Outcome of Human Umbilical Cord Blood Stem Cell Transplantation (CBT) for Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Versus Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Achieving a first complete remission (CR1) is an important prognostic factor for transplantation outcome. However, there are no data in the setting of cord blood transplantation (CBT) indicating whether the number of induction courses (1 or 2) needed to achieve CR1, is of prognostic significance. As CBT is advantageous for acute myelogenous leukemia (AML) patients (pts) with positive pre transplant measurable residual disease (MRD) (Milano F, NEJM 2016), it is conceivable that in the CBT setting, no difference in transplantation outcome will be observed between pts achieving CR1 after 1 or 2 inductions. Methods: Using the European Society for Blood and Marrow Transplantation (EBMT)/Acute Leukemia Working Party (ALWP) registry, we compared transplantation outcomes of adult pts aged ≥18 years with AML that underwent CBT in 2005-2020 in CR1, achieved following 1 versus (vs) 2 induction courses. Multivariate analysis (MVA) adjusting for differences between the induction groups was performed using a Cox's proportional-hazards regression model for main outcomes. Results: Three hundred and twenty-five pts were included comprising 243 (75%) with 1 and 82 (25%) with 2 induction chemotherapy courses. Median (range) follow-up was 65.4 (57.4-73.5) and 51.0 (34.8-61.5) months, respectively (p=0.6). Median age was 49.4 (19.0-70.9) and 52.1 (19.2-71.5) years (p=0.8), respectively. For patients with 1 and 2 induction courses, respectively, 49.4% and 57.3% were male, 225 (92.6%) and 78 (95.1%) pts had de novo AML, and 18 (7.4%) and 4 (4.9%) had secondary AML (p=0.6). Pts with 1 and 2 induction courses, respectively, were classified by cytogenetic risk as follows: intermediate, 62.0% and 79.2%, adverse, 33.2% and 19.5%, and favorable, 4.8% and 1.3% (p=0.02) (missing data~25%). The FLT3-ITD mutation was harbored by 33.7% and 32.3% of the pts (p=0.8), respectively (missing data ~6%). Conditioning was myeloablative (MAC) in 43.0% and 36.6% and reduced intensity (RIC) in 57.0% and 63.4%, respectively (p=0.31). Karnofsky performance score (KPS) was > 90 in 74.7% and 71% of the pts, respectively (p=0.5). The most frequent anti-graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CSA) and mycophenolate mofetil (MMF) in 75.6% and 82.5 %, or CSA with or without steroids in 16.1 % and 11.2%, respectively. Anti-thymocyte globulin (ATG) was administered to 32.9% and 25.6% of the CBT recipients, respectively (p=0.2). Engraftment rates were lower for pts achieving CR1 after 1 vs 2 induction courses (91.3% and 98.8% p=0.02) with corresponding day 60 absolute neutrophil count (ANC) > 0.5 x 10 9/L in 89.6% vs 96.3% of the pts (p=0.03). Day 180 incidence of acute GVHD grades II-IV was similar in both induction groups, 38.3% and 37.2% (p=0.8), as was 2-year total chronic GVHD, 23.4% and 27.5 %, respectively (p=0.6). In univariate analysis, the 2--year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were similar between patients achieving CR1 with 1 vs 2 induction courses with 22.6% vs 23.6% (p=0.87) 25.1% vs 30.4% (p=0.4), 52.3% vs 46.0% (p=0.3), 58.6% vs 50.0% (p=0.2), and 44% vs 44.1% (p=0.66), respectively. Similarly in MVA, there was no significant association between 2 courses of induction and NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p=0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p=0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p=0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p=0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p=0.5). Conclusions: In CBT recipients, we did not find any significant differences in outcomes in patients achieving CR1 after one or two induction courses. Notably, engraftment was better in patients receiving two courses of induction chemotherapy. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Sierra: Amgen: Other: Educational grant; Roche: Other: Educational grant; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Other: Educational grant; Jazz Pharmaceuticals: Research Funding; Janssen: Other: Educational grant; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding. Byrne: Incyte: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Developing training program for remotely piloted aircraft operators in the sphere of border protection: european context

