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The purpose of this study was to identify characteristics related to high resilience among older people exposed to the Jeju 4·3 incident. A total of 1,121 aged adults were assigned to low, medium, and high resilience groups, and factors associated with low and high resilience were investigated. High resilience was significantly associated with a low prevalence of depression and high levels of life satisfaction and psychosocial support, as well as with younger age, being a man, higher education level, and current employment. The results deepen our understanding of resilience in the aged people who experienced the early life trauma., Graphical Abstract

Objectives Earlier studies suggest that imbalance between effort and reward at work associates with exhaustion. Others have found that exhaustion increases turnover intentions; an important precursor of actual turnover that also associates with counterproductive work behaviors. Few, however, have studied the associations between effort‐reward imbalance (ERI) and employees’ intentions to leave their current employment, and whether exhaustion is underpinning that relationship. Here, we investigate the mediating role of exhaustion in the effort‐reward imbalance – turnover intentions relationship. Methods Data from three waves covering a time span of four years from the Swedish Longitudinal Occupational Survey of Health (SLOSH) were analysed using structural equation modeling. Cross‐lagged mediation analyses were conducted to estimate if associations from ERI to subsequent turnover intentions were mediated by exhaustion. Other causal directions (direct and reversed direct effects, reversed mediation) were also examined. Results A direct path from ERI T1 to turnover intentions T2 was found, but not from ERI T2 to turnover intentions T3. Additionally, results showed that ERI at time points T1/T2 associated significantly with exhaustion two years later (T2/T3). Also, exhaustion at T1 showed a small but statistically significant direct association with turnover intentions at T2 (no association was found between exhaustion T2 and turnover intentions T3). A small, but statistically significant indirect effect from ERI to turnover intentions was found (estimate 0.005; 95% CI 0.002‐0.010). Conclusions Providing a good balance between effort and reward for workers is essential to protect employee health and help retain employees in the organization.

Precarious employment is increasing and adversely affects health. We aimed to investigate how perception of precariousness in current employment impacts gender and migrant workers in Australia. Using cross-sectional interviews of 1292 workers born in Australia, New Zealand, India and the Philippines, data were collected on self-reported health, employment conditions and sociodemographics. Factor analysis of nine questions about perceptions of current employment revealed two dimensions, vulnerability and insecurity. Women had higher vulnerability scores (&micro, = 6.5 vs. &micro, = 5.5, t = 5.40, p-value (p) &lt, 0.000) but lower insecurity scores (&micro, = 8.6 vs. &micro, = 9.3 t = &minus, 4.160 p &lt, 0.0003) than men. Filipino-born workers had higher vulnerability compared with other migrant workers (&micro, = 5.8 t = &minus, 3.47 p &lt, 0.0003), and workers born in India had higher insecurity compared with other migrant workers (&micro, = 9.8 vs. &micro, = 8.9, t = &minus, 6.1 p &lt, 0.0001). While the prevalence of insecurity varied by migrant status, the negative effect on health was higher for Australian-born workers than migrants. Increasing levels of vulnerability and insecurity impacted self-reported health negatively (Coefficient (Coef).0.34 p &lt, 0.0001, Coef.0.25 p &lt, 0.0001, respectively). The combination of high vulnerability and high insecurity had the greatest impact on health (Coef. 2.37 p = 0.002), followed by high vulnerability and moderate insecurity (Coef. 2.0 p = 0.007). Our study suggests that understanding both changes in employment conditions over time as well as knowledge of cultural patterns may offer the best chance of understanding the impact of precarious employment experiences.

The current employment situation is relatively negative, compared to that in the last years. In order to improve the employment quality for graduates, the employment competitiveness of graduates should be reassessed, and effective job guidance for college graduates should be provided. In this paper, an evaluation system of college graduates' employment competitiveness based on the APM model of human resources is constructed, and the multi-grained rough set technique is used to evaluate the competitiveness of college graduates. Compared with traditional methods, this method can evaluate employment competitiveness of graduates more comprehensively, and thus provide accurate job guidance for companies or graduates, and has certain practical value.

Using microdata from the Current Employment Statistics survey and the Current Population Survey, I illustrate how the local spread of coronavirus disease 2019 (COVID-19) has differentially affected industry employment Industries that are not very telework friendly are more likely to have job loss related to its spread In addition, COVID-19's spread appears to be most correlated with temporary job loss, which could partially explain employment numbers improving slightly in May and June 2020

The University of Toronto – Department of Radiation Oncology (UTDRO) has had a well-established Fellowship Program for over 20 years. An assessment of its graduates was conducted to evaluate training experience and perceived impact on professional development. Graduates of the UTDRO Fellowship Program between 1991 and 2015 were the focus of our review. Current employment status was collected using online tools. A study-specific web-based questionnaire was distributed to 263/293 graduates for whom active e-mails were identified; questions focused on training experience, and impact on career progression and academic productivity. As a surrogate measure for the impact of UTDRO Fellowship training, a comparison of current employment and scholarly activities of individuals who obtained their Fellow of the Royal College of Physicians of Canada (FRCPC) designation in Radiation Oncology between 2000 and 2012, with (n = 57) or without (n = 230) UTDRO Fellowship training, was conducted. Almost all UTDRO Fellowship graduates were employed as staff radiation oncologists (291/293), and most of those employed were associated with additional academic (130/293), research (53/293), or leadership (68/293) appointments. Thirty-eight percent (101/263) of alumni responded to the online survey. The top two reasons for completing the Fellowship were to gain specific clinical expertise and exposure to research opportunities. Respondents were very satisfied with their training experience, and the vast majority (99%) would recommend the program to others. Most (96%) felt that completing the Fellowship was beneficial to their career development. University of Toronto, Department of Radiation Oncology Fellowship alumni were more likely to hold university, research, and leadership appointments, and author significantly more publications than those with FRCPC designation without fellowship training from UTDRO. The UTDRO Fellowship Program has been successful since its inception, with the majority of graduates reporting positive training experiences, benefits to scholarly output, and professional development for their post-fellowship careers. Key features that would optimize the fellowship experience and its long-term impact on trainees were also identified. Electronic supplementary material The online version of this article (10.1007/s13187-020-01767-5) contains supplementary material, which is available to authorized users.

Objective: The purpose of this study was to examine variables predictive of post-SCI return to employment and current employment among a large cohort of veterans with Spinal Cord Injury (SCI) treated within the Veterans Health Administration (VHA) SCI System of Care. Design: Cross sectional analysis of data obtained during in-person baseline interviews and follow-up phone interviews. Setting: Seven SCI Centers within Veteran Affairs Medical Centers. Participants: 1047 veterans with SCI receiving inpatient or outpatient care in VHA. Results: Only 29.8% were employed post-SCI, 27.9% reported employment within the immediate 5 years before the baseline interview, but only 9.2% reported current employment at the time of the baseline interview. Significant predictors of current employment among these veterans with SCI included recent employment experience, history of legal problems, duration of SCI, education, and life satisfaction. Conclusions: The baseline employment rate following SCI of a large, representative sample, was 29.8%. Greater duration of SCI predicted unemployment, likely due to the older age of this population. Additional years of education promoted current and post-SCI employment, while a history of legal problems was a barrier to employment.

PurposeThe purpose of this paper is to investigate China's employment stabilization policies in response to the coronavirus disease 2019 (COVID-19) pandemic and to discuss the accessibility of these policies in practice. In addition, by focussing on the problems and dilemmas encountered during the implementation of these policies, this paper proposes some future directions for reforming employment protection and social insurance to adapt to the changing employment structure and mode in China.Design/methodology/approachThe design and methodology of this paper utilises open sources and documentary materials on China's employment stabilization policies, employment protection and social insurance measures.FindingsThe employment stabilization policies/measures launched during the COVID-19 pandemic were formulated under an initial policy framework designed only for employees in a definite employment relationship and do not match the current employment structure and model. As a result, the accessibility of employment stabilization policies/measures is limited because some worker groups that are the most affected are not covered by the policies.Originality/valueThis paper provides timely analysis on the China's employment stabilization policies and evaluates the accessibility of these policies.

We aimed at determining differential characteristics of patients treated by a home treatment (HT) team compared to patients treated on hospital wards. Of 412 consecutively admitted patients, 194 (47.1%) were at least partially treated at home, whereas 218 (52.9%) received inpatient treatment only during an episode of acute illness. A multivariate logistic regression model identified current employment to increase the odds of HT (p

ObjectivesWorkers can be exposed to a range of different carcinogenic agents in the workplace. However, previous studies have often focused on prevalence of exposure to a single carcinogen, resulting in substantial knowledge gaps regarding the extent of multiple exposures in the workplace. This study aims to investigate the current prevalence of occupational exposure to multiple carcinogens among exposed workers in Australia.MethodsThe data for this study come from the Australian Work Exposures Study, a nationwide cross-sectional telephone survey of Australian workers aged between 18 and 65. Information was collected about the respondents’ current employment and numerous demographic factors using a web-based application (Occupational Integrated Database Exposure Assessment System) to conduct the interview, with predefined algorithms used to automatically assign exposures to carcinogens based on the respondents’ job tasks.ResultsThe majority (81%) of exposed respondents were assessed as being probably exposed to more than one carcinogen, and 26% reported exposure to five or more carcinogens. We found that after adjusting for occupation, exposure to multiple carcinogens was more likely among male respondents, while older workers (aged between 55 and 65) were less likely to be exposed to multiple carcinogens.ConclusionsThis study provides information on the prevalence of exposure to multiple carcinogens in the general population that has not previously been reported. This information could be useful for the intervention and control of occupational exposures to the prioritised carcinogens identified in this study.

Background Workers are exposed to physical, chemical and other hazards in the workplace, which may impact their respiratory health. Aims To examine the healthy worker effect in the Canadian working population and to identify the association between occupation and respiratory health. Methods Data from four cycles of the Canadian Health Measures Survey were utilized. The current occupation of employed participants was classified into 10 broad categories based on National Occupation Category 2011 codes. Data relating to 15 400 subjects were analysed. Results A significantly lower proportion of those in current employment than those not in current employment reported respiratory symptoms or diseases or had airway obstruction. Similarly, those currently employed reported better general health and had greater mean values for percent-predicted forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow between 25% and 75% of FVC (FEF25–75%) and FEV1/FVC ratio. Among males, females and older age groups, significant differences were observed for almost all the respiratory outcomes for those in current employment. Those in ‘Occupations unique to primary industry’ had a significantly greater likelihood of regular cough with sputum and ever asthma and had lower mean values of percent-predicted FEV1/FVC and FEF25–75% than those in ‘Management occupations’. Those in ‘Health occupations’ had the highest proportion of current asthma. Conclusions Participants in current employment were healthier than those not in current employment providing further support for the healthy worker effect. Those in ‘Occupations unique to primary industry’ had an increased risk of adverse respiratory outcomes and reducing workplace exposures in these occupations has the potential to improve their respiratory health.

