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Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

Introduction: Natural Killer cells (NK) play an important role in tumor immune-surveillance. The innate cell engager AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NK. This study evaluates AFM13's clinical and immunological activity. It examines the immunologic changes in the tumor and in peripheral blood (PB) as a function of the dose and method of administration of AFM13. Methods: Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 4 cohorts: 1.5 mg/kg IV weekly, 7 mg/kg IV weekly, 7 mg/kg continuous intravenous infusion (CIVI) over 5 days weekly and 200mg IV weekly. Each cohort consisted of 3 subjects with 3 additional subjects in cohort 4. Subjects received 8 weeks of therapy for up to 2 cycles. Response assessment was performed on week 11 of each cycle by mSWAT, photography, PET imaging and PB flow cytometry. A second cycle was administered if there was no progression. Subjects underwent skin biopsies and PB immunologic studies as follows: pretreatment, day 5, week 4 and week 8 of therapy. Biopsies were analyzed and evaluated by a pathologist and IHC image analyzer. PB samples were analyzed by flow cytometry. Results: Fourteen subjects were accrued. The median number of prior therapies was 4 (1-11) and 4 subjects had progressed on brentuximab vedotin. The disease etiologies, treatment emergent toxicities and response by cohort are presented in Table 1. An objective response rate of 40% was observed in the study. In the PB, flow cytometry revealed a decrease in circulating NK (CD16/56+ CD3- CD19- lymphocytes) during therapy with post therapy recovery. The activation marker CD69 on NK increased in responders (R) compared to non-responders (NR). Similarly, tumor biopsies in R showed increased infiltration and activation of CD56+ NK as opposed to NR (Figure 1). NK cytotoxicity through the expression of Granzyme B was seen in R vs. NR. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) showed a decrease in R vs. NR. Conclusions: AFM13 demonstrated a high ORR of 40% among a population of heavily pretreated subjects with CD30 positive lymphoproliferative T-cell malignancies. AFM13 exhibited activity post brentuximab vedotin failure. In addition, biological changes in NK infiltration and activation in the PB and tissue biopsy correlated with response. These data are the first to demonstrate that innate cell engagers modulate NK and T cell populations in the peripheral blood and tumor from patients and to determine that such changes are associated with patient benefit. Disclosures Sawas: Roche: Current equity holder in publicly-traded company; Affimed: Research Funding; Daiichi Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; Flatiron Health: Current Employment. Chen:Affimed: Research Funding. Lipschitz:Affimed: Research Funding. Rodig:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Affimed: Research Funding; KITE/Gilead: Research Funding; Immunitas: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

Background: The effects of spaceflight on human physiology are complex and represent a sum of many factors, the main two of which are microgravity and space radiation. The latter is composed of high-energy protons and HZE particles, along with secondary radiation produced in shielding and tissue. One major concern is short- and long-term radiation-induced injury to the hematopoietic system, one of the most radiosensitive tissues in the human body. Previous studies demonstrated functional and/or numerical changes in T and /or B-cells of crewmembers of STS-41B and STS-41D and altered myelopoiesis during STS-63 and STS-69. Although these changes reversed post return, they persisted in space and were more recently documented during a six month mission to the International Space Station. The main goal of NASA's space radiation research program is to enable human space exploration within acceptable risks and to reduce uncertainties regarding risk projections. We present the first ground based in vivo study evaluating the effects of high- and low-LET radiation on the human immune system by using a reconstituted human hematopoietic system in a humanized mouse model. We measure post-radiation depletion and repopulation kinetics, tumor formation and DNA damage. Methods: NSG mice were irradiated with 2Gy of gamma rays and injected 20 hours later with 2x105 CD34+cells isolated from cord blood. After a 12 week engraftment period, peripheral blood flow cytometry with anti-human and anti-mouse antibodies (human and mouse CD45, human CD3 and human CD19) was performed to confirm engraftment (>50% of human cells in moue blood, Figure 1). We irradiated the humanized-NSG mice (hu-NSG) with 0.2 or 0.4 Gy of 350 MeV/n28 Si-ions, which are established components of LET radiation. We measured changes in peripheral blood mononuclear cell counts (huCD45+PBMC) 7 and 30 days post irradiation to assess early effects and recovery kinetics. Multicolor flow cytometric immunophenotyping (FCI) analysis of tissue and blood samples was performed according to standard cell surface staining protocols. Conventional cytogenetic analysis was performed 5 months post radiation on enriched fractions of human HSC and progenitor cells, isolated from marrow of irradiated mice. We performed secondary transplants to transmit the genetic changes imparted by irradiation in the first animal to the secondary host system to allow further monitoring. In addition whole exome and transcriptome sequencing is underway on stem cell and progenitor (lineage negative) pools on a subset of mice. Results: To date 120 well engrafted NSG mice were irradiated with 0.2 or 0.4 Gy of 350 MeV/n28 Si-ions. No decrease versus a mild decrease of huCD45+ PBMCs was observed on day 7 in the 0.2 and 0.4 Gy radiated cohort respectively, with the latter demonstrating full recovery on day 30 compared to normal control mice (Figure 2). No lymphoproliferative or myeloproliferative disorder was noted in 46 irradiated mice using 8 color FCI analyses. Median percentage of peripheral blood mature B-cells, T cells and NK cells was 41%, 36.5% and 9% respectively. Kappa /lambda ratio, CD4/CD8 ratio and NK cell/T cell ratio were 0.9, 3.6, and 0.3 respectively. Bone marrow evaluation demonstrated 0.08% to 0.3% myeloblasts (median: 0.15%) positive for CD34 /CD117/CD33 and HLADR. Moderate monocytosis (CD64+/CD4+/HLA-DR+) was noted, ranging from 39% to 51% (median 47%). Preliminary results of cytogenetic analysis revealed diploid male and female karyotypes without abnormalities in at least 20 metaphases analyzed. Successful secondary transplants were performed in 30 mice. Results of whole exome and transcriptome sequencing are pending. Conclusions: This study shows for first time data on the effects of high -LET space type of radiation on human hematopoietic system in vivo. Preliminary results show that high-LET 350 MeV/n 28 Si radiation has relatively minor effects on peripheral blood cell counts and depletion/recovery kinetics. In addition our preliminary analysis did not demonstrate a leukemogenic effect in the short time period (months) assessed after the irradiation. The study is currently in progress and more data will be available. Disclosures No relevant conflicts of interest to declare.