Autoimmune pulmonary alveolar proteinosis in an adolescent girl with rapidly progressive dyspnea

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease, especially in pediatrics, but important to consider, as it may avoid unnecessary and/or invasive investigations and delayed diagnosis. This case report highlights an adolescent girl with rapid onset dyspnea but an unremarkable physical exam and initial testing. However, due to a high index of suspicion, a chest computed tomography (CT) scan was done, revealing a "crazy paving" pattern, which then prompted expedited assessment. This finding, however, is not as specific as often discussed and has a broad differential diagnosis, which will be reviewed in detail as part of this case. Furthermore, this report demonstrates a diagnostic approach for PAP that avoids lung biopsy, previously considered to be required for diagnosis of PAP, but is increasingly becoming unnecessary with more advanced blood tests and understanding of their sensitivity and specificity. Additionally, management strategies for PAP will be briefly discussed.Copyright © 2022 Canadian Thoracic Society.

Evaluation of clinical outcomes of COVID-19 in patients taking remdesivir in complex therapy in routine clinical practice

Remdesivir (GS-5734) is a new direct-acting antiviral drug in the nucleotide analogue class with antiviral activity against SARS-CoV-2 and the ability to inhibit RNA-dependent RNA polymerase. Preliminary results from phase III randomized clinical trials of remdesivir are inconsistent. Understanding the fact of the limited world experience with the use of remdesivir in COVID-19 required further study of its efficacy and safety in real clinical practice. The aim of the study is to evaluate the efficacy and safety of remdesivir in the treatment of patients with COVID-19. Material and methods. The study included 1422 patients with a novel coronavirus infection (COVID-19) who received remdesivir as part of complex therapy in a hospital setting at medical organizations of the Moscow public health system. Additionally, standard therapy was carried out, regulated by the Interim Guidelines "Prevention, Diagnosis and Treatment of Novel Coronavirus Infection (COVID-19)" of the Ministry of Healthcare of the Russian Federation, the current version. The efficacy of the drug was assessed based on primary and secondary efficacy points. Primary variable: 1) cumulative incidence of clinical outcomes in patients with COVID-19 treated with remdesivir as part of complex therapy;2) median time to clinical improvement according to the World Health Organization ordinal categorical scale (under clinical improvement, the patient is assumed to move >2 categories towards improvement in clinical condition). Secondary variables: 1) median time to achieve <2 NEWS scores lasting at least 24 hours or hospital discharge;2) mortality from all causes;3) duration of fever (>38 degreeC), days;4) duration of hospitalization, days;5) time to achieve elimination of the pathogen from the upper respiratory tract (no SARS-CoV-2 RNA), days. The safety of remdesivir was assessed based on the registration of adverse events using the method of spontaneous reports. Results. The analysis of clinical outcomes of treatment showed that 1195 (84.1%) patients recovered, death from all causes occurred in 227 (15.9%) patients. The median improvement in clinical status on the World Health Organization ordinal categorical scale was 6 days. The median time to reach a NEWS score of <2, lasting at least 24 hours, or hospital discharge was 4 days. The median duration of fever was 3 days from the start of remdesivir administration. The median length of hospital stays for patients included in the Register was 9 days. Adverse reactions associated with the use of remdesivir were recorded in 11 (0.7%) patients. Serious adverse reactions were not registered. During hospitalization, all adverse reactions were resolved. Conclusion. A retrospective analysis of data from the Registry of 1422 patients with COVID-19 who received remdesivir as part of complex therapy in medical organizations of the state healthcare system of Moscow in routine clinical practice showed clinical efficacy and a favorable safety profile of remdesivir (Remdeform, lyophilizate for solution for intravenous administration 100 mg, manufactured by JSC Pharmasyntez, Russia). The data obtained are consistent with previous randomized clinical trials of remdesivir and allow us to recommend its further use in patients with COVID-19 as part of complex therapy.Copyright © The Author(s), 2022.

EFFICACY AND SAFETY OF TWO DIFFERENT LOW-DOSE RITUXIMAB REGIMENS FOR CHINESE CHILDREN PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA

Background: Rituximab is one of the second-line treatments for ITP. At present, there are few studies on low-dose rituximab, lacking of a large number of prospective and randomized trials to support the efficacy and safety of lowdose rituximab, especially in children's ITP. Influenced by COVID-19, we used two low-dose rituximab regimens before and after March 2020 for second-line treatment of children's ITP. Aims: To compare the efficacy and safety of two different regimens for low-dose rituximab of children patients with chronic /refractory ITP, so as to provide basis for clinical treatment. Methods: 83 children patients were enrolled in this study and non-randomly assigned to receive 100mg/200mg (body weight 30kg) rituximab weekly for 4 weeks (group A, 53 cases) or a single dose of 375mg / m2 rituximab (group B, 30cases). The study was follow-up for at least half a year. Results: The baseline data of group A and B were the same. For group A: Overall and complete response (OR and CR) rates were 35.8% and 15%, respectively;the side effects rate is 3.8%. In responders, the median time to response was 4 (1 -12) weeks, with a median follow-up time of 12 (6 ∼ 36) months, 6 of 19 responders (31.6%) relapsed. For group B: OR and CR rates were 36.7% and 23%, respectively;the side effects rate is 10%. In responders, the median time to response was 1 (1 ∼ 4) weeks, with a median follow-up time of 11.5 (6 ∼ 17) months, 4 of 11 responders (36.4%) relapsed. No significant difference in the OR, NR, relapse free survival and incidence of side effects was observed in patients between the two groups. Image: Summary/Conclusion: The two low-dose rituximab regimens in the treatment of ITP in children both are safe and effective;The single-agent scheme is more recommended because of easier use and not increasing safety events.

IBRUTINIB AND RITUXIMAB AS FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA: A MULTICENTRE, REAL-WORLD UK STUDY

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

USEFULNESS of AN ELECTRONIC CONSULTATION SYSTEM between PRIMARY CARE HEALTH CENTERS and RHEUMATOLOGY DEPARTMENT of A TERTIARY HOSPITAL

Background: The EPISER study is the frst Spanish epidemiological study that has confrmed the great burden of rheumatic diseases in the general population: they consume a large quantity of health resources (doctor visits, medical products) and imply a high social impact in terms of work absenteeism. Rheumatic diseases represent almost 30% of Primary Care medical consultations in Spain1,2. Electronic consultation could be an alternative response to the increase of this demand, both to make an early diagnosis and derivation and to improve communication with Primary Care physicians3,4. Objectives: To analyze the demand of Primary Care and its resolution through the electronic consultation system of the Rheumatology Department of a tertiary hospital. Methods: Retrospective descriptive study of the data collected in the request and information system (Sistema de Peticiones Electrónicas, SIPE) that supports electronic consultation between primary care physicians of the health area and the Rheumatology Department of a tertiary hospital, between July 2020 and May 2021.The following variables were collected: age, sex, reason for consultation, response time in days and destination (primary care/outpatient follow-up). Descriptive statistics were used to present the results. Results: The last 500 consecutive electronic consultations registered in the system, referring to 496 patients, were collected. Mean age was 59.5±17.7 years;74.2% women. Mean response time was 2 days, median response time 1 day and range 0-45. The reasons for consultation (see Graph 1) were: osteoporosis assessment 55 (11%), treatment adjustment 50 (10%), appointment request 49 (9.8%), loss to follow-up 43 (8.6%), local-regional pathology assessment 39 (7.8%), infltration request 28 (5, 6%), suspected rheumatoid arthritis 19 (3.8%), fare 18 (3.6%), suspected polymyalgia rheumatica or giant cell arteri-tis 16 (3.2%), COVID vaccine consultation 14 (2.8%), Raynaud's phenomenon 13 (2.6%), monoarthritis assessment 12 (2.4%), assessment of polyarthritis 11 (2.2%), adverse effects of treatment 11 (2.2%), suspected spondyloarthritis 11 (2.2%), suspected psoriatic arthritis 8 (1, 6%), generalized pain 7 (1.4%), suspected Sjögren's syndrome 5 (1%), suspected systemic lupus erythematosus 1 (0.2%), suspected other systemic autoimmune diseases 9 (1.8%), others 81 (16.2%). Fifty-seven and four % (287) of the patients required an appointment at the Rheumatology outpatient clinic and in 42.6% of the patients (213) the electronic consultation was successful, so it was not necessary to refer the patient to the hospital. Conclusion: Forty-two and six percent of the queries were resolved thanks to the electronic consultation system in an average of two days, otherwise that patients would have been referred to specialized care. The main reasons for consultation were osteoporosis assessment and clarifcation of doubts about the treatment of patients who were already being followed up by the Rheumatology Department.