The COVID-19 lockdown approach in sub-Saharan Africa countries may not be as beneficial as intended due to the current employment, housing and health infrastructure challenges. Hence other infection prevention and control might need to be considered.

Labor market data indicate that there is a need for skilled employees in several areas. Given the right supports, individuals with autism spectrum disorder (ASD) can help to fill these positions. This chapter outlines the importance of understanding and integrating the employers’ perspective when improving employment outcomes for individuals’ with ASD. Potential barriers and facilitators to hiring individuals with disabilities are highlighted in this chapter. Current employment practices are presented, as well as employers’ perspectives on hiring individuals with ASD. A summary of employers’ training and support needs in order to successfully improve their employment practices and increase the employment rate of individuals with ASD is presented.

Backgrounds/aims/methods Although there are many secondary data analyses of the National Longitudinal Transition Study-2 (NLTS-2) to investigate post-school outcome for students with disabilities, there has been a lack of research with in-school service predictors and post-school outcome for students with specific disability categories. Methods/procedures This study was a secondary data analysis of NLTS-2 to investigate the relationship between current employment status and in-school services for individuals with intellectual disability. Statistical methods such as descriptive statistics and logistic regression were used to analyze NLTS-2 data set. Results The main findings included that in-school services were correlated with current employment status, and that primary disability (i.e., mild intellectual disability and moderate/severe intellectual disability) was associated with current employment status. Conclusion/implications In-school services are critical in predicting current employment for individuals with intellectual disability. Also, data suggest additional research is needed to investigate various in-school services and variables that could predict employment differences between individuals with mild and moderate/severe intellectual disability.

According to the Interim Measures for Social Assistance issued in 2014, employment assistance has been officially designated as one of the eight basic programs in social assistance system in China, and its significance is obvious. However, very little is known about the youth recipients' experiences of employment assistance and the extent to which available forms of employment assistance have been helping them to enter labor market. This article uses a qualitative method to examine employment assistance by analyzing the structure and process elements of activation social assistance paradigm from the perspective of youth recipients. It finds that the employment assistance youth recipients have received as of limited importance to help them get out of social assistance and become self-sufficient. That is to say, current employment assistance in urban China may be limited in activating the youth recipients.

Background Anecdotal reports of an oversupply of pharmacy graduates are a growing concern for Australian pharmacists. However, limited data exists regarding pharmacists’ employment experiences and perceptions of current career opportunities in Australia. Aim To understand Australian pharmacists’ and pharmacy interns’ employment experiences by exploring their satisfaction and perspectives on current employment opportunities. Method An electronic survey was distributed to pharmacists and pharmacy interns across Australia between March and June 2016. National professional organisations for pharmacists assisted with the distribution of the survey. Follow‐up interviews were conducted to further explore survey findings. Results A total of 306 individuals completed the survey (83% pharmacists; 17% interns). The majority of pharmacists and interns reported high satisfaction with current employment and professional practice opportunities; however, there is a misalignment between their rated satisfaction and their perspectives on future employment prospects. Key themes that emerged included personal networks for employment, salary and location, and concerns for the future of the profession. The results suggested a confused workforce that are glad to have jobs, but not confident that they could move to other positions if required, or further, that there will be even fewer jobs available in the future. Conclusion This study provided valuable insight to the Australian Pharmacist workforce, by improving our understanding of pharmacists’ employment experiences and perspectives. Further exploration of themes identified in this study is required to better inform the future of pharmacy professional practice and employment.

Background/Aims: Role functioning is an important part of recovery and psychiatric rehabilitation for people with schizophrenia. However, little is known about why some people and not others return to socially valued roles such as employment. While the demographic and clinical correlates of employment have been extensively studied, little is known about how employment interest forms and develops into actual employment activity. The aim was to compare demographic and clinical correlates of employment interest to correlates of actual employment participation. Methods: A community sample of 255 working-age adults with schizophrenia or schizoaffective disorder were interviewed about their current employment status and current employment interest. Univariate logistic regression was used to examine the demographic and clinical correlates of both employment interest and participation. Findings: Age, employment history and severity of current hallucinations were associated with both employment interest and participation, while illness severity pattern, illness course, severity of disability, and severity of avolition were associated only with employment participation. Conclusions: Resilience of employment interest to the clinical symptoms of schizophrenia is a promising finding. Those with more severe illness patterns and more impaired functioning can remain good candidates for vocational rehabilitation, because interest and motivation for employment may be unaffected.

Objective: This brief examines the evidence that is currently available to inform the provision of psychological services within aged care services, considering both residential care and home care settings. Method: A narrative literature review of the literature evaluating psychological approaches for common conditions in aged care settings was conducted, focusing on the assessment and treatment of common mental health disorders and dementia. Information on the current employment and training of Australian psychologists in geropsychology was also summarised. Results: While further research is required, existing literature provides a clear rationale for the benefit of psychological approaches to address a range of conditions, including the management of dementia. There is only limited research focusing specifically on the home care setting, despite the increasing number of older adults who receive aged care services in their own homes. The current provision of psychological services in Australia is critically low, driven in part by funding limitations. Meanwhile, substantial gaps remain in the training provided to provisional psychologists. Conclusion: A number of key recommendations are made to address the growing need for age-specific psychological assessments and interventions to be included as part of the delivery of aged care services in this country. Given the continued high prevalence of mental health disorders and dementia within aged care settings, as well as even higher rates of subthreshold conditions, improved access to psychological services for older Australians must become a priority.

The current study explores factors predicting return to work in a sample of patients with neurological and neuropsychiatric disorders who have attended a prevocational readiness and social skills training programme many years after trauma. Participants were community-dwelling adults with long-term disabilities (N = 67). Results of univariate analyses followed by multivariate logistic regression analysis revealed that both pre-injury (prior) and post-injury (current) factors influenced the likelihood of employment in our sample: prior employment, current employment readiness, current cognitive competence (particularly memory and executive functioning) and emotional adjustment. Our findings demonstrate that both pre-trauma and current factors interact in predicting return to work not only for individuals with traumatic brain injury (TBI), but also for a broader group of patients with long-term disabilities due to a variety of neurological and neuropsychiatric conditions. Thus, our findings provide p...

Background: The phase 1b/2 CARTITUDE-1 study (NCT03548207) is evaluating ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed/refractory (R/R) multiple myeloma (MM). Cytokine release syndrome (CRS), a known side effect of CAR-T therapy, can be mild to life-threatening and requires careful monitoring and management. Here, we analyzed CRS and cytokine profiles in CARTITUDE-1. Methods: Eligible patients (aged ≥18 years) had a diagnosis of MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. Bridging therapy was permitted after apheresis. At 5-7 days prior to cilta-cel infusion, lymphodepletion was performed with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days. Cilta-cel was administered as a single infusion at a target dose of 0.75×106 (range: 0.5-1.0×106) CAR+ viable T cells/kg. CRS was graded using Lee et al (Blood 2014) in the phase 1b portion and American Society for Transplantation and Cellular Therapy (ASTCT) in the phase 2 portion. In this combined analysis, Lee et al criteria were mapped to ASTCT criteria for patients in the phase 1b portion. Serum samples for cytokine profiling were collected prior to lymphodepletion, prior to cilta-cel infusion and 2 hours post-infusion on Day 1, at regular time points until Day 100, and if CRS was suspected or reported. Results: A total of 97 patients with R/R MM were treated with cilta-cel; median follow-up for this analysis was 8.8 months (range: 1.5-20.4). CRS was reported in 92 (94.8%) patients. A total of 48 (49.5%) patients had grade 1 CRS, 38 (39.2%) had grade 2, 4 (4.1%) had grade 3, and 1 had grade 5 (1.0%); maximum toxicity grade according to the ASTCT consensus grading system could not be derived for 1 patient with CRS in the phase 1b portion. Median time to CRS onset from cilta-cel infusion was 7.0 days (range: 1-12). Median duration of CRS was 4.0 days (range: 1-27, excluding n=1 with 97 days). Supportive measures to treat CRS or CRS symptoms were administered to 87 (89.7%) patients, most commonly tocilizumab (69.1%), acetaminophen (68.0%), corticosteroids (20.6%), and anakinra (18.6%). CRS resolved in 91 (98.9%) patients; the patient with grade 5 CRS/hemophagocytic lymphohistiocytosis died on Day 99 subsequent to sequelae of grade 4 CRS. Across all patients, levels of interleukin (IL)-6, IL-10, and interferon-γ peaked at Days 7-14 post-cilta-cel infusion. Conclusions: CRS after cilta-cel treatment was low grade and manageable in most patients with R/R MM. The low rate of grade ≥3 CRS, median time to CRS onset of 7.0 days, and median duration of 4.0 days suggests outpatient dosing of cilta-cel may be feasible; this approach is being explored in the phase 2 CARTITUDE-2 study (NCT04133636). Disclosures Lin: Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Martin:Janssen: Research Funding; AMGEN: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding; GSK: Consultancy. Cohen:Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Usmani:Celgene: Other; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Incyte: Research Funding. Madduri:AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Foundation Medicine: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Wang:Legend Biotech USA Inc.: Current Employment. Berdeja:CRISPR Therapeutics: Consultancy, Research Funding; EMD Sorono: Research Funding; Teva: Research Funding; Servier: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Genentech, Inc.: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; CURIS: Research Funding; Bioclinica: Consultancy; Amgen: Consultancy, Research Funding; Bluebird: Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Prothena: Consultancy; Lilly: Research Funding. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.