The study reveals the theoretical and practical approaches of developing training programs for Remotely Piloted Aircraft operators in the sphere of border surveillance of the state border protection agencies of the European Union and Ukraine using multicriteria optimization to find required rational parameters. The results of the study within the educational grant of Frontex Agency conducted by the team of experts from the Border Guard Services of Ukraine and EU countries were used to enhance the training program of air reconnaissance units of border protection bodies at the Main Training Centre of the Border Guard Service of Ukraine based on the best EU practices, in order to ensure obtaining of knowledge and practical skills by personnel of the border guard Remotely Piloted Aircraft external crews, which will increase the level of interoperability and professional competence of border guards while conducting border surveillance tasks.

AB0882-HPR ANCA-ASSOCIATED VASCULITIS: A CLINICAL PRACTICE ASSESSMENT

Background:AAV (ANCA-associated vasculitis) is a group of progressive, rare, severe autoimmune diseases1,2. AAV can affect blood vessels in different parts of the body resulting in damage to vital organs such as the lungs, kidneys, nervous system, gastrointestinal system, skin, eyes, and heart.2 There are currently no approved therapies for remission-induction in patients with AAV. The current treatment armamentarium for AAV is comprised of various immunosuppressive therapies in combination with steroid treatment. Understanding clinical practice gaps in the management of AAV, can inform development of tools to improve physician practices.Objectives:This medical education activity aims to assess physicians’ knowledge on the various manifestations of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), current guideline-recommended treatment strategies for remission induction in patients with AAV, as well as recent clinical trial data for combination therapies used for remission induction.Methods:A 24-question survey consisting of multiple-choice knowledge and case-based questions was made available to nephrologists and rheumatologists without monetary compensation or charge. The questions were designed to evaluate knowledge regarding the various manifestations of AAV and the results from clinical trials that have compared the efficacy of combination therapies used for remission induction in patients with AAV. As well as application of guideline-recommended therapies and clinical trial data for remission induction in patients with AAV within clinical practice. The survey launched online on a website dedicated to continuous professional development. (www.medscape.org/viewarticle/920320) on July 15, 2020. Data were collected until October 1, 2020.Results:363 nephrologists and 190 rheumatologists completed the survey. Physicians demonstrated gaps in the following areas:TopicIncorrect Responses to Knowledge and Clinical Decision-Making Questions (%)NephrologistsRheumatologistsSystemic diseases associated with AAV59%45%How to confirm diagnosis of AAV42%25%Therapy selection to induce remission that would be consistent with guidelines recommendations71%51%Guideline-recommended therapy for patients that do not respond to the induction regimen32%34%Definition of refractory disease95%94%Most effective maintenance strategy for a patient once remission is achieved80%64%Where would an emerging therapy such as a C5a receptor inhibitor fit into the therapeutic armamentarium of AAV?62%47%What are the guideline-recommended therapies to reduce remission in patients without organ-threatening disease?71%51%Most effective maintenance strategy for a patient once remission is achieved80%64%Guideline-recommendations on length of time to continue maintenance therapy31%35%Conclusion:This educational research on assessment of physicians’ (nephrologists and rheumatologists) clinical practices yielded important insights into clinical gaps related to understanding of the disease pathophysiology and progression of AAV, guideline recommendations on diagnosing and managing AAV with guideline-directed medical therapies (GDMTs), strategies for the management of relapsing and refractory disease in AAV and positioning of emerging therapies in the treatment paradigm.References:[1]www.medscape.org/viewarticle/920320.[2]Hutton HL, et al. Semin Nephrol 2017;37(5):418–35.[3]Al-Hussain T, et al. Adv Anat Pathol 2017;24(4):226–34.Disclosure of Interests:Sarah Mendly Grant/research support from: Supported by an independent educational grant from Vifor Pharma, George Boutsalis Grant/research support from: Supported by an independent educational grant from Vifor Pharma