ASSESSING THE UTILIZATION OF INPATIENT ECONSULTS DURING COVID-19

BACKGROUND: Electronic consultations (eConsults) are formal, asynchronous clinical consultations between primary care providers and specialists. With increasing implementation of inpatient eConsult programs, studies have classified the most frequently consulted departments and reported hospitalist satisfaction, with logistic discussion of inpatient eConsults. However, there are no studies analyzing the time to inpatient eConsult response and the prevalence of COVID-19 in eConsult patients. METHODS: A retrospective chart review of inpatient eConsults at a single U.S. tertiary care medical center from 3/26/20 to 10/8/20. We reviewed patient demographics, COVID-19 status, type of consult question, time to response, conversion rate to a face-to-face visit, and recommendation for outpatient specialty follow-up. RESULTS: There were 538 documented eConsults for 417 patients, with an average age of 52.8 years, 59.0% male, 72.9% white. The most frequently eConsulted departments were Physical Medicine and Rehabilitation (25.7%), Hematology Oncology (13.2%), and Cardiology (7.80%). Inpatient eConsults were predominately regarding patient management questions (87.9%), compared to questions about diagnosis (14.3%) and interpretation of labs or imaging (14.9%). eConsults with multiple question types (15.8%) were more frequent than previously observed in studies of outpatient eConsults. The majority of eConsults were answered and resolved by specialists after one note (61.7%);however, 34.9% of eConsults were followed virtually with multiple notes, and 3.35% were converted to face-to-face consults. Outpatient specialty follow-up was recommended in 12.6% of eConsults. Only 92 (17%) eConsults were linked to orders, enabling measurement of the time the note was signed by the consultant attending physician. The median time from eConsult order until the attending note signature was 14.1 hours. 65.2% of these eConsults had a response within 1 day. 68 study patients (16.3%) were hospitalized with COVID-19, comprising 123 (22.9%) inpatient eConsults. 1.63% of COVID-19 eConsults were converted to face-to-face consultations versus 3.86% of non-COVID-19 eConsults. 72 patients (17.3%) had multiple eConsults, with 39 (9.35%) of these patients having eConsults to multiple different specialties. Of these 39 patients, 21 had COVID-19 during their hospitalization, a higher proportion than the nonCOVID-19 cohort, χ2 (1, N = 417) = 28.083, p < 0.001. CONCLUSIONS: Evaluation of our inpatient eConsult program demonstrates that the majority of eConsults were regarding patient management, with few consults requiring conversion to face-to-face encounters. The findings also reveal an association of multiple specialty eConsults for COVID19 patients. Additionally, inpatient eConsults provide an avenue for reducing consultant exposure to COVID-19. Further efforts can focus on improving the workflow in an effort to optimize consultant response times and assessing the conclusion of outpatient specialty follow-up recommendations.

Development of a digital tool for home-based monitoring of skin disease for older adults

The COVID-19 pandemic has accelerated the adoption of telemedicine. However, current tools pose substantial barriers for older adults and those with low digital literacy. By implementing user-centered design, we developed a digital tool, Dermatology for Older Adults (DORA), for home-based monitoring of skin disease, specifically designed for older adults. DORA is a virtual assistant based on REDCap and Twilio APIs that automates image and symptom collection and allows communication between patients and the research team. We evaluated the feasibility, usability, patient compliance, retention, and clinical utility of DORA. Eligibility criteria included patients >70 years with any skin disease, access to a smartphone, and no cognitive impairment. We recruited 62 patients aged 70-94 (mean age 77), 39% female, 81% white from Stanford’s Dermatology Clinic from August-December 2021. We asked patients to send weekly photos and answer a questionnaire of a single skin lesion for 4 weeks, then monthly for 4 months. We measured response time, photo quality, and participant satisfaction using mHealth app usability questionnaire (MAUQ). The median response time was 1.4 days (IQR 0.6-3.4). Four participants dropped out. 83% completed photo submission requests (48% at initial request, 19% after 1st reminder and 16% after 2nd reminder). 80% of all questionnaires requested (131 of 163) were completed. Four dermatology clinicians evaluated the quality of the first 88 images and reported good confidence in triaging skin diseases. MAUQ scores were high for ease of use (5.6 SD1.3), interface satisfaction (5.5 SD1.3), and usefulness (5.2 SD1.3). Patients were consistently able to use DORA to submit photos and symptoms and reported high usability and satisfaction. Patient retention was high, and clinicians felt confident making triage recommendations based on DORA images. This approach can be used in other settings where digital literacy barriers and unequal access to dermatologists contribute to healthcare disparities.

Real-world experience (RWE) of safety and efficacy of 6-weekly pembrolizumab 400mg (pem6w) plus axitinib (axi) in patients (pts) with advanced renal cell carcinoma (aRCC)