Background Updating prognostic models for multiple myeloma is important in the context of changing treatment options. Previously we have described the value of the prognostic marker SKY92, which identifies high-risk multiple myeloma patients, as well as the value of the combined SKY92-ISS marker. With the introduction of revised ISS, it is of interest to evaluate the value of the updated combination of SKY92 with R-ISS. Within the HOVON87/NMSG18 trial, stratification into 3 groups was described: high-risk: 11% SKY92 high-risk (HR) + R-ISS II-III, low-risk: 15% SKY92 standard risk (SR) + R-ISS I and intermediate risk (74%, other). The 3-year PFS rates were 54% (95%CI: 38-77%), 27% (95%CI: 21-37%) and 7% (95%CI: 1-46%) for SKY-RISS I, II and III, respectively (p < 0.001). The 3-yr OS rates for SKY-RISS I to III were 88%, 66% and 26% (p=6×10-7). Here we describe the validation of SKY92-RISS in the CoMMpass dataset. Methods SKY92 was determined using RNA-seq data available from the CoMMpass dataset. Briefly, the SKY92 score was obtained as a weighted summation of the expression given by the available Ensembl gene IDs, corresponding to the probe sets of the SKY92 classifier. Renormalization of the original SKY92 discovery data (HOVON65/GMMG-HD4) allowing a direct remodeling between the Affymetrix probe-set expressions (i.e. SKY92) and RNAseq Ensembl gene IDs. Only Ensembl gene IDs with an average log2 expression >8 were used. Revised ISS status was determined as described. For optimal comparison to the discovery cohort of the HOVON87/NMSG18 trial, the analysis was limited to 93 patients older than 65 years in the CoMMpass data set, that did not receive transplant, and for whom RNA-Seq at diagnosis, R-ISS and follow-up data were available. Results The median follow-up is 41 months. SKY92 identified 24 high-risk patients (24/93: 26%). The 3-yr PFS and OS rates of standard-risk patients were 49% and 80% respectively, compared to 23% and 44% for high-risk, resulting in a significant log rank test (p < 0.005). The R-ISS classified patients into the low-risk R-ISS I (24% of patients), intermediate-risk R-ISS II (63%) and high-risk R-ISS III (13%). The 3-yr PFS rates were 76% (RISS I), 33% (RISS II) and 33% (RISS III); for OS: 100% (RISS I), 68% (RISS II) and 33% (RISS III; PFS, p = 0.07; OS, p < 0.001). SKY92 and R-ISS were independent prognostic factors in terms of OS and PFS. The SKY-RISS classification resulted in 20% low-, 61% intermediate- and 18% high-risk patients (Figure 1). The 3-yr PFS rates were 81% (95%CI: 64-100%), 42% (95%CI: 30-59%) and 12% (95%CI: 3-44%; p < 0.001) and 3-yr OS rates were 100% (95%CI: 100-100%), 77% (95%CI: 66-89%) and 32% (95%CI: 16-61%; p Out of 69 patients classed as standard risk using the SKY92 classifier (80% 3-yr OS rate), 17 and 52 were classified as SKY-RISS I and II, respectively, resulting in a 3-yr survival rate of 100% and 74%, respectively. In contrast, out of 24 SKY92 HR patients (44% 3 yr OS rate), 5 were classified as SKY-RISS II (100% alive at 3 years) with the remainder true high-risk patients (32% alive at 3 years). Out of 12 RISS III patients (3-yr OS, 33%), 5 were classified as SKY-RISS II (3-yr OS: 60%) and 7 as SKY-RISS III (3-yr OS: 14%). Conclusion This study demonstrates the value of gene expression profiling - SKY92 - alongside revised ISS. They form a solid combination, improving on either marker separately. Both models combined clearly identified more high-risk patients correctly, whilst also placing low risk patients into a more appropriate risk category. This was shown in the discovery set and was subsequently applied to an independent set, confirming the validity and usability of the SKY-RISS. Disclosures Kuiper: SkylineDx: Current Employment, Current equity holder in private company. Van Vliet:SkylineDx: Current Employment, Current equity holder in private company. Van Beers:SkylineDx: Ended employment in the past 24 months. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Background: C-CAR088, an anti-BCMA CAR T-cell therapy is a novel 2nd generation 4-1BB chimeric antigen receptor T (CAR-T) cell therapy targeting BCMA which is specifically and highly expressed on multiple myeloma (MM) cells. C-CAR088 is manufactured in a serum-free, automated and digital, closed system. Initial, early clinical trial results in patients with R/R MM supported preclinical findings and showed promising efficacy and manageable safety profile (Yao, Blood (2019) 134 (Supplement_1): 50.) Methods: The dose escalation and expansion studies have been conducted at four medical centers in China to evaluate the safety and efficacy of C-CAR088 in patients with R/R MM who were previously treated with at least 2 lines of therapy including proteasome inhibitors (PIs) and IMiDs. C-CAR088 is administered to patients as a single intravenous dose after a standard 3-day cyclophosphamide/fludarabine conditioning regimen. Results: As of July 15, 2020, 24 patients were infused and 21 patients had evaluable data for safety and clinical response at dose levels of 1.0 x 106 CAR-T cells/kg (n=3), 3 x106 CAR-T cells/kg (n=11) and 4.5~6x106 CAR-T cells/kg (n=7). The median vein to vein time was 16 days. The manufacturing success rate was 100%. The median age of patients dosed was 60 years (range: 45-74 years).The median number of prior lines of therapy was 4 (range: 2-12 prior therapies). There were 17 (81%) patients with at least one and 12 (57.1%) patients with at least two high risk cytogenetic tumor changes. Five patients (23.8%) had bridging therapy. C-CAR088 treatment was well tolerated. 20 of 21 (95%) patients had Grade 1-2 CRS and one patient experienced Grade 3 CRS. Median time to CRS was 6.5 days (range: 1-11 days) and median duration of CRS was 5 days (range: 2-10 days). Four patients (19%) received tocilizumab for CRS treatment. Only one patient experienced a Grade 1 neurotoxicity event. No dose-limiting toxicities were observed and all adverse events were reversible. The best overall response (BOR) included 6 complete responses (CRs), 10 very good partial responses (VGPRs) and 4 partial responses (PRs). Median follow-up was 182 days (range: 30-375 days). The median duration of response has not been reached. In the 3 x106 CAR-T cells/kg dose group, 5/11(45%) patients achieved a CR. The C-CAR088 PK profile in peripheral blood showed a trend of a dose dependent profile. AUC0~28day and Cmax increased and Tmax decreased with dose (P Conclusion: The clinical trial results in patients with R/R MM treated with C-CAR088 show a favorable safety profile and promising signs of efficacy. We will continue to evaluate these patients to understand the long-term effect of C-CAR088 in multiple myeloma patients. Clinical trial information: NCT04322292、NCT03815383、NCT03751293、NCT04295018 Research Sponsor: Cellular Biomedicine Group, Inc. Disclosures Zhu: Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zheng:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yan:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Lv:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Lan:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yang:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Huo:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Han:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhao:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Qin:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Wu:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yao:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Ren:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhang:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Huang:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Humphries:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company. Yao:Cellular Biomedicine Group Inc: Current Employment, Current equity holder in publicly-traded company.

The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including homeobox (HOX) and MEIS1 genes. In 5-10% of AML cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognostic group of blood cancers. The KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations such as NPM1, IDH1/2, EZH2, and DNMT3A. Therefore, there is strong rationale for targeting these AML subsets which may be exquisitely sensitive to inhibition of the menin-KMT2A chromatin complex. KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction. KOMET-001 (NCT04067336) is an ongoing Phase 1/2A open-label study evaluating KO-539 in adult patients (pts) with relapsed and/or refractory AML agnostic to oncogenic mutational type. The Phase 1 dose-escalation objectives are to assess safety and tolerability, characterize the pharmacokinetics (PK), and determine a recommended Phase 2 dose. The Phase 2A dose expansion portion will assess anti-leukemic activity, PK, safety and tolerability in select genetic subtypes of AML. Preclinically, the drug is shown to be highly protein bound (>99%) across animal species. Using physiologically-based PK (PBPK) modeling, the estimated human efficacious dose was estimated to be 600 mg po qd. As of data cutoff on August 10, 2020, 6 pts with relapsed and/or refractory AML have been enrolled in the trial. Dose escalation began with single pt cohorts at 50 mg po qd in 28 day cycles and has proceeded through to 200 mg dosing cohorts. An expansion of 3 pts at 200 mg was initiated to better characterize the PK and exposure of KO-539. To date, 3 enrolled pts have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28 day DLT-assessment window. Grade 3 (G3) or higher drug related adverse events have included G3 tumor lysis syndrome (TLS) at 50 mg and a G3 embolic event at 100 mg. KO-539 has been well tolerated with no dose interruptions or discontinuations due to drug related adverse events. There were no treatment-related deaths, and two pts discontinued treatment due to disease progression. Peak drug concentrations were attained between 2-3 hours after daily oral dosing with an elimination half-life of greater than 24 hours. KO-539 has demonstrated evidence of biologic activity in pts in the first 3 dose levels treated to date. The 50 mg pt with a KMT2A-r and the 200 mg pt with a p53 mutation and PICALM-AF10 fusion exhibited evidence of tumor lysis syndrome and markedly decreased hydroxyurea requirements with blood count stabilization, respectively. A third pt (100 mg dose level) with SETD2 and RUNX1 co-mutations achieved a complete remission with confirmed negative MRD by flow cytometry after two cycles of therapy and continues on treatment. The biologic activity of KO-539 at lower doses may be explained by inhibition of the CYP3A4 enzyme by concomitantly administered azole antifungals. KO-539 is metabolized into at least two metabolites with comparable activity to KO-539; total drug concentrations (i.e., KO-539 plus active metabolites) exhibited a dose-dependent increase. Although KO-539 is a CYP3A4 substrate, preclinical data suggest both KO-539 and its metabolites act as inhibitors, potentially providing an advantage in overcoming drug resistance attributable to CYP3A4 metabolism by bone marrow stroma. The physiology of the bone marrow sinusoids also allows both unbound and protein-bound drug to reach the sites of leukemic involvement. The high level of protein binding may therefore provide an opportunity for organ-specific targeted action while possibly limiting off target effects. The potential advantage associated with the CYP3A4 inhibitory characteristics of KO-539 to overcome drug-resistance in the bone marrow stroma also continues to be investigated. In conclusion, the early biologic activity of KO-539 in relapsed AML is encouraging, and its unique PK characteristics may be advantageous for clinical benefit. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the conference. Disclosures Wang: Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Altman:BioSight: Other: No payment but was reimbursed for travel , Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Kartos: Research Funding; Fujifilm: Research Funding; France Foundation: Consultancy; PrIME Oncology: Consultancy; Novartis: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Janssen: Consultancy; ASH: Consultancy; Amphivena: Research Funding; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Amgen: Research Funding; ImmunoGen: Research Funding; Genentech: Research Funding; Aprea: Research Funding; AbbVie: Other: advisory board, Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Cancer Expert Now: Consultancy; PeerView: Consultancy. Pettit:PharmaEssentia: Other: advisory board; Kura Oncology: Other: advisory board; CTI Biopharma: Other: advisory board. Walter:Kite: Consultancy; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; New Link Genetics: Consultancy; Selvita: Research Funding; Seattle Genetics: Research Funding; StemLine: Research Funding; Agios: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Arog: Research Funding; Argenx: Consultancy; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Burrows:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Tomkinson:Kura Oncology: Current Employment. Martell:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Fathi:Daiichi Sankyo: Consultancy; Amphivena: Consultancy, Honoraria; Astellas: Consultancy; Celgene: Consultancy, Research Funding; PTC Therapeutics: Consultancy; TrovaGene: Consultancy; Takeda: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria.