Overcoming NOTCH1-Driven Chemoresistance in T-Cell Acute Lymphoblastic Leukemia Via Metabolic Intervention with Oxphos Inhibitor

The inferior cure rate of T-cell acute lymphoblastic leukemia (T-ALL) is associated with inherent drug resistance. The activating NOTCH1 gene mutations have been reported to cause chemoresistance at the stem cell level1. Direct NOTCH1 inhibition has failed in clinical trials due to a narrow therapeutic window but targeting key oncogenic and metabolic pathways downstream of mutated NOTCH1 may offer novel approaches. We previously reported that rapid transformation of thymocytes at the DN3 differentiation stage into preleukemic stem cells (pre-LSC) requires elevated Notch1 in addition to the presence of Scl/Lmo11. Notably, we showed that cellular metabolism of NOTCH1-mutated T-ALLs depends on Oxidative Phosphorylation (OxPhos) and that OxPhos inhibition using the complex I inhibitor IACS-010759 (OxPhos-i) is efficacious in NOTCH1-mutated T-ALL patient derived xenografts (PDXs)2. Here, we investigated the link between NOTCH1-mutated chemoresistance and OxPhos in pre-leukemic and leukemic cells, utilizing comprehensive molecular and functional assays. We hypothesized that chemotherapy aided by OxPhos-i overcomes chemoresistance, depletes LSCs and combats T-ALL. First, we analyzed the role of OxPhos in downstream Notch1 targets at the pre- and leukemic stage considering four stages of thymocyte differentiation (D1-D4), in a mouse model of human T-ALL1. Gene set enrichment analysis (GSEA) implicated increased expression of Notch1 target genes starting at DN1, and OxPhos target genes were the highest-ranked gene set at DN3. Next, activation of Notch1 by its ligand DL4 and inhibition of OxPhos reduced viability of pre-LSCs, indicating that ligand-dependent activation of Notch1 signaling upregulates the OxPhos pathway and sensitizes pre-LSCs to OxPhos-i. To clarify the role of Notch1 signaling, we examined the effect of IACS-010759 on pre-leukemic thymocytes harboring LMO1, SCL-LMO1, NOTCH1, LMO1-NOTCH1 and SCL-LMO1-NOTCH1 with and without DL4 stimulation. We found that in the absence of DL4, only thymocytes harboring the Notch1 oncogene responded to OxPhos-i, whereas all DL4-stimulated thymocytes responded regardless of Notch1 status (Fig. 1a). In addition, at the leukemic stage, we found elevation of the OxPhos pathway driven by oncogenic Notch1 when we compared transcriptomes of SCL-LMO1 induced T-ALL in the presence or absence of the NOTCH1 oncogene. In line with the murine T-ALL NOTCH1 model, we performed transcriptome analysis of two independent T-ALL patient cohorts prior to chemotherapy, COG TARGET ALL (n=263) and AALL1231 (n=75), comparing transcriptomes of NOTCH1-mutated vs NOTCH1-wt T-ALLs. We found co-segregation of NOTCH1 mutations with significant upregulation of OxPhos and TCA cycle genes and downregulation of apoptosis signaling. Aiming to reverse the NOTCH1-controlled anti-apoptotic program and chemoresistance, we next tested the combination of Vincristine, Dexamethasone and L-Asparaginase (VXL) with IACS-010759. When compared to vehicle, OxPhos-i or VXL alone, only the VXL-OxPhos-i treatment caused an energetic crisis indicated by decreased OCR and ECAR (Seahorse), which translated to a profound reduction of viability (CTG, flow cytometry) in T-ALL cell lines (n=9) and primary T-ALL samples (n=5). Additionally, the IACS-VXL combination in vivo resulted in pan-metabolic blockade, which caused metabolic shut-down and triggered early induction of apoptosis in leukemic cells in peripheral blood, spleen and bone marrow (Fig. 1b). Single cell Proteomic analysis (CyTOF) of spleen showed reduced expression of cell proliferation marker -ki67, c-myc, ERK and p38 proteins, and reduction in number of leukemic cells. Finally, this combination therapy resulted in reduced leukemia burden and extension of overall survival across all three aggressive NOTCH1-mutated T-ALL PDX models (p<0.0001) (Fig.1 c, d). In summary, we demonstrated that targeting OxPhos with IACS-010759 in combination with chemotherapy facilitates eradication of chemoresistant NOTCH1-driven T-ALL through direct targeting of the key metabolic regulators of OxPhos conferred by mutant NOTCH1 in T-ALL. Clinical trials rewiring metabolism by incorporation of OxPhos-i to standard-of-care therapy in patients with NOTCH1-mutated T-ALL are warranted to improve patients' outcomes. Disclosures Jabbour: Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Teachey:Sobi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy. Rezvani:Takeda: Other: Licensing agreement; GemoAb: Membership on an entity's Board of Directors or advisory committees; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; Virogen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Affimed: Other: Educational grant; Formula Pharma: Membership on an entity's Board of Directors or advisory committees. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Lorenzi:Precision Pathways: Consultancy. Konopleva:Calithera: Research Funding; Kisoji: Consultancy; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Cellectis: Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Agios: Research Funding; AstraZeneca: Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding.