Background: The KEYNOTE 426 trial demonstrated pem 200mg plus axi twice daily (bd) is effective in aRCC. Pharmacokinetic modelling of pem 400 mg every six weeks demonstrated similar observed exposures to pem 200 mg every three weeks. In NHS Scotland, pem6w + axi was used during the COVID-19 pandemic to reduce hospital visits and for pts' convenience. Here, we evaluate the RWE of pem6w + axi in aRCC. Methods: Electronic medical records of pts on pem6w + axi between 1 May 2020 & 1 Jun 2021 in two large cancer centers in Scotland were analyzed retrospectively for pts' characteristics, treatment related adverse events (TRAE) and efficacy. Results: Total of 93 pts were identified (Table). At data cut off of 8 Sep 2021, with a median follow-up of 7 months (mo) (interquartile range (IQR) 5 mo;range 0-15 mo), 73 pts (78%) were alive. Clinician assessed radiological response was evaluable in 87 pts. Overall response rate (ORR) including partial response + complete response was noted in 49 pts (56%) with median time to response of 80 days (d). Clinical benefit rate including pts with ORR and stable disease was seen in 72 pts (83%). At data cut off, 24 pts (26%) had progressed with a median time to progression of 117 d (IQR: 85d). Median overall and progression free survival were not reached and follow-up continues. 81 pts (87%) had any grade and 28 pts (30%) had grade 3/4 TRAE. Immune related AE (irAE) of any grade occurred in 60 pts (65%) and grade 3/4 in 19 pts (20%). Common grade 3/4 irAE were transaminitis (10%), colitis (8%), nephritis (2%) and skin (2%). 28 (30%) and 14 pts (15%) respectively required steroids and hospitalisation for irAE with median hospital stay 6 d (range: 2-43 d). 10 pts suffered a second irAE requiring steroids and 5 pts had a second hospital stay with median hospital stay of 6 d. Any grade AE and grade 3/4 AE related to axi occurred in 67 (72%) and 14 pts (15%) respectively. Axi dose was escalated from 5mg to 7mg bd in 12 pts (13%), reduced to 3mg bd in 35 pts (38%) and 2mg bd in 10 pts (11%). 21pts (23%) on Pem and 15pts (16%) on axi discontinued treatment due to TRAE. Conclusions: Our RWE demonstrates that pem6w + axi appears to have comparable safety profile to pem 200mg + axi reported in Keynote 426 study, with the added benefits of less frequent hospital visits. Further follow up continues for efficacy in this heterogeneous pts population. Pt characteristics, total=93 (%).

A randomized phase II trial of carboplatin with or without nivolumab in metastatic triple-negative breast cancer

Background: Platinum agents induce DNA crosslinking and cause accumulation of genotoxic stress, which leads to immune activation via IFN-γ signaling, making the combination with nivolumab (PD-1 antibody) an attractive strategy to enhance the benefit of either agent alone in metastatic triple-negative breast cancer (mTNBC). Methods: In this phase II open-label, investigator-initiated, multicenter trial, patients with unresectable locally advanced or mTNBC treated with 0-1 prior lines of chemotherapy in the metastatic setting were randomized 1:1 to carboplatin (AUC 6) with or without nivolumab (360 mg) IV every 3 weeks. Stratification factors included: germline BRCA (gBRCA) status, prior neo/adjuvant platinum, and number of prior lines of metastatic therapy. After approval of PD-L1 inhibition for mTNBC, the study was amended to include first-line mTNBC only and PD-L1 status was added as a stratification factor. Patients randomized to carboplatin alone were allowed to crossover at progression to receive nivolumab (+ nab-paclitaxel post-amendment). The primary objective was to compare progression-free survival (PFS) per RECIST 1.1 criteria of carboplatin with or without nivolumab in first-line mTNBC in the S intent-to-treat (ITT) population. Key secondary objectives were objective response rate (ORR), overall survival (OS), clinical benefit rate, and duration and time to objective response. PD-L1 status was confirmed centrally using the SP142 Ventana assay (positive, ≥1% IC). Paired researchbiopsies at baseline, on-treatment and at progression were performed, if safely accessible. The trial closed to accrual prior to reaching target accrual due to approval of PD-1 inhibition in combination with platinum-based chemotherapy for PD-L1+ mTNBC. Results: Between 1/30/2018 and 12/9/2020, 78 patients enrolled. Three patients did not receive protocol treatment, and the safety analysis was conducted among the 75 that received any treatment;37 received carboplatin + nivolumab (Arm A), 38 received carboplatin alone (Arm B). Median age was 59.1 yrs (range: 25.4-75.8). Four patients (5.3%) had a known gBRCA1/2 mutation. Sixty-two (82.7%) patients received 0 prior lines (ITT population) and 13 (17.3%) 1 prior line of metastatic therapy. Sixty-seven patients (89.3%) experienced any grade ≥2 treatment-related adverse event (AE). The most frequent AE were platelet count decrease (n=40;53.3%), anemia (n=36;48.0%), neutrophil count decrease (n=33;44.0%) and fatigue (n=24;32.0%). Grade 3/4 AE were observed in 46 (61.3%) patients, and there was one grade 5 AE (COVID19 pneumonia). Any grade ≥2 immune-related AE (irAE) were observed in 25 of the 37 (67.6%) patients treated with carboplatin + nivolumab. Grade 3/4 irAE were observed in 11 (29.7%) patients. In the ITT population (32 on Arm A;30 on Arm B), median PFS was 4.2 months with carboplatin + nivolumab, and 5.5 months with carboplatin (stratified HR 0.98, 95% CI [0.51-1.88];p=0.95). ORR was 25% vs. 23.3%, respectively. At a median follow-up of 23.5 months, median OS was 17.5 months vs. 10.7 months (stratified HR 0.63, 95% CI [0.32-1.24];p=0.18). In patients with PD-L1+ mTNBC (13 on Arm A;11 on Arm B), median PFS was 8.3 months and 4.7 months, respectively (stratified HR 0.63, 95% CI [0.21-1.89];p=0.41). ORR was 23.1% vs. 27.3%, respectively. Median OS was 17.5 months vs. 9.6 months (stratified HR 0.59, 95% CI [0.20-1.75];p=0.34). Conclusions: Addition of nivolumab to carboplatin in patients with previously untreated mTNBC, unselected by PD-L1 status, did not significantly improve PFS. A trend toward improved PFS and OS was observed in patients with PD-L1+ mTNBC. Tissue, blood and intestinal microbiome biomarker analyses are planned;bulk tumor and single-cell sequencing, and TCR sequencing in peripheral blood are ongoing.