Background: Multiple Myeloma (MM) is a rare and heterogeneous blood cancer of the plasma cells. Various new therapies have been introduced and are used in combination to combat the heterogeneity. Despite ongoing research and the development of innovative therapies, improvements for the fast progressing (high-risk) patients have been limited. Disease behavior and clinical outlook of patients that look very similar in the absence of clinical and cytogenetic high-risk features, vary considerably. Their fast progression could not have been foreseen at diagnosis as their initial features were uninformative. In order to identify high-risk patients for selective innovative treatment strategies in trials and clinical practice, it is important to have a conclusive assessment of the patient's risk profile at diagnosis. This assessment should include their Gene Expression Profile (GEP). Aim: To show that GEP is an important and indispensable contributor in selecting high-risk MM patients. Method: Six datasets were combined: MRC-IX (n=180), HOVON-87/NMSG-18 (n=148), EMN-02/HOVON-95 (n=249), GIMEMA-MMY-3006 (n=112), a Czech cohort (n=27 E-MTAB-1038) and the MMpredict non-trial cohort (n=89, [Chen YT. et al. CLML. 2019 19(10):e60-61]). Pooled, a total of n=805 MM patient samples were available including corresponding GEP data, iFISH, ISS annotation and Overall Survival (OS). Patients were risk classified in three strata as proposed by Kuiper R. et al. Blood. 2015 Oct 22;126(17):1996-2004: Low Risk (LR) as SKY92 standard risk + ISS I; Intermediate Risk (IR) as SKY92 standard risk + ISS II or III; and High Risk (HR) as SKY92 high risk. Subsequently, each stratum is further refined into: patients with high-risk iFISH t(4;14) and/or del(17p) (iFISH); and patients without these markers (non-iFISH). The Cox proportional Hazards model was applied to estimate survival. Results: The combination of SKY92+ISS identified three risk strata in the cohort: n=188 for LR (23%), n=448 for IR (56%) and n=169 for HR (21%). The OS of the HR stratum was significantly shorter than the LR stratum (hazard ratio=6.0, p Conclusion: Currently used risk stratification methods are sub-optimal and the use of these markers leave 53% of high-risk patients unidentified. This might impact the clinical strategy for that unidentified high-risk patient as a physician could have escalated their treatment. Furthermore, it might influence the conclusion on the effectiveness of investigational therapeutic treatment in clinical trials. Lastly, clinical trials focused on high-risk patients, will reach full inclusion much faster and obtain earlier read-outs as GEP, here SKY92, identifies additional and true fast progressing high-risk patients. SKY92 should therefore be added as risk stratification method for a holistic view on a patient's course of disease. Figure 1: Kaplan Meier plots for the three SKY92 + ISS strata: low risk (LR; figure 1B), intermediate risk (IR; figure 1C) and high risk (HR; Figure 1D) and their respective splits based on presence of iFISH markers t(4;14) and/or del(17)p or absence of both. Figure 1 Disclosures Van Vliet: SkylineDx: Current Employment, Current equity holder in private company. Chen:SkylineDx: Current Employment, Current equity holder in private company. Van Beers:SkylineDx: Ended employment in the past 24 months. Kuiper:SkylineDx: Current Employment, Current equity holder in private company. Valent:SkylineDx: Current Employment, Current equity holder in private company. Spaan:SkylineDx: Current Employment, Current equity holder in private company. Zamagni:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Sanofi: 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oliva:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Larocca:Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chng:Abbvie: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy.

Background SEA-CD70 is being developed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Current treatment options are limited for patients (pts) with relapsed or refractory (r/r) MDS or r/r AML and outcomes remain poor. SEA-CD70 is an investigational humanized, non-fucosylated monoclonal antibody targeting CD70. Expression of CD70 is limited in normal tissue, but is aberrantly expressed on malignant myeloid blasts while absent from healthy hematopoietic progenitor cells. CD70 and its ligand, CD27, may play a role in malignant blast cell survival and/or tumor immune evasion. SEA-CD70 uses a novel sugar-engineered antibody (SEA) platform to produce a non-fucosylated antibody with enhanced effector function. The proposed mechanism of action of SEA-CD70 includes elimination of CD70 positive cells via enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and mediation of complement-dependent cytoxicity (CDC). Additionally, SEA-CD70 has the potential to block the interaction of CD70 with CD27, which may disrupt signals that enhance blast proliferation and survival and may modulate the immune system to limit immune evasion and increase antigen specific T cell responses. Methods SGNS70-101 is a phase 1, open-label, multicenter, dose-escalation, and cohort expansion study designed to establish the safety, tolerability, and preliminary activity of SEA-CD70 in pts with myeloid malignancies (NCT04227847). Dose escalation is ongoing. In dose escalation, pts must have r/r MDS with 5-20% blasts which has failed prior treatment with a hypomethylating agent (HMA), and have no other therapeutic options known to provide clinical benefit for MDS. After conclusion of dose escalation, monotherapy expansion cohorts will be opened for pts with MDS and for pts with AML. Primary objectives are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70. Secondary objectives are to assess antitumor activity, PK, and immunogenicity of SEA-CD70. Once dose escalation is complete and the recommended monotherapy dose is identified, combination cohorts will be considered in AML and MDS. The study is currently enrolling with sites opening in the US and EU. Disclosures Aribi: Seattle Genetics: Consultancy. Advani:OBI: Research Funding; Takeda: Research Funding; Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Donnellan:Kite Pharma/Gilead: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; MedImmune: Research Funding; TCR2 Therapeutics: Research Funding; Genentech: Research Funding; PTC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Celularity: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Takeda: Research Funding; H3 Biomedicine: Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fathi:Astellas: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; AbbVie: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Vachani:Blueprint: Consultancy; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Abbvie: Consultancy. Yang:AROG: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding; AstraZeneca: Research Funding. Ho:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

BACKGROUND aGVHD, a common complication of allogeneic stem cell transplant (alloSCT), is driven by proinflammatory cytokines and chemokines that activate the immune system, resulting in end-organ damage. Steroids are first-line treatment but up to 50% of pts are steroid refractory (SR), resulting in high mortality and morbidity. RUX, a JAK1/JAK2 inhibitor, inhibits cytokine-dependent activation of the JAK-STAT pathway and cell proliferation and differentiation, which prevents worsening of aGVHD and allows recovery. JAK pathway inhibition by RUX may also lead to modulation of proinflammatory cytokines and prognostic GVHD biomarkers. The phase 3 randomized REACH2 trial (NCT02913261) in SR aGVHD demonstrated superiority of RUX vs BAT, with a significantly higher overall response rate (ORR; complete [CR] + partial response [PR]) at D28 (62% vs 39%; P < .001) and higher durable ORR at D56 (40% vs 22%; P < .001) (Zeiser R, et al. N Engl J Med. 2020). In this exploratory analysis of REACH2, we assessed whether baseline (BL) levels of proinflammatory cytokines and GVHD markers were prognostic for response and how this changed over time related to treatment. METHODS Pts (N = 309; ≥ 12 y old with grade II-IV SR aGVHD after alloSCT) were randomized 1:1 to RUX (starting at 10 mg bid) or investigator-selected BAT and stratified by aGVHD grade; 295 pts had valid biomarker levels. Serum samples were collected at BL, D14, and D28 and biomarkers, including inflammatory cytokines, soluble receptors of cytokines, chemokines, and tissue-specific markers for gastrointestinal (GI), liver, and skin GVHD, were assessed (Table). Biomarker levels at BL were stratified by response (CR, PR, none [NR]) at D28 for each treatment arm; those that differed by response were analyzed by logistic regression (LR) to assess the association (CR+PR vs NR), adjusting for treatment. The analysis was repeated, adjusting for key covariates that had significant impact on the biomarker-response relationship. Change in biomarkers over time (BL to D28) was assessed via geometric mean values at each visit, along with fold change from BL for each treatment arm. RESULTS Of 22 GVHD biomarkers assessed, 17 (77%) were evaluable (Table). Higher median BL levels of proinflammatory cytokines (IL-6, IL-8, TNF-α), soluble cytokine receptors (IL2RA, TNFRSF1A, ST2) and tissue-specific GVHD markers (REG3A, HGF) were generally observed in NR vs CR pts (Table) and were further analyzed. Higher BL levels of these markers were significantly associated with a lower probability of OR (P[OR]) in the LR analysis (Figure). An interaction term was investigated to assess whether there was a differing biomarker effect within treatment groups; however, this was insignificant and not retained. The addition of skin involvement to the LR for all biomarkers had an impact on P(OR), with increased P(OR) for pts with skin involvement at BL. Liver involvement at BL was added to the LR for HGF, IL6, REG3A, TNFα, and TNFRSF1A. The LR models showed a significant decrease in P(OR) for pts with liver involvement at BL. GI involvement did not have a significant impact for any biomarker. Geometric mean levels of TNFα, TNFRSF1A, IL2RA, REG3A, and ST2 decreased from BL to D14 in CR pts in the RUX arm but increased with BAT. NR pts had increases in these biomarkers regardless of treatment; however, longer follow-up is needed. Treatment had an underlying impact on P(OR) but no further impact on the effect of biomarkers on P(OR). Maximum change from BL was observed at D14; a slight return to BL levels was observed at D28 in CR pts. Surprisingly, IL6 levels increased with RUX regardless of response. IL6, like TNFα, is directly modulated by the JAK-STAT pathway and was therefore expected to decrease with RUX. CONCLUSIONS This is the first biomarker study in a phase 3 trial in GVHD. BL levels of IL6, IL8, TNFα, IL2RA, TNFRSF1A, ST2, REG3A, and HGF tended to be higher in NR vs CR pts; higher levels were associated with lower P(OR) when adjusted for treatment arm. Skin and liver involvement also had an impact on response. Skin involvement was associated with higher P(OR), regardless of biomarker BL levels, possibly because no skin involvement implied other organ involvement and tended to be associated with a higher overall severity grade at BL. CR pts in the RUX group had lower BL levels of TNFα and showed trends toward decreases from BL to D14 in the soluble cytokine receptors ST2, TNFRSF1A, and IL2RA and tissue-specific marker REG3A. Disclosures Socié: Elsalys: Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Niederwieser:Amgen: Speakers Bureau; Daiichi: Research Funding; Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Szer:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Or:Hadassah Hebrew University Medical Center: Consultancy, Current Employment. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Shire: Other: Travel grand. Forcade:JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau; Sanofi: Other: Travel grant for congress; Novartis: Other: Travel grant for congress. Civriz Bozdag:Novartis: Research Funding. Chaturvedi:Novartis: Current Employment. Wilke:Novartis Pharma AG: Current Employment, Other: Stock owner. Zeiser:Novartis: Honoraria; Incyte: Honoraria; Malinckrodt: Honoraria.

