UK Joint Advisory Group consensus statements for training and certification in endoscopic retrograde cholangiopancreatography

Background and study aims Despite the high-risk nature of endoscopic retrograde cholangiopancreatography (ERCP), a robust and standardized credentialing process to ensure competency before independent practice is lacking worldwide. On behalf of the Joint Advisory Group (JAG), we aimed to develop evidence-based recommendations to form the framework of ERCP training and certification in the UK. Methods Under the oversight of the JAG, a modified Delphi process was conducted with stakeholder representation from the British Society of Gastroenterology, Association of Upper Gastrointestinal Surgeons, trainees and trainers. Recommendations on ERCP training and certification were formulated after formal literature review and appraised using the GRADE tool. These were subjected to electronic voting to achieve consensus. Accepted statements were peer-reviewed by JAG and relevant Specialist Advisory Committees before incorporation into the ERCP certification pathway. Results In total, 27 recommendation statements were generated for the following domains: definition of competence (9 statements), acquisition of competence (8 statements), assessment of competence (6 statements) and post-certification support (4 statements). The consensus process led to the following criteria for ERCP certification: 1) performing ≥ 300 hands-on procedures; 2) attending a JAG-accredited ERCP skills course; 3) in modified Schutz 1–2 procedures: achieving native papilla cannulation rate ≥80%, complete bile duct clearance ≥ 70 %, successful stenting of distal biliary strictures ≥ 75 %, physically unassisted in ≥ 80 % of cases; 4) 30-day post-ERCP pancreatitis rates ≤5 %; and 5) satisfactory performance in formative and summative direct observation of procedural skills (DOPS) assessments. Conclusions JAG certification in ERCP has been developed following evidence-based consensus to quality assure training and to ultimately improve future standards of ERCP practice.

The ups and downs of DNA methylation: an interview with Gerd Pfeifer

In this interview, Professor Gerd Pfeifer speaks with Storm Johnson, Commissioning Editor for Epigenomics, on his work to date in the field of DNA methylation. Dr. Pfeifer received a PhD degree from the University of Frankfurt, Germany. After postdoctoral work, he became a faculty member at the Beckman Research Institute of the City of Hope (Duarte, CA) in 1991. He is currently a full professor at the Van Andel Institute in Grand Rapids, MI. Dr. Pfeifer has served on several NIH advisory committees and has published over 300 research papers. Dr. Pfeifer's research interests are cancer etiology, molecular carcinogenesis and epigenetics. His expertise is in cellular and molecular biology. His lab currently works on epigenetic mechanisms of gene regulation in cancer and other diseases.

De ‘polder’-strategie van de natuurbeschermings- beweging in Nederland, 1930-1960

The ‘poldermodel’ strategy of thenatureconservationmovementinthe Netherlands, 1930-1960 This article analyses the strategies applied by the early nature conservation movement in the Netherlands to exert influence at the political level. Before the 1970s, conservationist civil society organisations preferred informal deals, advisory committees, and negotiated agreements with government departments and state agencies. It is argued that the balance between urging for formal legislation, on the one hand, and agreeing to informal deals, on the other, conformed to specifically Dutch forms of governance known as the ‘polder model’. The nature conservation movement was indeed successful in the period 1930-1960 to secure a place for itself in policy negotiations regarding nature and landscape. The strategy of informal deals and policy consultations was not interrupted by the German occupation during the Second World War, but conservationists discovered its limitations in the 1950s: without formal legislation, they did not have enough leverage in negotiations with other stakeholders.

Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Antibody Response to Vaccination with BNT162b2, mRNA-1273, and ChADOx1 in Patients with Myeloid and Lymphoid Neoplasms