Safety and Efficacy of Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL)

Background: First-line conventional chemoimmunotherapy in MCL can be improved. Promising results have been seen with Bruton tyrosine kinase inhibitors (BTKis) in combination with venetoclax (V) and an anti-CD20 monoclonal antibody in patients (pts) with relapsed/refractory or TN MCL. Acalabrutinib (A) is a next-generation, highly selective, covalent BTKi currently approved for relapsed/refractory MCL. We report initial safety and efficacy results of the ongoing, multicenter, open-label phase 1b study of A, V, and rituximab (R) (AVR) in TN MCL. Methods: TN MCL pts aged ≥18 y with ECOG PS ≤2 were eligible. Starting on cycle 1 day 1, A was administered at 100 mg BID until disease progression or discontinuation for other reasons. R was administered at 375 mg/m 2 on day 1 of each 28-day cycle for 6 cycles, followed by maintenance every other cycle for pts achieving complete response (CR) or partial response (PR), through cycle 24. Starting on cycle 2 day 1, V was administered via an initial 5-wk ramp-up schedule (20, 50, 100, 200, and 400 mg/d) to 400 mg/d, through cycle 25. Dose-limiting toxicity (DLT) was assessed from cycle 2 day 1 to cycle 3 day 28. Primary endpoint was AVR safety. Secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) per Lugano criteria. Positron-emission tomography (PET)/computed tomography (CT) scans were performed after 3 and 6 cycles and to confirm CR at any time. CT scans were performed after 3, 6, 9, and 12 cycles, and then every 6 cycles. Longitudinal minimal residual disease (MRD) was assessed using the clonoSEQ assay in peripheral blood at PR, CR, every 6 cycles post-CR, and treatment end. Results: 21 pts were enrolled (median age 66 y [range 51-85];ECOG PS ≤1 20 [95%];Ann Arbor stage IV disease 19 [90%];bulky disease >5 cm 7 [33%];intermediate- and high-risk simplified MCL International Prognostic Index scores 11 [52%] and 4 [19%], respectively;blastoid variant 1 [5%];and Ki-67 proliferation index ≥50% 3 [14%]). Fifteen (71%) pts had bone marrow (BM) involvement at baseline. As of March 19, 2021, median time on study was 16 mo (range 8-26.2). Median (range) number of cycles administered was 15 (7-27) for A, 13.5 (5-23) for 400 mg daily V, and 12 (6-15) for R. Seventeen (81%) pts remain on study treatment and 4 (19%) have discontinued (progressive disease: n=1;COVID-19 infection: n=3). No DLTs were observed;V 400 mg daily after ramp-up was the dose chosen for triple therapy. Most common any-grade AEs in ≥20% of pts were diarrhea (13 [62%]), headache (11 [52%]), fatigue (10 [48%]), neutropenia (6 [29%]), paresthesia (6 [29%]), cough (6 [29%]), dyspnea (6 [29%]), myalgia (5 [24%]), dizziness (5 [24%]), and hypoesthesia (5 [24%]). Grade 3/4 AEs in ≥2 pts were neutropenia (5 [24%]) and pneumonia (2 [10%]). Serious any-grade AEs in ≥2 pts were COVID-19 infection (4 [19%]) and pneumonia (2 [10%]). In the 4 pts with COVID-19 infection, the events led to triple-drug discontinuation and death in 3 pts and to dose holds of A and V and event resolution in 1 pt (all considered unrelated to study treatment). Diarrhea led to V dose reduction in 1 pt. AEs led to dose holds in 12 (57%) pts and were associated with A, V, and R in 52%, 48%, and 14%, respectively. Events of clinical interest are shown in Table 1. At the end of cycle 6, ORR was 100%, with CR/PR in 90%/10% by PET/CT alone (11 of the 13 CRs by PET/CT lacked BM confirmation);the CR/PR rate by Lugano criteria with BM confirmation was 38%/62% (Table 2). Median DOR was 19 mo (95% CI 17-not estimable [NE]) overall, and not reached when the 3 pts with COVID-19 deaths were censored. Median PFS and OS were not reached. The 1-y PFS and OS rates were 89% (95% CI 62-97) and 95% (95% CI 71-99), respectively. Treating the 3 COVID-19 deaths as censored, the 1-y PFS rate was 93.8% (95% CI 63.2-99.1). Median time to initial response and best response was 2.8 mo. Twelve of 16 (75%) pts with available MRD results at cycle 6 achieved MRD negativity (10 -6), including 6 pts with