Introduction: It is anticipated that many patients with hemophilia are likely to switch from one coagulation factor product to a newer agent within the next few years. New replacement factor formulations have been developed using several approaches that have theoretical benefit. However, except for pharmacokinetic properties, it may be difficult to determine whether they are superior to current clinically successful preparations. Rurioctocog alfa pegol (Adynovate®), a pegylated, extended half-life factor VIII (FVIII) concentrate, received United States Food and Drug Administration approval in 2015. Its efficacy and safety for the treatment of hemophilia A have been demonstrated in multiple studies (Konkle et al. 2015; Gruppo et al. 2019; Mullins et al. 2017). The ATHN 2: Factor Switching Study provided the opportunity to longitudinally observe previously treated hemophilia patients switching to rurioctocog alfa pegol to identify dosing regimens, patient satisfaction with the change in therapy, impact on health states and productivity. Methods: The ATHN 2: Factor Switching Study is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at ATHN-affiliated sites in the US. This multi-center, longitudinal, observational study enrolled male and female children and adults with moderate or severe congenital hemophilia A or B (factor VIII or IX clotting activity ≤5% of normal) who were previously treated with plasma-derived or recombinant factor replacement products with ³50 exposure days. Patients receiving care from one of 30 hemophilia treatment centers were enrolled into 2 arms: 1) a prospective arm including those switching factor replacement products who were followed for Results: Patients (n=59) with hemophilia A were enrolled into the rurioctocog alfa pegol sub-study by May 1, 2020. Mean (± standard deviation [SD]) age was 25 ± 18 years (range = 4-77 years); 72.9% (n=43) were in the prospective arm and 27.1% (n=16) in the retrospective arm; 11.9% (n=7) had moderate hemophilia A and 88.1% (n=52) had severe disease. All were taking rurioctocog alfa pegol as prophylaxis. At study end, results for dosing (Table 1) indicated the most common treatment regimen was twice weekly (45.1%, n=23), and mean nominal dose was 50 ± 10 U/kg. Patients were highly adherent to prophylaxis with rurioctocog alfa pegol with a mean total VERITAS-Pro score of 31.4 ± 8.4; adherence improved slightly over time (32.6 ± 9.0 at baseline vs 29.2 ± 4.2 at month 12). Patients strongly preferred rurioctocog alfa pegol vs all prior factor products for controlling bleeding, convenience, finding time to take and ease of administering FVIII, and how often they were required to take factor (Table 1). Overall, 76.5% of patients were very satisfied or satisfied with rurioctocog alfa pegol. Assessment of health states indicated that patients generally had no or slight problems with mobility, activities, or self-care; and were not in pain or anxious/depressed. Patients generally missed no time from work or school. Overall health was self-rated at 89.0 ± 13.0 on a scale from 0 (worst health) to 100 (best health) and remained stable from baseline (88.0 ± 14.0) to month 12 (87.8 ± 15.3). Conclusions: Moderate and severe hemophilia A patients enrolled in ATHN 2 who received rurioctocog alfa pegol for prophylaxis enjoyed excellent health, had little to no school or work impairment and were adherent to, and satisfied with, their treatment regimen. Disclosures Recht: Spark: Research Funding; CSL Behring: Consultancy, Other: personal fees; Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Genentech: Consultancy, Other: personal fees, Research Funding; Pfizer: Consultancy, Other: personal fees; BioMarin: Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding. Guelcher:Novo-Nordisk: Consultancy; Octapharma: Consultancy; Genentech, Octapharma, CSL Behring, Takeda, Pfizer, Novo Nordisk: Consultancy; Takeda: Consultancy. Neufeld:Bayer: Other: DSMB; genetech: Consultancy; Novo Nordsik: Consultancy; Octapharma: Consultancy; Takeda: Consultancy; Imara Pharma: Other: DSMB service; ApoPharma/Chiezi: Other: DSMB service; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Acceleron Pharma: Consultancy, Other: DSMB. Ragni:Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; BioMarin: Consultancy, Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; Takeda: Research Funding; Sangamo: Consultancy, Research Funding; Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Sidonio:Biomarin: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Grifols: Research Funding; Spark: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Takemoto:Novartis: Other: DMBC; Genentech: Consultancy. Tarantino:Spark: Membership on an entity's Board of Directors or advisory committees; CDC: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; HRSA: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other; Sobi: Membership on an entity's Board of Directors or advisory committees. Caicedo:Takeda: Current Employment. Denne:Takeda: Current Employment.

Background: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components, including ITK, are maintained which suggests malignant T cells exploit this growth and survival pathway to their advantage. Antigen-presenting cells, abundant in the lymphoma microenvironment, also may provide antigen to drive TCR signaling through ITK. CPI-818 is a first-in-class, irreversible ITK inhibitor with selectivity for ITK. In preclinical studies, CPI-818 blocks TCR signaling in vitro and is efficacious in murine models and canines with T-cell lymphomas. We report results from the dose escalation portion of an ongoing phase 1/1b trial of CPI-818 in patients with relapsed/refractory T-cell lymphoma (CPI-818-001 study, NCT03952078). The trial is being conducted at sites in the United States, Australia, and South Korea. Methods: In dose-escalation, cohorts (3+3 design) enrolled patients with cutaneous and peripheral T-cell lymphoma who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; ECOG status 0-1; and adequate organ function. CPI-818 was administered in ascending dose levels (100, 200, 400, 600mg BID) continuously for up to sixteen 21-day cycles, until progression or unacceptable toxicity. In dose expansion, PTCL-NOS and CTCL patients are receiving CPI-818 at a dose of 600 mg BID. The primary objectives of the study are to evaluate the safety and to establish the maximum tolerated dose (MTD) or the maximum administered dose of CPI-818. Safety events will be assessed according to the NCI-CTCAEv5. Secondary objectives include evaluating pharmacokinetics and efficacy as assessed by the investigator using standard response criteria at the end of every 3 cycles. ITK occupancy in peripheral blood T cells and tumor tissue as well as biomarkers associated with anti-tumor activity in tumor and blood samples are being evaluated. Results: In dose-escalation, sixteen patients were enrolled in four cohorts: 100 mg BID (n=4), 200 mg BID (n=3), 400 mg BID (n=5), and 600 mg BID (n=4). No dose-limiting toxicities were observed in any of these cohorts and the MTD was not reached. Treatment related adverse events (TRAEs) were reported in 9 (47.4%) patients and were all Grade 1-2 in severity. The most common (>1 patient) were fatigue (15.8%), nausea (10.5%), and rash (10.5%) and no infections were reported. By flow cytometry, no consistent changes in circulating non-malignant or total T cell number or phenotype were observed. Pharmacodynamic analysis revealed ITK engagement by CPI-818 in all cohorts when CPI-818 is dosed BID. With increasing dose, the trough ITK occupancy in both blood and tissue increased. At doses of 200 mg and greater, trough occupancies were >75%. Near complete ITK inhibition (98%) was achieved at 600 mg BID and therefore, this dose was selected as the expansion cohort dose and higher doses were not explored. Reduction in serum cytokines including IL2 (six of eight patients), IFNg (eight of eight patients), and TNFa (eight of eight patients) was observed 24hr post-dose in patients treated with doses of 400 and 600mg, but not at lower doses. In dose escalation, a total of four PTCL patients were enrolled at doses of 200 mg BID or greater. A confirmed complete response was achieved in one PTCL-NOS patient in the 200mg BID cohort. Among 7 CTCL patients enrolled, a Nodal CR, improved mSWAT and slowing of Sézary cell expansion were seen (Figure 1). Given the safety profile, the PK/PD findings, and the early signs of efficacy, PTCL-NOS and CTCL cohorts were expanded at 600mg BID. To date, two patients with PTCL-NOS and one patient with CTCL have been recently enrolled in expansion cohorts. Conclusion: The dose-escalation part of the CPI-818-001 trial demonstrated that the 100, 200, 400 and 600 mg BID doses are well tolerated. Clinical activity was observed in both PTCL-NOS and CTCL. Reduction of serum levels of canonical T cell cytokines is consistent with on-mechanism drug inhibition of inflammatory T cell pathways. Disease specific expansion cohorts for PTCL-NOS and CTCL are enrolling patients at a dose of 600 mg BID. Disclosures Khodadoust: Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Feldman:Abbvie: Honoraria; Pharmacyclics: Honoraria, Other, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Bayer: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Kim:miRagen: Research Funding; Elorac: Research Funding; Neumedicine: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Solingenix: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mehta-Shah:Karyopharm Therapeutics: Consultancy; Verastem: Research Funding; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus: Research Funding; Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Genetech/Roche: Research Funding. Kim:Mundipharma: Research Funding; Donga: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Horwitz:ASTEX: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy. Buggy:Corvus Pharmaceuticals: Consultancy, Current Employment, Current equity holder in publicly-traded company. Hotson:Corvus Pharmaceuticals: Current Employment. Hill:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Munneke:Corvus Pharmaceuticals: Current Employment. Mahabhashyam:Corvus Pharmaceuticals: Current Employment. Miller:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Janc:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mobasher:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