Background: In general, patients with hematological diseases are predisposed to develop infections. Severe COVID-19 infection associated with high mortality is more likely in these patient cohorts compared to the general population. Due to immune defects related to the primary disease and/or to immunosuppressive treatment regimes, vaccination efficacy may be reduced in patients with hematological diseases. So far, data on this area are limited. Aim: To evaluate vaccination-related antibody response to BNT162b2, mRNA-1273, and ChADOx1 in patients with hematological disorders. Patients and methods: In this interim analysis of a prospective, observational single-center study, we report antibody levels at least 2 weeks after COVID-19 vaccination. A FDA/CE approved electrochemiluminescent assay (ECLIA) (Elecsys®, Roche, Mannheim, Germany) was used to quantify antibodies, pan Ig (including IgG) against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The assay has a measurement range of 0.4 to 250 U/mL, with a concentration ≥0.8 U/ml considered as positive. Data were analyzed for patients without detection of anti-N (nucleocapsid) SARS-CoV-2 antibody (i.e., without having passed SARS-CoV-2 infection). All tests were performed according to the manufacturer's instructions in an accredited laboratory at the University Hospital Mannheim. Results: Between February 2021 and July 2021, a total of 175 patients with hematological diseases were included in this study. The median age was 66 years (range 21-90 years), and 81 (46.3%) were female. The antibody levels were measured at least 14 days (median, 58 days) after the 2 nd vaccination. The patients were vaccinated with BNT162b2 (BioNTech, n=134), mRNA-1273 (Moderna, n=19), ChADOx1 (AstraZeneca, n=12), or got the first vaccination with BNT162b2 and the second with ChADOx1 (n=10). Overall, 145/175 (82.9%) were diagnosed with a malignant hematological disease (myeloid neoplasms, n=108; lymphoid neoplasms, n=37) and 30/175 with a non-malignant hematological disease (autoimmune disease, n=24; benign, n=6). 124 patients (70.1%) were on active therapy, and 51 patients (29.1%) were previously treated or treatment naïve. Correlation to specific therapies is ongoing and will be presented. In general, vaccination-related antibody response was positive (≥0.8 U/mL) in 148/175 (84.6%) patients with a median level of 208.6 U/mL (range 0.8-250.00) and negative (<0.8 U/mL) in 27/175 (15.4%) patients. The distribution of the negative cohort regarding the disease subgroups were as followed: myeloid neoplasms 7/27 (25.9%), lymphoid neoplasms 16/27 (59.3%), non-malignant hematological disease 4/27 (14.8%). Within the negative cohort, 21/27 (77.8%) were treated on active therapy, 6/27 (22.2%) were previously treated or treatment naïve. In myeloid neoplasms, patients with classical myeloproliferative neoplasm (MPN) had the highest negative result for antibodies with 4/7 (57.1%) followed by myelodysplastic syndrome (MDS) 2/7 (28.6%). Interestingly, all patients with chronic myeloid leukemia (CML) had a measurable immune response. In lymphoid neoplasms, patients with low-grade non-hodgkin lymphoma (NHL) (predominately chronic lymphocytic leukemia, CLL) had the highest negative antibody result 13/16 (81.3%) followed by high-grade NHL 4/8 (50%; predominately diffuse large b-cell lymphoma, DLBCL). In non-malignant hematological diseases, only patients with autoimmune diseases had a negative result. Conclusion: A remarkable group of patients with hematological disease were measured with no or low immune response after 2 nd COVID-vaccination, especially those with low-grade NHL, MDS and autoimmune disease. It seems that the percentage of patients with MPN and low response is less critical. No problems appeared in CML patients. Further explorations are needed with focus on potential risk of COVID infections despite full vaccination: The potential of 3 rd booster vaccination should be explored within clinical trials. Disclosures Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Kreil: Novartis: Research Funding. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Jawhar: Takeda: Honoraria, Other: Travel support; Blueprint Medicines: Honoraria; Stemline: Consultancy, Honoraria; Celgene: Other: Travel support; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Clonal Tracking By Whole Genome Sequencing Permits Comprehensive Mapping of the Genomic Landscape in Pre- and Post-Gene Therapy Sickle Cell Patients