Cabopoint: A phase II study of second-line cabozantinib in patients with metastatic renal cell carcinoma (RCC)

Background: Cabozantinib is an approved therapy for advanced RCC (in the USA) and in treatment-naive patients with intermediate/poor risk, as well as following VEGF-targeted therapy (in Europe). Trial design: Cabopoint (NCT03945773) is a phase II, open-label study of cabozantinib in adults with unresectable, locally advanced or metastatic clear-cell RCC, whose disease progressed after checkpoint inhibitor therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. A target of 250 patients at 50 European sites will receive cabozantinib (60 mg once daily;self-administered at home) for ≤ 18 months after the last patient receives their first dose. Safety assessments will occur every 2 weeks up to week 4, then every 4 weeks. Patients may continue cabozantinib after disease progression if there is clinical benefit. During follow-up, patients who discontinue early will be contacted every 12 weeks to assess survival and subsequent therapy. Each cohort will have an interim analysis when 60% of patients reach 12 months of follow-up. Cabopoint has been adjusted to allow the trial to continue during the COVID-19 outbreak, protecting participants in compliance with the study protocol.1 Alternative arrangements include: study drug dispensation to the participant's home if they cannot attend the study site;safety assessments at the study site or remotely at a local health care provider, within the protocol defined window;tumour assessments at a local radiology facility if they cannot attend the study site. Enrolment is permitted if the patient can be managed in compliance with the protocol and alternative arrangements.1 The limitations, risks and impact on data privacy of such arrangements will be accounted for and documented.

Daratumumab, Bortezomib and Dexamethasone (DVd) at First Relapse for Patients with Relapsed/ Refractory Multiple Myeloma (RRMM): A UK Myeloma Research Alliance (UK-MRA) Real-World Multicentre Analysis