The role played by N-linked glycans (NLGs) in the immunogenicity of therapeutic Factor VIII (tFVIII) proteins is poorly understood. Our study addresses this question using peptidomic profiling data on HLA-class-II (HLAcII)-presented peptides from dendritic cell (DC)-protein processing and presentation assays (PPPAs) performed across three independent experiments reported in the literature (Sorvillo et al. (2016), Peyron et al. (2018), and Diego et al. (2020)). Assuming that the number of peptides presented on HLAcII molecules is directly proportional to immunogenicity potential (IP), we asked if the NLGs on tFVIII proteins provide some degree of protection from proteolytic processing within DCs for the amino acid (AA) residues in their immediate vicinity. If NLGs are protective, then we expect an attenuated IP, which would reflect in lower counts of associated AAs. We examined the effects of NLGs both pointwise (i.e., at the single glycated asparagine residue) and at the glycosylation umbrella (GUMB), a term we defined as being −5 to +5 AAs from the glycated asparagine residue of all NLGs. Our first step in addressing these effects was to construct 2×2 contingency tables of the number of AA residues in the HLAcII bound and unbound fractions, and the number of AA residues falling either within the set of NLGs or within the set of GUMBs. We statistically evaluated our question by using Fisher's Exact tests of the hypothesis of no association, and calculated the odds ratio (OR) and its 95% confidence interval (CI). Results from the pointwise tests of the effect of NLGs reported in Figure 1 suggest that overall NLGs exert a protective effect in that non-glycated AAs were at significantly greater risk of being in the fraction of peptides bound to and presented by HLAcII molecules. The results from these statistical analyses-listed as OR (95% CI LB, 95% CI UB)-were: 7.0 (2.6, 21.9) for Diego et al.; 5.6 (0.9, 230.6) for Sorvillo et al. with 25 nM tFVIII; 6.5 (1.0, 269.0) for Sorvillo et al. with 50 nM tFVIII; 3.7 (1.1, 19.8) for Peyron et al.; and 4.4 (2.3, 9.3) for all data combined. The data from Sorvillo et al. (2016; for their experiments using 50 nM tFVIII but not for their experiments using 25 nM tFVIII), Peyron et al. (2018), and Diego et al. (2020), as well as the combined data, all revealed significantly greater risk of non-glycated AAs being in the HLAcII bound/presented fraction relative to glycated AAs. While the results from Sorvillo et al. with 25 nM tFVIII was not statistically significant, this was most likely due to the effects on power of its "small sample size" as the data was trending. The results for the GUMB-level tests reported in Figure 2 are even more robust with the data suggesting a protective effect of the GUMBs in that the AAs not located in their immediate vicinity (as defined above) were at significantly greater risk of being in the bound fraction of peptides presented on HLAcII molecules in all experiments, as well as in the combined data. The results from these statistical analyses-listed as OR (95% CI LB, 95% CI UB)-were: 6.0 (4.5, 8.2) for Diego et al.; 19.9 (6.7, 97.6) for Sorvillo et al. with 25 nM tFVIII; 7.3 (3.9, 15.6) for Sorvillo et al. with 50 nM tFVIII; 2.5 (1.8, 3.6) for Peyron et al.; and 3.8 (3.2, 4.6) for all data combined. In conclusion, these results-from the tFVIII proteins tested using peptidomic profiling of HLAcII-presented peptides from DC-PPPAs performed across three independent experiments-demonstrate NLGs provided significant protection from either proteolytic processing in DCs or peptide binding to HLAcII molecules, or both, and thus lower IP. Our results support the conclusion that NLGs play a significant role in the immunogenicity of tFVIII proteins. Disclosures Luu: Haplogenics Corporation: Current Employment. Hofmann:CSL Behring: Current Employment. Dinh:Haplogenics Corporation: Current Employment. Powell:Haplogenics Corporation: Membership on an entity's Board of Directors or advisory committees. Mead:CSL Behring: Current Employment. Escobar:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: 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; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: 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. Maraskovsky:CSL Behring: Current Employment. Howard:Haplogenics Corporation: Membership on an entity's Board of Directors or advisory committees.

Introduction: Lack of factor VIII/IX (FVIII/FIX) in hemophilia A/B (HA/HB), respectively, results in reduced thrombin generation, leading to recurrent/spontaneous bleeds. Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody, currently under clinical investigation for subcutaneous prophylaxis of HA/HB patients with/without inhibitors. Breakthrough bleeds occurring in HA/HB patients while on concizumab prophylaxis may be treated with FVIII/FIX. We aimed to compare the in vitro effect of recombinant FVIII (rFVIII) and FIX (rFIX) in HA and HB plasma, respectively, in the absence or presence of concizumab. Methods: rFVIII/rFIX was added to HA/HB pooled plasma at 0.25, 0.5 or 1 IU/mL (corresponding to post-administration plasma concentrations of 12.5, 25 and 50 IU/kg rFVIII and 12.5−25, 25−50 and 50−100 IU/kg rFIX) in the absence or presence of concizumab (1,500, 4,500 or 15,000 ng/mL). In a separate experiment, 33 plasma samples from eight HA patients, who were on concizumab prophylaxis as part of the phase 2 explorer5 trial (NCT03196297), were spiked with 0.5, 1 and 1.5 IU/mL rFVIII. Pre-dose samples (before concizumab prophylaxis) from seven of these patients were also included. Thrombin generation was measured after initiation with 1 pM tissue factor (PPP-Low, Thrombinoscope). Statistical analysis of the effects conferred by each (combination of) drug(s) was performed by ANOVA analyses. Results: A significant (p1,500 ng/mL and 0.5 IU/mL rFIX combined with 15,000 ng/mL concizumab, i.e., a 10% smaller effect of rFIX was observed in the presence of concizumab than in its absence. The thrombin peak obtained upon adding 1.0 IU/mL rFIX to plasma without concizumab was similar to the thrombin peak in the presence of concizumab and 0.5 IU/mL rFIX. This suggests that in the presence of concizumab, a 2-fold reduced dose of rFIX would be sufficient to obtain the same plasma thrombin generation capacity as with 1.0 IU/mL rFIX in the absence of concizumab. Conclusion: rFVIII/rFIX increased the thrombin peak in HA and HB plasma, respectively, both in the absence and presence of concizumab. The combined effects of rFVIII/rFIX with concizumab were mainly additive with an up to 20% additional effect caused by drug-drug interaction with rFVIII and a 10% reduction with rFIX. No signs of exaggerated thrombin generation were observed by combining concizumab with rFVIII/rFIX. Therefore, the data support rFVIII/rFIX use for bleed treatment in patients on concizumab prophylaxis. As rFVIII/rFIX and concizumab have additive effects in terms of thrombin generation capacity, data suggest that clinical effectiveness could be achieved with rFVIII/rFIX doses in the lower range recommended for such products. Disclosures Kjalke: Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company. Andersen:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

Background: The optimal interruption schedule for NOACs in patients undergoing invasive procedures has not been determined. This analysis describes periprocedural interruption of edoxaban in real world EMIT AF/VTE study. Methods: EMIT AF/VTE was a prospective, non-interventional study conducted in 7 European countries that collected detailed information on periprocedural management of edoxaban from 5 days before to 30 days after procedure in patients with AF or VTE. Results: Among 1155 patients, pre-procedural interruption occurred in 781 (68%) patients (median 2 days, IQR 1.0-2.0) and post-procedural interruption in 308 (27%) patients (median 3 days, IQR 1.0-8.0); 279 (24.2%) patients had both pre- and post-procedural interruption. Edoxaban interruption in some patients differed from 2018 EHRA Recommendations for NOAC use in AF. Of 294 patients receiving minor risk procedures, for whom no interruption is recommended, 173 (58.8%) had preprocedural interruption (median 1 day). Of 581 patients with low bleeding risk procedures, for whom ≥24h preprocedural interruption is recommended, 188 (32.4%) had no interruption. Of 280 patients receiving high bleeding risk procedures, for whom ≥48h interruption is recommended, 46 (16.4%) had no interruption. Clinical events are shown in Table. Conclusion: Edoxaban interruption schedules in routine practice were not always consistent with EHRA guidelines; nevertheless, rates of clinically significant bleeding or acute thromboembolic events or coronary syndromes were low in the EMIT study. Table Disclosures Colonna: Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; BayerAG: Honoraria; Italian Cardiology Association: Other: Non-financial support; European Society of Cardiology: Other: Non-financial support; Pfizer/BMS: Honoraria. von Heymann:Daiichi Sankyo: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bayer AG: Honoraria; Pfizer GmBH: Honoraria; CSL Behring: Honoraria; NovoNordisk Pharma: Honoraria; EACTA and EACTS: Other; DGGG: Other; Mitsubishi Pharma: Honoraria; Ferring GmbH: Honoraria; Biotest GmbH: Honoraria; Leo Pharma GmBH: Honoraria; German Society of Anaesthesiology and Intensive Care Medicine: Other. Saxena:Daiichi Sankyo: Honoraria, Research Funding. Vanassche:Boehringer Ingelheim: Honoraria; 367 Leo Pharma: Honoraria; Bayer: Honoraria; Daiichi Sankyo: Honoraria, Research Funding. Jin:Daiichi Sankyo: Current Employment. Wilkins:Daiichi Sankyo: Honoraria. Chen:Daiichi Sankyo: Current Employment. Unverdorben:Daiichi Sankyo: Current Employment.

Introduction PBPK models incorporate complex drug and system (ie, physiology) information into a mathematical framework to support dose selection while considering various patient factors (eg, age, sex, and comorbidity). Through "predict-learn-confirm cycles," PBPK models enable dose prediction to optimize clinical study design. BIVV001 (rFVIIIFc-VWF-XTEN), a new class of FVIII replacement therapy designed to break the von Willebrand factor (VWF) half-life ceiling (Chhabra et al.Blood. 2020; Konkle et al.Blood. 2018), consists of a single recombinant FVIII fused to dimeric Fc (to permit recycling of BIVV001 by a naturally occurring pathway via Fc neonatal receptors [FcRn]), a VWF D′D3 domain, and two XTEN® polypeptides (XTEN® is a registered trademark of Amunix Pharmaceuticals, Inc.). In a Phase 1 study (Lissitchkov et al.Blood. 2019), four once-weekly BIVV001 50 IU/kg infusions provided high sustained FVIII activity with a mean half-life of 41.3 hours. We aimed to build and verify an initial PBPK model to characterize BIVV001 activity levels in adults with severe hemophilia A. Methods To our knowledge, this is the first time that a PBPK model has been studied in hemophilia. We assumed that the distribution of BIVV001 and recombinant FVIII Fc fusion protein (rFVIIIFc) (Eloctate®) involves the FcRn recycling pathway that is similar to monoclonal antibodies. First, to evaluate the feasibility of the modeling approach, we built a PBPK model (Simcyp, Sheffield, UK) that captured FcRn-dependent recycling of Fc fusion proteins. Model input parameters were adjusted to capture observed rFVIIIFc activity levels with a prediction error of Results To fit the BIVV001 data, the PBPK model input parameters, KD1, vascular reflection coefficient (σv), and Kup, were modified compared with those used for the rFVIIIFc PBPK model. The PBPK model captured observed BIVV001 exposure with a low prediction error ( Conclusions We have developed a PBPK model that accurately predicts the high sustained FVIII activity levels observed with BIVV001 exposure in adults with severe hemophilia A. The PBPK model framework can be a useful tool in the development of FVIII replacement therapies for hemophilia A. Disclosures Xia: Sanofi:Current Employment, Current equity holder in publicly-traded company.Katragadda:Sanofi:Current Employment, Current equity holder in publicly-traded company.Teutonico:Sanofi:Current Employment, Current equity holder in publicly-traded company.Macha:Sanofi:Current Employment, Current equity holder in publicly-traded company.Demissie:Sanofi:Current Employment, Current equity holder in publicly-traded company.Benson:Sanofi:Current Employment, Current equity holder in publicly-traded company.