THU0651-HPR ONLINE EDUCATION YIELDS SIGNIFICANT GAINS IN RHEUMATOLOGISTS’ KNOWLEDGE OF THE ROLE OF ENTHESITIS IN THE DIAGNOSIS AND MANAGEMENT OF PSA

Background:Physicians face challenges staying up-to-date with the latest research and accessing the ever-growing field of knowledge is time-consuming. Online education can make these clinician’s tasks more efficient and less time-consuming.Objectives:As part of a larger curriculum, we developed an online CME activity titled: “Enthesitis in Psoriatic Arthritis: Disease, Diagnosis and Decisions”. The goal of this study was to assess whether this online CME accredited video discussion improves physicians’ understanding of the role of enthesitis in the diagnosis and management of patients with psoriatic arthritis (PsA) in clinical practice.Methods:Rheumatologists participated in an online CME activity (https://www.medscape.org/viewarticle/910671) consisting of a 30-minute video discussion between 2 experts with accompanying slides. Educational effect was assessed using a 4-question repeated pairs, pre-/post-assessment. A chi-square test was used to determine if a statistically significant improvement (P<.05 significance level) existed in the number of correct responses from the pretest and posttest scores. Cramer’s V was used to estimate the level of impact of the education. The CME activity launched on March 28, 2019, and the data were collected through June 7, 2019.Results:A total of 145 rheumatologists completed the pre- and post activity assessments. Overall the activity had a signficiant impact (P<.0001) on rheumatologists’ knowledge of the role of enthesitis in the diagnosis and management of PsA, with a Cramer’s V value of 0.153 indicating a noticeble educational impact. The average percentage of correct responses rose from 54% pre-activity to 69% post-activity. A repeated pairs analysis showed that 22% of rheumatologists improved their knowledge and 47% reinforced their knowledge, respectively. The change in percentage of correct responses from pre- to post-assessment for all questions are shown in table. Almost 40% of rheumatologists had a measurable improvement in confidence in their ability to evaluate the presence of enthesitis according to a clinical exam or ultrasound.Table.Impact of education on rheumatologists’ knowledge of enthesitisQuestion #Question topicAggregated dataLinked Learner ResultsaAverage % of correct responses Pre- vs. Post-educationP-value% ImprovedblearnersPre- vs. Post-education% ReinforcedclearnersPre- vs. Post-education1.Immunopathology of PsA75% vs 84%.057912%72%2.Prevalence of enthesitis in patients with PsA44% vs 68%<.000133%34%3.Clinical trial outcomes in patients with enthesitis43% vs 56%.034522%34%aEach individual learner tracked pre and post-educationbIncorrect answer pre-education, Correct answer post-educationcCorrect answer pre-education, Correct answer post-educationConclusion:This online CME activity significantly improved rheumatologists’ understanding of role of enthesitis in the diagnosis and management of PsA. However, there is clearly room for further improving physicians’ knowledge of clinical trial outcomes with biologics in patients with enthesitis, since 44% of rheumatologists provided incorrect answers to question 3 post-education. This topic can be addressed in future education.Acknowledgments:This CME-certified activity was supported by independent funding from Novartis AG.Disclosure of Interests:Adriana Stan Grant/research support from: The CME-certified activity was supported by an independent educational grant from Sandoz., Marinella Calle Grant/research support from: This CME-certified activity was supported by an independent educational grant from Novartis AG, Peter Schoonheim Grant/research support from: This CME-certified activity was supported by independent funding from Sandoz., Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau

THU0585 ONLINE EDUCATION YIELDS SIGNIFICANT GAINS IN RHEUMATOLOGISTS’ KNOWLEDGE OF THE JAK INHIBITORS MODE OF ACTION AND CLINICAL TRIAL DATA

Background:Physicians face challenges staying up-to-date with the latest research and accessing the ever-growing field of knowledge is time-consuming. Online education can make these clinician’s tasks more efficient and less time-consuming.Objectives:This study assessed whether the online CME accredited round-table-discussion with title “Meet the JAKs: Understanding the Role of Janus Kinase Inhibition in RA” improves physicians’ understanding mechanism of action (MOA) of current and emerging Janus kinase (JAK) inhibitors and rationale for their development in rheumatoid arthritis (RA).Methods:Rheumatologists participated in an online CME activity (https://www.medscape.org/viewarticle/913625) consisting of a 30-minute video discussion between 2 experts with accompanying slides. Educational effect was assessed using a 4-question repeated pairs, pre-/post-assessment. A chi-square test was used to determine if a statistically significant improvement (P<.05 significance level) existed in the number of correct responses from the pretest and posttest scores. Cramer’s V was used to estimate the level of impact of the education. The CME activity launched on June 4, 2019, and the data were collected through September 3, 2019.Results:A total of 107 rheumatologists completed the pre- and post activity assessments. Overall the activity had a signficiant impact (P<.001) on rheumatologists’ knowledge of JAK inhibitors and relatedclinical trial data with a Cramer’s V value of 0.319 indicating an extensive educational impact. The average percentage of correct responses rose from 47% pre-activity to 78% post-activity. The repeated pairs analysis (each individual learner tracked pre- and post-education) showed that 34% of learners improved their knowledge and 44% reinforced their knowledge. The change in percentage of correct responses from pre- to post-assessment achieved statistical significance for all 3 questions presented: (1) understanding the MOA of JAK inhibitors vs biologics (64% at baseline rising to 82% post acivity;P<0.01), (2) understanding the specificity of different JAK inhibitors (49% at baseline rising to 85% post acivity;P<.001), (3) knowledge of clinical trial outcomes with JAK inhibitors (29% at baseline rising to 67% post acivity;P<.001) and (4) 60% of rheumatologists gained confidence in their ability to describe the MOA of current and emerging JAK inhibitors.Conclusion:This online CME activity significantly improved rheumatologists’ understanding of JAK inhibitors mode of action. However, there is clearly room for further improving physicians’ knowledge of clinical trial outcomes with these agents, since one third of rheumatologists provided incorrect answers to question 3 post-activity) and this topic can be further addressed in future education.Acknowledgments:This CME-certified activity was supported by anindependent educational grant from AbbVie.Disclosure of Interests:Adriana Stan Grant/research support from: The CME-certified activity was supported by anindependent educational grant from Sandoz., Marinella Calle Grant/research support from: This CME-certified activity was supported by anindependent educational grant from Novartis AG, Camille Scot-Smith Grant/research support from: This CME-certified activity was supported by anindependent educational grant from AbbVie, Ronald van Vollenhoven Grant/research support from: BMS, GSK, Lilly, UCB, Pfizer, Roche, Consultant of: AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Janssen, Pfizer, Servier, UCB, Speakers bureau: AbbVie, Pfizer, UCB