Recent advances in clonal stem cell tracking strategies have enabled interrogation of unperturbed human hematopoiesis. Whole genome sequencing (WGS) can be used to map the clonal dynamics of hematopoietic stem and progenitor cells (HSPCs) by employing spontaneous somatic mutations as unique clonal tags (Lee-Six et al., Nature, 2018). These tags allow for retrospective analysis of individual stem cell clones and the construction of phylogenetic trees mapping out stem cell relatedness, with mutations being acquired in a near-linear fashion over the course of an individual's life. The unprecedented level of information obtained in these studies is particularly well-suited to understanding genomic changes in gene therapy trials aimed at curing diseases such as sickle cell disease (SCD). In addition to mapping relatedness between stem cells, sequencing data can be used to better define mutational signatures for HSPC clones that have been successfully gene-modified as well as those that lack an integrated copy of the therapeutic vector. Given this method's ability to identify low frequency mutations in individual HSPC clones, mutations with extremely low variant allele frequencies can be detected much more readily than through traditional bulk sequencing approaches, something that is particularly relevant given recent safety concerns in some SCD gene therapy trials. In this study, we have mapped the clonal dynamics of HSPCs obtained from pre- and post-gene therapy samples from 4 SCD patients who have undergone autologous gene therapy performed using a BCL11A shmiR lentivirus vector (NCT 03282656, 12-36 months follow-up). HSPCs from mobilized peripheral blood (pre-gene therapy), bone marrow aspirates (both pre- and post-gene therapy) or unmobilized peripheral blood (post-gene therapy) were expanded as single clones and 1508 individual colonies were then sequenced using WGS to an average sequencing depth of 12.3x. Initial results indicate that the mean mutation burden per cell in a pre-gene therapy sample is elevated for some patients compared to what would be expected based on patient age in similar studies. In pre-gene therapy samples, the structure of the phylogenetic trees appeared to be highly polyclonal, indicating that there were no significant clonal expansion events prior to gene therapy. In one patient where we undertook extensive profiling, approximately 15-20 excess mutations per HSPC were observed across the entire genome 24 months after transplantation, presumably acquired as a consequence of gene therapy and/or reconstitution post-transplantation, which is equivalent to approximately one year of normal ageing without a transplantation intervention. However, no clonal expansions or driver mutations were identified at this 24 month follow-up timepoint, suggesting that no strong selective advantage or pre-leukemic events were present prior to or following the gene therapy protocol. Extending this approach to a wider range and larger number of patients will allow for comprehensive mapping of the genomic landscape and clonal evolution of stem cells in sickle cell patients and will also set the stage for improved assessment of safety and potential leukemia-initiating events in the context of gene therapy. Disclosures Esrick: bluebird bio: Consultancy. Williams: bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding. Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Kent: STRM.bio: Research Funding.

Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Background Eculizumab, the first C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH), transformed PNH treatment by improving survival to that of an age- and sex- matched general population. Previous analyses demonstrating the survival benefit of eculizumab in patients with PNH leveraged historical data and were limited by small patient numbers and short follow-up durations; few evaluated survival of patients receiving eculizumab compared with untreated patients. The objective of the current analysis was to describe the baseline characteristics and overall survival of a large international cohort of eculizumab-treated patients compared with a contemporaneous untreated cohort using data from the prospective, observational International PNH Registry (NCT01374360). Methods Data from patients enrolled in the Registry after March 16, 2007 with complete information for birth date, sex, enrollment date, and treatment status were included (database cut-off, April 12, 2021). Ever-treated patients were those who received eculizumab for a minimum treatment period of 35 days while enrolled in the Registry; never-treated patients did not receive eculizumab at any time before or during Registry participation. Univariate and multivariate analyses were performed using a Cox proportional hazards that incorporated the following parameters at baseline as covariates: treatment status, presence of high disease activity (HDA), age, sex, history of bone marrow failure (BMF), history of thrombotic events (TE), transfusion dependence, and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2. HDA was defined as lactate dehydrogenase (LDH) ratio ≥1.5 × upper limit of normal (ULN) and ≥1 of the following: history of major adverse vascular events (including TE); anemia (hemoglobin <10 g/dL), or physician-documented abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction at any time before and including baseline. Baseline was defined as the date of eculizumab treatment initiation (ever-treated patients) or date of Registry enrollment (never-treated patients). Survival time was analyzed using a left-truncation approach that mapped time in patients' survival based on disease start date, defined as the earliest date of first-reported PNH diagnosis, PNH symptom, or first consistent flow cytometry result. Results Baseline characteristics of the 4627 patients included in the analysis (mean [SD] age at disease start, 40.2 [18.71] years; 53% female; 75% white) were comparable between the ever-treated and never-treated groups (n=1892 and n=2735, respectively). Compared with never-treated patients, more ever-treated patients had LDH ≥1.5 × ULN (90% vs 35%), and fewer had <10% PNH granulocytes (3% vs 57%) or history of BMF (45% vs 76%). The univariate Cox proportional hazard ratio (HR) for mortality in ever-treated vs never-treated patients was 0.48 (95% CI, 0.39-0.60; P<0.0001), indicating a 52% increase in survival in the treated group (Table). Among ever-treated patients, those with HDA at baseline experienced the largest reduction in mortality risk (HR [95% CI], 0.46 [0.33-0.64]; n=174); however, decreased mortality was also evident in ever-treated patients without HDA (HR, 0.65 [0.39-1.10]; n=212) or with unknown HDA status (HR, 0.50 [0.32-0.76; n=120) at baseline. Overall survival probability by treatment status was consistently greater in ever-treated vs never-treated patients through 20 years of follow-up; survival probability at 20 years was 82% (ever-treated) vs 69% (never-treated). Although long-term survival probability was greatest throughout follow-up in ever-treated patients with HDA at baseline, increased survival among ever-treated patients was evident in all 3 HDA status groups (Figure). Conclusion In this analysis of Registry data, treatment with the C5 inhibitor eculizumab improved patient survival compared with a never-treated cohort at a comparable time point in their disease course. Covariates were assessed at baseline only and competing risks and time on treatment were not controlled for, which are potential limitations. Survival benefits conferred by eculizumab treatment were observed regardless of HDA status at baseline, were more pronounced in treated patients with HDA vs those without HDA, and were maintained through 2 decades of real-world follow-up. Figure 1 Figure 1. Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin: Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Szer: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies

Background: BR101801 not only blocks the signaling responsible for cell growth caused by PI3K, but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation and stimulates decreasing stability of the oncogenic protein, c-Myc(AACR2020 abstract #655). This phase I study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the BR101801 (PI3Kγ/δ and DNA PK inhibitor) in patients with advanced hematologic malignancies. Method: This is a Phase I, multi-center, open-label, first-in-human study. The Phase Ia (dose escalation) part of the study was designed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of BR101801. BR101801 was administered orally once daily in 28-day cycles. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results: 11 patients were enrolled and have been treated at 4 dose levels: 50mg, 100mg, 200mg, 325mg and expanded 200mg through fifth cohort escalation. Pathological subtypes include 7 PTCL, 2 DLBCL, 1 MZBL and 1 composite CTCL/MF. 3 females and 8 males have been treated to date. Median age is 58 (range 30-71) and ECOG PS is in the range of 0-1. All patients had taken at least one prior chemotherapy. 10 of total patients have completed at least one cycle except 1 premature drop-out case due to disease progression. First interim analysis after completion of cycle 3 of the last patient of 200mg QD cohort had been conducted, which was to include 5 patients (1 DLBCL and 4 PTCLs). No DLT had been identified in Cohorts 1-3, and 2 patients discontinued the study treatment due to adverse event (G4 thrombocytopenia, not related to IP) and disease progression, respectively. The PK values from multiple dosing range of 50mg to 200mg cohort resulted in an approximate 2.92-fold and 4.97 fold increase in exposure based on Cmax and AUCtau, respectively. BR101801 PK profile showed that the exposure of concentration increased in a dose dependent manner and there was no accumulation observed in the dose range of 50mg to 200mg. 2 DLTs was observed at 325mg QD cohort. The dose was de-escalated to the previous lower dose level (200mg QD) and was expanded to 3 additional patients. The expansion cohort is ongoing at present. 2 of 11 patients had G3 skin reaction and 3 had G3 hepatotoxicites. All adverse effects were manageable and recovered to grade 0-1 upon BR1010801 discontinuation. Total 5 patients have been currently ongoing. For overall tumor response assessment, 4 SDs and 2 PRs have been obsereved. Summary/Conclusion: 200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL. This study is registered at clinicaltrials.gov identifier NCT04018248. Disclosures Kim: AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Curran: Servier pharmaceuticals and Amgen: Consultancy. Kim: Boryung pharmaceuticals: Current Employment.