BACKGROUND. SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 kinase inhibitor investigated in unselected AML patients in the First-in-Human, Dose Escalation (DE) and Cohort Expansion (CE) DIAMOND trial (clinicaltrials.gov identifier: NCT03008187). The study has completed the DE part showing an acceptable safety profile up to the recommended dose (RD), with initial evidence of single agent efficacy1. Preclinical studies conducted in vitro - using a panel of 26 AML cell lines harboring different genetic alterations - and in vivo - in xenograft mouse model bearing MOLM-16 cell line - showed a direct correlation between the activity of SEL24/MEN1703 and the inhibition of S6 phosphorylation (pS6) protein, a downstream target of PIM/FLT3 signaling pathway. AIM. To assess the degree of target engagement and its preliminary correlation with the anti-leukemic effect of SEL24/MEN1703 in samples collected from patients enrolled in the DE part of DIAMOND trial. METHODS. S6 phosphorylation has been longitudinally monitored in the DIAMOND study through an optimized assay for multiparametric analysis of phospho-protein activation. The assay allows a quantitative assessment of pS6 at single cell level among blast cells as well as the identification of blast subpopulations in both peripheral blood (PB) and bone marrow (BM). Blast counts were monitored to assess whether the target engagement did translate into blast count reduction. RESULTS. Two cohorts of patients, treated at 100 mg (one dose level below RD) and 125 mg (RD) were analyzed, for a total of n=9 evaluable patients on PB and n=7 on BM. At screening we observed a heterogeneous positivity for pS6 marker in blast cells (range: 1%-53 %) both in PB and in BM, consistent with the unselected AML patient population recruited in the trial. Overall, 7/9 PB and 4/7 BM samples showed pS6 inhibition in blast cells at the end of the Cycle 1 in comparison with screening (range: 70%-94% and 26%-76% in PB and BM, respectively) (Figure 1). In the cohort treated at 100 mg such strong pathway inhibition did not correlate with blast count reduction. Interestingly, in samples from a patient treated at 125 mg who harbored the highest burden of pS6+ blast cells (>25%), a correlation between pathway inhibition and blast count reduction was observed suggesting that a higher burden of blasts with activated pS6 might be more sensitive to the inhibition of the pathway (Figure 1). CONCLUSIONS. The longitudinal PD assessment through the modulation of pS6 activation by flow cytometry confirmed that meaningful target engagement was achieved, both in PB and BM, in patients treated with SEL24/MEN1703 at 100 and 125 mg. Preliminary data suggest that the FLT3/PIM pathway inhibition might be associated with blast count reduction, particularly in case of high baseline activation of pS6. Longitudinal monitoring of PD will be continued in the CE part of DIAMOND trial. REFERENCES. 1. Solomon et al, EHA 2020 Disclosures Tomirotti: Menarini Ricerche: Current Employment. Bellarosa:Menarini Ricerche: Current Employment. Walter:Genentech: Consultancy; Selvita: Research Funding; StemLine: Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Brzózka:Ryvu Therapeutics: Current Employment. Baldini:Menarini Ricerche: Current Employment. Salerno:Menarini Richerce: Current Employment. Binaschi:Menarini Ricerche: Current Employment. Laurent:Menarini Ricerche: Current Employment. Pellacani:Menarini Ricerche: Current Employment.

Aims: We previously reported results of the first machine learning study to identify the novel biomarkers associated with crude incidence of TEs in PV patients (pts) treated with hydroxyurea (HU) (Verstovsek et al, Blood 2019). In the current study, we have expanded the database to perform an in-depth machine learning analysis of biomarkers predicting the annual standardized incidence rate (IR) of TEs in PV pts treated with HU. In addition, we examined the IR of TEs in HU-treated pts and pts treated first with HU, then switched to ruxolitinib (HU-RUX). Methods: The study is part of PV-AIM (polycythemia vera advanced integrated models for prevention of TEs). The US OPTUM database includes the electronic medical records from 105 million pts (2007-2020), including 82 960 PV pts with a median record length of 8.4 years. TEs were assessed (A) before the treatment (Tx) initiation in both groups; (B) while on HU (median: 29 months) and (C) while continuing HU or switching to RUX (median, 17 months). A total of 3852 HU-alone pts and 130 HU-RUX pts passed inclusion/exclusion criteria. To avoid selection bias, only HU-alone pts treated prior to RUX market launch were included (n=704). Cohorts were then matched by selecting the nearest cases from the HU-alone groups based on the propensity scores calculated from the total Tx period, gender, race, age at index, and geographical division (n=130 pts in both HU-alone and HU-RUX). TEs were identified from a restrictive list of ICD-CM diagnosis codes defined in the RESPONSE study (Kiladjian et al, Lancet Haematol 2020). Annualized IR of TEs were then calculated per 100 pts for each of the above Tx periods for each cohort. A random survival forest (RSF) model was then constructed for HU-alone pts, with at least 6 months of HU Tx and 18 months of follow-up, to predict the risk of TEs 6 to 18 months after the first HU Tx. Pts with at least 1 lab test and 1 observation obtained at 3 to 6 months post index were included in the model (n=1012). The features also included demographics, history of TEs, phlebotomy and anti-coagulant use. The performance was assessed on a 70:30 train:test split using Receiver Operating Characteristic-Area Under the Curve (ROC-AUC). RSF variable importance was then used to identify the variables with the largest impact on prediction of TEs. The feature interactions for the top 10 features were mapped and assessed in terms of risk of TEs via log-rank using a brute-force combinatorial approach. Risk was assessed in the context of total population and in pts with/without a history of TEs. Optimal interactions were presented as interpretable 4-group Kaplan-Meier plots. Lastly, the feature interactions were scored for synergy in the context of risk of TEs based on the difference in expected and observed pairwise probabilities. Results: The RSF model achieved an accuracy of > 0.80 AUC for prediction of TEs 6 to12 months after the first HU Tx. RSF variable importance revealed that the history of TEs had the largest effect on prediction (>2-fold) relative to other features. The top observational and lab variables in terms of feature importance were body mass index and neutrophil percentage (NEP), respectively, followed by the previously observed lymphocyte percentage (LYP) and RDW. The largest synergistic pairwise interactions (Table 1) were NEP + RDW (Figure 1a), followed by LYP + RDW (Figure 1b), which occurred in pts without history of TEs. The pre-Tx baseline incidence of TEs in the HU-alone and HU-RUX groups were 8.7 and 10.8, respectively. The rates of TEs decreased by 36% and 22% to 5.6 and 8.4, respectively during the HU Tx. Following the switch to RUX, the rate of TEs was maintained in the HU-RUX group at 8.3 (−1%) but increased to 10.53 (+89%) in the HU-alone group during the same period of 17 months (Figure 2). Conclusion: An in-depth machine learning analysis to identify the markers that predict TEs in HU-treated PV pts revealed interaction of key hematological parameters with RDW. This finding could help recognize the pts at high risk of TE and possibly prevent a major cause of morbidity and mortality. The results reconfirm the role of RDW, as well as NEP/LYM ratios in predicting TE occurrence, routine lab parameters in the clinic, but not usually taken into account. Finally, we observed a renewed increase in TEs in HU-treated pts after an initial decrease, which was not the case in pts switching to RUX in the same period. We aim to present similar biomarker analyses on RUX pts in the final presentation. Disclosures Verstovsek: Promedior: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; ItalPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding. De Stefano:Janssen Cilag: Other: Non-financial support; Celgene: Other: Non-financial support, personal fee; Bayer: Other: Non-financial support; Amgen: Other: Personal fee; Novartis: Other: Personal fee, Research Funding. Heidel:Novartis: Consultancy, Honoraria, Research Funding. Zuurman:Novartis Pharma A.G.: Current Employment. Zaiac:Novartis: Current Employment, Current equity holder in private company. Bryan:Novartis: Current Employment. Buckley:Novartis: Current Employment. Mathur:Novartis: Current Employment. Morelli:Novartis: Current Employment. Bigan:Novartis: Consultancy. Ruhl:Boston Consulting Group: Current Employment. Meier:Novartis: Consultancy.