Introduction: Daratumumab in combination with bortezomib and dexamethasone (DVd) demonstrated a superior overall response rates (ORR) and progression free survival (PFS) compared to Vd in the CASTOR phase 3 trial for patients with RRMM. On this basis, DVd was recommended in March 2019 for UK patients with RRMM that had 1 prior line (PL). Discrepancies in outcomes between patients treated in clinical trials compared to routine practice is well recognised due to a combination of patient, disease and treatment-related factors. In addition, bortezomib is often administered once-weekly in routine practice to minimise neuropathy, while CASTOR used bi-weekly bortezomib dosing. As a result, the real-world outcomes of patients treated with DVd are yet to be determined. The primary aims of this analysis was to assess the ORR and PFS for patients with RRMM with 1PL treated with DVd in routine practice. Secondary aims were to assess OS, time to next treatment (TTNT), and efficacy in different sub-groups (high risk cytogenetics, previous proteasome inhibitor (PI) exposure, refractoriness of prior therapies, bi-weekly vs weekly bortezomib schedule, and previous treatment free interval (TFI)). Methods: This was a retrospective analysis from 14 centres (academic and community hospitals;7 within the West Midlands Research Consortium (WMRC)) treated with DVd between March 2019 and June 2021. Patients received daratumumab (IV and then SC from June 2020) weekly in cycles 1-3, on day 1 of a 3-week cycle during cycles 4-8, and then monthly from cycle 9 to progression. SC Bortezomib was predominantly given weekly for cycles 1-8 although 5 centres used bi-weekly dosing for selected patients with aggressive disease. Adverse events were graded as per CTCAE criteria. Results: 288 patients were included, with a median age of 69 years (range 20-88) (Table 1). Patients received a median of 1 PL (range 1-2) with 93% (269) 1PL, 7% (18) 2 PL (due to COVID-19 measures). The majority had an ECOG performance status of 0-2 (98%) and most received weekly bortezomib (n=201). This population differed from those with 1PL treated on CASTOR in being older, more were ISS 3 (31% vs 19%, p=0.0145), and more had prior bortezomib exposure (71% vs 51%, p=0.0003), 4% were PI refractory, 9% had a GFR of <30ml/min (<20ml/min was an exclusion from CASTOR), and 2% had an ECOG performance status of ≥3. The ORR was 76%, with >VGPR in 54% (Table 2), with no significant difference in response between patients receiving biweekly vs weekly bortezomib (85% vs 83%;p=0.71). The median time to response was 1.6m. With a median follow up of 15m, the median PFS was 14m (95% CI 11.6-16). High cytogenetic risk patients had inferior outcomes: median PFS 10m (95% CI 6-14) for high risk vs not reached for standard risk (p=0.043);as did those with advanced ISS: median PFS was not reached, 15 and 12m for stage I, II and III respectively (p=0.05). For 15 patients with extramedullary disease (EMD), the median PFS was 3m (95% CI 1-5). Median PFS for patients who were PI refractory was shorter (10m vs 15m for PI sensitive patients (p=0.006)). There was no difference in median PFS for patients with prior PI exposure vs no prior PI (15 vs 13m;p=0.75), or according to weekly or bi-weekly bortezomib schedule (11 vs 15m;p=0.14). The median TTNT was 21m (95% CI 17-25). Overall, the median duration of treatment was 8m and 25 patients (9%) stopped treatment to receive a second autologous stem cell transplant. Those that had a prior TFI of >12m had a longer median PFS of 21m vs 10m (p=0.0004). The median OS has not been reached, with an estimated 2-year OS of 74%. For patients with high risk cytogenetics the median OS was 16m (95% CI 9-23;vs not reached for standard risk;p=0.0006), with estimated 2-year OS in the high risk group of 36%. There was no difference in OS for patients treated with biweekly vs weekly bortezomib (not reached for either;p=0.38). DVd was generally well tolerated with 6% stopping due to adverse events (CASTOR 9.5%). Grade 3 or 4 toxicity occurred in 62 (22%) most comm nly neutropenia and thrombocytopenia, with any grade infusion reactions reported in 27 (9%). Conclusions: These real-world data of DVd at 1 st relapse demonstrated good tolerability and high response rates with a weekly bortezomib schedule despite a more heterogenous population. However, high risk patients by cytogenetics, ISS or EMD had inferior outcomes as did those treated within 12 months from first line treatment. [Formula presented] Disclosures: Cook: Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria, Research Funding;Oncopeptides: Consultancy, Honoraria;Roche: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding. Pratt: Binding Site: Consultancy;BMS/Celgene: Consultancy;Gilead: Consultancy;Janssen: Consultancy;Takeda: Consultancy;Amgen: Consultancy. Kishore: Celgene: Other: Attending fees;Jannsen: Other: Attending fees;Sanofi: Other: Attending fees;Takeda: Other: Attending fees. Yong: Amgen: Honoraria;Autolus: Research Funding;BMS: Research Funding;Janssen: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding;GSK: Honoraria;Takeda: Honoraria. Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses.

Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL)

