: Current Employment;MorphoSys: Research Funding;Novartis: Consultancy, Research Funding, Speakers Bureau;Roche: Research Funding;Seattle Genetics: Consultancy, Research Funding;Miltenyi: Research Funding;Gilead: Consultancy, Research Funding, Speakers Bureau;Amgen: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. Sumbul: argenx: Current Employment. Wang: Takeda: Consultancy, Honoraria, Other: Advisory board;Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board;Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees;Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board;GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board;Genentech: Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Membership on an entity's Board of Directors or advisory committees;DAVA Oncology: Consultancy, Speakers Bureau;Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau;Novartis: Consultancy, Honoraria, Other: Advisory Board;Mana Therapeutics: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau;Rafael Pharmaceuticals: Other: Data safety monitoring committee;Gilead: Consultancy, Honoraria, Other: Advisory board;Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board;PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board;Genentech: Consultancy;MacroGenics: Consultancy. Wierzbowska: Jazz: Research Funding;Pfizer: Honoraria;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Astellas: Honoraria, Membership on an entity's Board of Directors or advisory comm ttees;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS: Honoraria. Yao: Statagize LLC: Current Employment;Puma Biotechnology, Inc.: Ended employment in the past 24 months;Argenx: Consultancy. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Research Funding;TaiHo: Membership on an entity's Board of Directors or advisory committees;Otsuka: Membership on an entity's Board of Directors or advisory committees;Onconova: Research Funding;Pfizer: Membership on an entity's Board of Directors or advisory committees;Tolero: Research Funding;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Paladin: Membership on an entity's Board of Directors or advisory committees;MedImmune: Research Funding;AbbVie: Honoraria;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Forma Therapeutics: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;Geron: Research Funding;Genentech: Research Funding;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Jazz: Research Funding. Kantarjian: Immunogen: Research Funding;Astra Zeneca: Honoraria;KAHR Medical Ltd: Honoraria;Astellas Health: Honoraria;Pfizer: Honoraria, Research Funding;NOVA Research: Honoraria;Ascentage: Research Funding;Precision Biosciences: Honoraria;Novartis: Honoraria, Research Funding;Aptitude Health: Honoraria;Ipsen Pharmaceuticals: Honoraria;Jazz: Research Funding;Daiichi-Sankyo: Research Funding;BMS: Research Funding;Amgen: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;Taiho Pharmaceutical Canada: Honoraria. Borthakur: Protagonist: Consultancy;Ryvu: Research Funding;Astex: Research Funding;GSK: Consultancy;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;University of Texas MD Anderson Cancer Center: Current Employment;ArgenX: Membership on an entity's Board of Directors or advisory committees.

COVID-19 Vaccination after Allogeneic Stem Cell Transplantation: Real Word Data on Safety and Efficacy. a Single Center Experience

Introduction Different vaccines have been recently approved by FDA and EMA for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating a protection rate ranging from 60% to almost 95% in phase II/III trials. Immunocompromised patients, including those undergoing allogeneic stem cell transplantation (allo-SCT), were excluded from vaccine trials. While EBMT recommended the vaccination for transplanted patients, data concerning efficacy and safety in this particular setting are scarce. Since infections represent a relevant cause of transplant-related mortality and the treatment and management of SARS-CoV-2 infection in allo-SCT patients proved to be challenging and complex, we prospectively evaluated the safety and the development of protective response against SARS-CoV-2 vaccines in our allogeneic transplanted patients. Materials and Methods Starting in March 2021, allogeneic stem cell transplanted patients with different hematological diseases underwent COVID-19 vaccination. Taking into account the EBMT recommendations, we considered patients suitable for vaccination when (1) they were at least 3-6 months after allo-SCT, (2) didn't have any graft versus host (GvHD) activity, and (3) received less than 0,5 mg/kg steroids as part of the immunosuppressive treatment. There was no recommendation for a specific type of vaccine, with the only exception for life-attenuated vaccines, which are mostly contraindicated in the post allo-SCT setting. Vaccinated patients were regularly monitored for the potential development of adverse events. The anti-SARS-CoV-2 Spike protein antibodies were measured in blood samples to assess the humoral response. In case of no response with undetectable anti-Spike antibodies 2 week after the second dose of vaccine, we repeated the measurements at regular intervals until week + 6-8 after the completion of vaccination. Patients with no measurable antibodies 8 weeks after completion of the vaccination were considered as no responders. Results Between 03/2021 and 06/2021 a total of 83 patients underwent COVID-19 vaccination (including first and second dose) during the post allo-SCT follow-up. Patients' characteristics are listed in Table 1. Most patients (77%) received BNT162b2, while only a small subgroup (8%) underwent a mixed vaccination after a first dose of ChAdOx1-S. We considered the mixed vaccination mostly to maximize the response. Overall, the two vaccine doses were well tolerated, with only 5% of patients developing a reactivation of GvHD. No relevant grade 3 or 4 organ toxicities were observed. Overall, 66% of patients in our cohort showed a humoral response. The incidence of positive serology was lower in patients who underwent the vaccination within the first 18 months after allo-SCT (29% vs 83% for patients >18 months after allo-SCT, p< 0.001). In multivariate analysis other risk factors that were associated with poor or no response were lack of immune reconstitution (p< 0.001) and ongoing immunosuppressive therapy (p= 0.009). The age of patients at the time of vaccination, sex, intensity of conditioning regimen and the use of ATG did not prove to have an influence for a humoral response during the post-transplant follow up. Discussion The achievement of a protective immunity against SARS-CoV-2 represents a crucial event for a frail population, like allogeneic stem cell transplanted patients. So far and to our knowledge little is known about the safety and efficacy of the COVID-19 vaccination in this particular setting. Here, we report one of the first series of patients undergoing COVID-19 vaccination after allo-SCT. We demonstrated that a humoral response can be achieved, especially for those patients who are in the long-term follow-up, underwent immune reconstitution and are free from immunosuppressive drugs. For the other patients, who represent the frailer subgroup, in the absence of a documented immune response after 2 doses of vaccine, the option of a third dose in order to increase the probability of response should be evaluated in prospective clinical trials. [Formula presented] Disclosures: Viardot: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;University Hospital of Ulm: Current Employment;Amgen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Roche: Consultancy, Honoraria;Agios: Consultancy, Honoraria, Research Funding;Astellas: Consultancy, Honoraria, Research Funding;Jazz: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Ulm University Hospital: Current Employment;Abbvie: Consultancy, Honoraria, Research Funding;Oxford Biomedicals: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Astex: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;AstraZeneca: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding;Helsinn: Consultancy, Honoraria;Pfizer: Research Funding;Berlin-Chemie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;GEMoaB: Consultancy, Honoraria. Sala: Novartis: Consultancy, Honoraria;Celgene/BMS: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Jazz: Consultancy, Honoraria.