P991Pattern of rapid activity is preserved in persistent AF in selected locations after pulmonary vein isolation

Funding Acknowledgements Our research group receives an educational grant from Abbott Inc. Introduction. There is evidence to suggest that structural remodelling in psAF potentially gives rise to areas of rapid cycle length activity that may act as driving mechanisms. We describe a new method to compare rapid activity (RA) in psAF prior to and after pulmonary vein isolation, in extended AF segments (EAFS). We focus on patterns of RA, based on the hypothesis that AF drivers are transient but recur in the same locations. Methods. Five patients (61 ± 8 years of age, 3 male) for catheter ablation of psAF were included. 3D maps were collected with a double spiral 20 pole catheter. In stable locations, pre and post PVI, 37s EAFS were recorded using 8s segments, automatically every 1s, creating a 7s overlap between segments. Dominant cycle length (DCL) was determined for every 8s segment by a fully automated algorithm. RA was defined as the rapidest 20th percentile for each patient. RA episodes consisted of continuous segments with rapid DCL (black lines in Fig 1) and terminated with a non-rapid segment (red lines on Fig 1). Episodes were truncated where overlap occurred (Box 1 and Box 2 in Fig 1). The pattern of RA was assessed by the number, cumulative duration and mean duration of RA episodes within an EAFS pre and post PVI. Results. Mean DCL of EAFS increased significantly in 4/5 patients after PVI, the number of EAFS with rapid activity showed a reduction in all patients. The percentage of new sites with RA post PVI was 27%. The number of sites that retained RA post PVI was 14 ± 11.3 (58.3%; Table 1). Of these, number and cumulative duration of RA did not change in 4/5 patients, and mean duration of RA remained stable in 5/5. Conclusion. An automated DCL algorithm shows that, in most cases, global AFCL prolongs significantly with PVI overall, but selected foci retain RA and RA patterns. These may represent active drivers, as their activity appears to be independent of their surroundings. Table 1 Patient ID Number of segments Mean AFCL ± SD of all segments Number of EAFS with rapid activity Pre-PVI Post-PVI P Pre-PVI Post-PVI New sites 1 145 135 ± 8.9 141 ± 9.8 &lt;0.001 94 62 15 2 121 154 ± 12.9 162 ± 15.0 &lt;0.001 94 72 11 3 172 148 ± 13.7 160 ± 16.6 &lt;0.001 108 82 25 4 301 172 ± 22.9 174 ± 21.5 0.418 198 189 58 5 200 177 ± 9.9 215 ± 18.1 &lt;0.001 87 43 14 Pre and Post PVI cycle length and EAFS with rapid activity. (AFCL: AF cycle length; EAFS: Extended AF segments; PVI: Pulmonary vein isolation) Abstract Figure.

PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

Post Allograft Rituximab Responsive Cytopenia (RRC)

Background: Cytopenia post allograft can be multi-factorial. Known causes include viral infection, septicaemia, graft versus host disease (GVHD), nutritional deficiency, myelotoxic drugs, relapsed malignancy but immune mediated cases are increasingly observed. There remains a group of cases where no obvious cause is identified. The incidence of this complication is small but may be underestimated and treatment options and results are not defined. Aim: This single centre analysis retrospectively evaluated cases of post-transplant cytopenia presumed to be immune mediated or with no obvious cause and response to antiCD20 antibody (Rituximab) therapy. Study period was 2012 to 2019. Data was collected from electronic patient records, case notes and haematology data base. Results: From 2012 to 2019, 988 patients received allograft (n=390) or autograft (n=598) for haematological malignancy or bone marrow failure syndrome. Twenty-four cases received Rituximab for cytopenia post allograft (24/390, 6.2%). Median age was £9yr. (range: 19-68), 19 were males (79.2%) and allograft were done for severe aplastic anaemia (n=4), Ac. Leukaemia (n=6), Hodgkins disease (n=4), non-Hodgkins lymphoma (n=4), MPD/MDS (n=5) and myeloma (n=1). Conditioning was reduced intensity in n22 case, myeloablative in 2 cases and included campath (n=18) or ATG (n=2) in 20 cases (83.3%). Donor was sibling (n=6) or unrelated (n=22) and 23 (96%) patients received PBSC. All allografts were donor/patient CMV matched (NN: 15, PP: 9). Rituximab was used at a median of 171 days post transplant (range: 55-6174). Cytopenia was trilineage in 8, bilineage in 10 and single lineage in 6 cases. Median haematological parameters were as follows: Hb 78gm/L (68-152), WBC: 2x109/L (0-12), Platelets 28x109/L (4-638). DCT was positive in 7 of the 15 cases where results were available. Seventeen of the 22 cases who had bone marrow evaluation showed hypocellular marrow with no malignancy (3 had normocellular marrow) . Seven of the 10 cases where reticulocyte count pre-rituximab was available, showed response above 2% . Cytopenia was not related to infection, viruses, it B12 or folate deficiency. Response to rituximab therapy was defined as CR (normal counts, transfusion independence, no treatment with steroids or G-CSF), Stable (improvement in counts with platelets>50, Hb>100 and ANC>1.0 without support) or no response. Rituximab was delivered weekly in the dose of 375mg/m2 for 4 weeks. Twelve patients achieved complete response (50%), 3 achieved stabilization (12.5%) and 9 did not show any response (37%) for overall response rate of 63%. All patients with positive DCT responded to Rituximab (7/7, 100%) but even in negative DCT group 4 responded (4/8, 50%). Response was 100% in single lineage cytopenia (6/6), 40% in bilineage cytopenia (4/10) and 63% in trilineage cytopenia (5/8) [p=0.052]. Three patients received second course of Rituximab for recurrence of cytopenia and all achieved second complete response (all three had autoimmune haemolysis). Numbers are too small to identify the predictors but there was trend towards better outcome in patients younger than 40 yrs. age (10/12 vs. 5/12, p=0.035) and patients with Hodgkins disease (4/4 vs. 11/20, p=0.09) but there was no effect of gender, intensity of conditioning, use of campath/ATG or CMV status. Treatment was well tolerated and infusion reactions were uncommon. We identify that the main drawback of this analysis is substantial amount of missing data, especially haematological investigations that precludes identification of predictors or trends. Conclusion: Rituximab should be considered as an option for management of post allograft cytopenia with immune aetiology or with no identified cause. Response rate is substantial and the benefit is sustained. It will be useful to have larger cohort of cases to identify the predictors of response. Disclosures Kulkarni: Therakos, Clegene: Honoraria. Murray:Therakos: Honoraria. Castleton:Novartis, Pfizer, Amgen: Consultancy, Honoraria. Cavet:AMGEN, Autolus, Celgene, EUSA, Jansen/J&J, Novartis,: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wiseman:Novartis, Celgene: Consultancy, Honoraria. Somervaille:Novartis: Consultancy. Sommerfeld:Gilead: Other: Educational grant. Bloor:Abvie, Gilead, Novartis, Autolus, Celgene, etc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational grant.