Background: High-risk LBCL is associated with poor prognosis after first-line anti-CD20 mAb-containing regimens, highlighting the need for novel treatments. Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for treatment of relapsed/refractory (R/R) LBCL after ≥2 lines of systemic therapy. Here we report the primary analysis of ZUMA-12, a Phase 2, multicenter, single-arm study of axi-cel as part of first-line therapy in patients with high-risk LBCL. Methods: Eligible adults had high-risk LBCL, defined by histology (double- or triple-hit status [MYC and BCL2 and/or BCL6 translocations] per investigator) or an IPI score ≥3, plus a positive interim PET per Lugano Classification (Deauville score [DS] 4/5) after 2 cycles of an anti-CD20 mAb and anthracycline-containing regimen. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide and fludarabine) followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. Non-chemotherapy bridging could be administered before conditioning per investigator discretion. The primary endpoint was investigator-assessed complete response (CR) rate per Lugano. Secondary endpoints included objective response rate (ORR;CR + partial response), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary analysis occurred after all treated patients had ≥6 months of follow-up. Results: As of May 17, 2021, 42 patients were enrolled and 40 were treated with axi-cel. Median age was 61 years (range, 23-86);68% of patients were male, 63% had ECOG 1, 95% had stage III/IV disease, 48% had DS4, 53% had DS5, 25% had double- or triple-hit status per central assessment, and 78% had IPI score ≥3. A total of 37 patients had centrally confirmed double- or triple-hit histology or an IPI score ≥3 and were evaluable for response, with 15.9 months of median follow-up (range, 6.0-26.7). The CR rate was 78% (n=29;95% CI, 62-90);89% of patients had an objective response, and median time to initial response was 1 month. Among all 40 treated patients, 90% had an objective response (80% CR rate). At data cutoff, 73% of response-evaluable patients had ongoing responses. Medians for DOR, EFS, and PFS were not reached;12-month estimates were 81%, 73%, and 75%, respectively. The estimated OS at 12 months was 91%. All 40 treated patients had AEs of any grade;85% of patients had Grade ≥3 AEs, most commonly cytopenias (68%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 3 patients (8%) and 9 patients (23%), respectively. Median times to onset of CRS and NEs were 4 days (range, 1-10) and 9 days (range, 2-44), with median durations of 6 days and 7 days, respectively. All CRS and most NEs (28/29) of any grade resolved by data cutoff (1 ongoing Grade 1 tremor);39/40 CRS events resolved by 14 days post-infusion and 19/29 NEs resolved by 21 days post-infusion. Tocilizumab was administered to 63% and 3% of patients for management of CRS or NEs, respectively;corticosteroids were administered to 35% and 33% of patients for CRS and NE management. One Grade 5 event of COVID-19 occurred (Day 350). Median peak CAR T-cell level in all treated patients was 36 cells/µL (range, 7-560), and median expansion by AUC 0-28 was 495 cells/µL × days (range, 74-4288). CAR T-cell levels peaked at a median of 8 days post-infusion (range, 8-37). Higher frequency of CCR7+CD45RA+ T cells in axi-cel product, previously associated with greater expansion of CAR T cells (Locke et al. Blood Adv. 2020), was observed in ZUMA-12, compared with the ZUMA-1 study in R/R LBCL (Neelapu et al. New Engl J Med. 2017). Conclusion: In the primary analysis of ZUMA-12, axi-cel demonstrated a high rate of rapid and complete responses in patients with high-risk LBCL, a population with high unmet need. With 15.9 months of median follow-up, responses were durable as medians for DOR, EFS, nd PFS were not yet reached and over 70% of patients remained in response at data cutoff. No new safety signals were reported with axi-cel in an earlier line. Overall, axi-cel may benefit patients exposed to fewer prior therapies, and further trials in first-line high-risk LBCL are warranted to assess axi-cel in this setting. [Formula presented] Disclosures: Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees;Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding;Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties;Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Dickinson: Janssen: Consultancy, Honoraria;Takeda: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;Amgen: Honoraria;Celgene: Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria;MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau;Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau. Munoz: Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau;Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding;Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role;Alexion, AstraZeneca Rare Disease: Other: Study investigator;Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Oluwole: Pfizer: Consultancy;Curio Science: Consultancy;Janssen: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding. Herrera: Takeda: Consultancy;Genentech: Consultancy, Research Funding;Merck: Consultancy, Research Funding;Seagen: Consultancy, Research Fundi g;AstraZeneca: Consultancy, Research Funding;Kite, a Gilead Company: Research Funding;Gilead Sciences: Research Funding;Tubulis: Consultancy;ADC Therapeutics: Consultancy, Research Funding;Bristol Myers Squibb: Consultancy, Research Funding;Karyopharm: Consultancy. Ujjani: Loxo: Research Funding;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;TG Therapeutics: Honoraria;Gilead: Honoraria;ACDT: Honoraria;Kite, a Gilead Company: Honoraria;Adaptive Biotechnologies: Research Funding;Atara Bio: Consultancy;AbbVie: Consultancy, Research Funding;Pharmacyclics: Consultancy, Research Funding. Lin: Sorrento: Consultancy;Legend: Consultancy;Novartis: Consultancy;Bluebird Bio: Consultancy, Research Funding;Gamida Cell: Consultancy;Janssen: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Juno: Consultancy;Vineti: Consultancy;Takeda: Research Funding;Merck: Research Funding;Kite, a Gilead Company: Consultancy, Research Funding. Riedell: Bayer: Honoraria;Karyopharm Therapeutics: Consultancy, Honoraria;Morphosys: Research Funding;Celgene/Bristol-Myers Squibb Company: Consultancy, Honoraria, Research Funding;Verastem Oncology: Honoraria;Kite, a Gilead Company: Honoraria, Research Funding, Speakers Bureau;Novartis: Consultancy, Honoraria, Research Funding;Takeda: Consultancy;BeiGene: Consultancy;Calibr: Research Funding;Xencor: Research Funding;Tessa Therapeutics: Research Funding. Kekre: Gilead: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Celgene: Consultancy, Honoraria. Lui: Gilead Sciences: Other: stock or other ownership;Kite, a Gilead Company: Current Employment, Other: travel support. Milletti: Kite, aGilead company: Current Employment;Gilead Sciences: Other: stock or other ownership. Dong: Kite, a Gilead Company: Current Employment;Gilead Sciences: Other: stock or other ownership;GliaCure/Tufts: Consultancy, Other: advisory role, Patents & Royalties. Xu: Kite, A Gilead Company: Current Employment;Gilead Sciences: Other: stock or other ownership. Chavez: MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy;ADC Therapeutics: Consultancy, Research Funding;Merk: Research Funding;AstraZeneca: Research Funding;MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau;BMS: Speakers Bureau.

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.