Background: ABP 798 is a proposed biosimilar to rituximab reference product (RP). Regulatory approval of biosimilars is based on a totality of evidence (TOE) approach which includes similarity in analytical characteristics (structural and functional), in mechanism of action (MoA) -clinical pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and in comparative clinical studies. Evidence from analytical, functional, clinical PK/PD, and efficacy and safety evaluations indicate that ABP 798 is similar to rituximab RP. Similarity of efficacy and safety in patients with non-Hodgkin lymphoma (NHL) was demonstrated in a randomized, double-blind, comparative clinical study in which the primary analysis was based on data from central, independent, and blinded assessments of disease and the sensitivity analysis was based on data using investigator assessments of disease. Here we present in vitro chemo synergy, preclinical in-vivo tumor efficacy data and show how the results of the sensitivity analysis using investigator assessments of the response rate from the NHL clinical study further add to the TOE supporting similarity of ABP 798 with the RP. Methods: In vitro synergy with chemotherapeutic agents was investigated by assessing the effect of docetaxel, gemcitabine, or doxorubicin with ABP 798 and rituximab RP in SU-DHL-6 cell lines and measured using the ATP-based cell viability endpoint (ATPLite). In vivo efficacy was assessed by evaluating the anti-tumor activity of ABP 798 and rituximab RP in NHL xenograft models in NOD/SCID mice using CD20-expressing RL and Raji cell lines. A sensitivity analysis was conducted to assess the robustness of the results of the primary efficacy endpoint of the proportion of patients with the best overall response of complete response, partial response, or unconfirmed complete response (ORR) in the NHL comparative clinical study using the investigator's assessment of disease on the full analysis set. Waterfall plots of the maximum percent reduction in the sum of the products of the greatest diameters (SPD) for index nodal lesions based on both the central, independent, blinded assessment of disease and the investigator's assessment of disease were used. Results: In vitro study results demonstrated synergistic activity of the combination of docetaxel and ABP 798 or the RP (synergy score = 6.35±0.69 [with ABP 798]; 6.79±0.12 [with RP]). In contrast, combinations with gemcitabine (synergy score = 2.68±0.20 [with ABP 798] and 2.54±0.29 [with RP]) or doxorubicin (synergy score = 1.95±0.56 [with ABP 79]) and 3.23±0.53 [with RP]) were additive. In RL cell lines, ABP 798 inhibited tumor growth similarly to rituximab RP, with no statistical difference between dose groups at 3 and 30 mg/kg (p = 0.951 and p = 0.996, respectively). In Raji cells, ABP 798 and rituximab RP significantly and similarly inhibited tumor growth when compared to an IgG1 isotype control (p < 0.001 for 3 and 30 µg/kg doses). ABP 798, at both dose levels, inhibited tumor growth similarly to rituximab RP by 27-41%, with no statistical difference. In the NHL comparative clinical study, risk difference (RD) of ORR with 1-sided 95% lower and upper confidence limits from the adjusted linear model was 7.7% (-3.2%, 18.6%) using central, blinded, independent assessments of the modified full analysis set based on randomized treatment assignment. The sensitivity analysis using investigator assessments of disease of the full analysis set of all randomized subjects based on the randomized treatment assignment received was RD = 0.5% (-7.8%, 8.8%). Waterfall plots of the maximum percent reduction in the SPD for index nodal lesions further demonstrate similarity of efficacy with central or local assessments of disease. Conclusions: In vitro and in vivo preclinical studies demonstrated chemo synergy and in vivo tumor efficacy. The sensitivity analysis of ORR using local assessments in the NHL comparative clinical study was consistent with results from the primary efficacy analysis; the maximum percent reduction in index nodal lesions was similar for central and local assessments of disease. These results further support that ABP 798 is similar to the RP across a range of efficacy evaluations as well as primary and secondary mechanisms of action and add additional supporting data to the TOE. Disclosures Niederwieser: Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding; Amgen: Speakers Bureau. Hamm:Amgen: Consultancy. Cobb:Amgen: Consultancy. Thway:Amgen: Current Employment, Current equity holder in publicly-traded company. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tucci:Amgen: Consultancy. Delwail:Amgen: Consultancy. Hajek:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Hanes:Amgen: Current Employment, Current equity holder in publicly-traded company.

Introduction: The randomized, open-label, multicenter, phase 3 CANDOR study compared carfilzomib, dexamethasone, and daratumumab (KdD) to carfilzomib and dexamethasone (Kd) in patients with multiple myeloma who have relapsed after 1-3 prior lines of therapy (ClinicalTrials.gov, NCT03158688). In the previously reported primary analysis (Dimopoulos et al, Lancet 2020), a significant progression-free survival (PFS) benefit was demonstrated in patients treated with KdD vs patients treated with Kd (hazard ratio [HR], 0.63 [95% CI, 0.46-0.85]; two-sided P=0.0027). However, after a median follow-up of 16.9 months, median PFS was not reached in the KdD arm. Here, we report updated efficacy and safety outcomes from the CANDOR study. Methods: Adult patients with relapsed or refractory multiple myeloma (RRMM) received 28-day cycles of KdD or Kd (randomized 2:1). In the primary analysis, PFS was the primary endpoint and overall survival (OS) a key secondary endpoint. In this prespecified interim OS analysis, statistical testing was based on the actual number of OS events observed by the data cutoff (approximately 36 months after enrollment of the first patient); PFS was summarized descriptively. Disease progression was determined locally by investigators in an unblinded manner and centrally by the sponsor using a validated computer algorithm (Onyx Response Computer Algorithm [ORCA]) in a blinded manner. PFS and OS were compared between the KdD and Kd arms using a stratified log-rank test, and HRs were estimated by a stratified Cox proportional-hazards model. Results: Patients were randomized to KdD (n = 312) and Kd (n = 154). Of all randomized patients, median age was approximately 64 years; 42% received previous lenalidomide, and 33% were lenalidomide refractory; 90% received previous bortezomib, and 29% were bortezomib refractory. At the data cutoff date of June 15, 2020, 199 (63.8%) patients in the KdD arm and 88 (57.1%) in the Kd arm remained on study. Among patients treated with KdD and Kd, 140 (44.9%) and 85 (55.2%) had PFS events, respectively; median follow-up was 27.8 months (KdD) and 27.0 months (Kd). Median PFS by ORCA was 28.6 months for the KdD arm versus 15.2 months for the Kd arm (HR, 0.59 [95% CI, 0.45-0.78]; Figure). OS data were not mature and will be updated at a future prespecified analysis. Median treatment duration was 79.3 weeks with KdD versus 40.3 weeks with Kd. Grade ≥3 adverse events (AEs) occurred in 87.0% and 75.8% of patients in the KdD and Kd arms, respectively, and fatal AEs occurred in 8.8% and 4.6%; one fatal AE in the KdD arm (due to arrhythmia) and one fatal AE in the Kd arm (due to COVID-19 pneumonia) had occurred since the primary analysis. Carfilzomib treatment discontinuation rates due to AEs were 26.0% with KdD and 22.2% with Kd. Exposure-adjusted AE rates per 100 patient years were: 171.2 and 151.9 for grade ≥3 AEs and 6.9 and 5.6 for fatal AEs in the KdD and Kd arms, respectively. Updated data by key subgroups will be presented. Conclusion: With approximately 11 months of additional follow-up, a 13.4-month improvement in median PFS was observed in patients treated with KdD (28.6 months) versus patients treated with Kd (15.2 months; HR, 0.59 [95% CI, 0.45-0.78]). Safety was consistent with previously reported results. KdD continues to show a favorable benefit-risk profile and represents an efficacious treatment option for patients with RRMM. Figure 1 Disclosures Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau. Quach:GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria. Mateos:EDOMundipharma: Consultancy; Adaptive: Consultancy; Pharmamar: Consultancy; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Landgren:Pfizer: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Cellectis: Consultancy, Honoraria; Seattle Genetics: Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding. Leleu:Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria; AbbVie: Honoraria; Carsgen: Honoraria; Karyopharm: Honoraria. Siegel:Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy; Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Weisel:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Gavriatopoulou:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Oriol:Janssen: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Rabin:Janssen, BMS/Celgene, Takeda, Karyopharm, Amgen: Consultancy; Janssen, BMS/Celgene, Takeda: Other: Travel; Jansse, BMS/Celgene, Takeda: Speakers Bureau. Nooka:GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Ding:Amgen: Current Employment. Zahlten-Kumeli:Amgen: Current Employment, Current equity holder in publicly-traded company. Usmani:Celgene: Other; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding.

Background: Midostaurin, a multikinase inhibitor that directly inhibits FLT3, is approved for the treatment of adult patients (pts) with newly diagnosed, FLT3-mutated AML. In the phase 3 RATIFY study (NCT00651261), younger adults (aged ≤ 60 y) who received midostaurin plus standard chemotherapy (CT) had significant improvements in survival compared with those that received placebo plus standard CT. To further evaluate the safety and efficacy of midostaurin in FLT3-mutated AML, a phase 3b (NCT03379727) study was initiated that allowed enrollment of younger and older (aged > 60 y) pts and variations in CT regimens, including idarubicin or daunorubicin for 7+3 or 5+2. Methods: This is an open-label, single-arm, multicenter study in adults fit for CT with newly diagnosed AML, ECOG performance status (PS) ≤ 2, and a documented FLT3 ITD or TKD mutation. Pts must start their first induction cycle with 7+3 (cytarabine [Ara-C] 100-200 mg/m2/d on days 1-7 + daunorubicin 60-90 mg/m2/d or idarubicin 12 mg/m2/d on days 1-3) or 5+2 (a reduced-dose regimen with these agents) per investigator's discretion and enroll by day 7 of the first induction cycle. Pts are assigned to the 7+3 group if their Ara-C duration is ≥ 7 days, independent of daunorubicin/idarubicin duration, and to the 5+2 group in other cases. Pts may not switch once started on 7+3 or 5+2. Pts receive Ara-C consolidation (dose per investigator's choice). Midostaurin 50 mg bid is administered on days 8-28 of each 28-day induction/consolidation cycle and daily for ≤ 12 cycles of maintenance. Pts are discontinued from the study if not in either complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of induction, relapse during consolidation/maintenance, receive a stem cell transplant (SCT), or experience toxicities leading to discontinuation. The primary and secondary endpoints are safety and the proportion of pts achieving CR/CRi, respectively. Results: Pts were recruited throughout Europe; study enrollment was closed January 28th, 2020, with 318 pts screened and 17 screen failures. Safety and efficacy analyses focused on 301 pts who received treatment and 300 pts who met all study criteria, respectively. The median age (range) was 59 (19-85) y, and 47.2% were aged > 60 y. Most pts had a FLT3-ITD mutation (82.7%), with 17.6% having a FLT3-TKD mutation. At data cut-off on March 31st, 2020, 63 pts were still receiving treatment. All 301 pts entered induction, 69% entered consolidation, and 26% entered maintenance; 28.7% underwent SCT. The majority of pts (80.4%) were treated with midostaurin plus 7+3; 19.6% received 5+2. Approximately 55.1% received idarubicin and 44.9% received daunorubicin for induction. Pts who received daunorubicin for induction were younger (62.2% vs 45.2% were aged < 60 y) and had a lower frequency of ECOG PS=2 (10.4% vs 18.1%) vs those who received idarubicin. Overall, 242 pts achieved CR/CRi (80.7%). The CR/CRi rates in older vs younger pts, female vs male pts, and pts who received daunorubicin vs idarubicin for induction were similar (Table). The majority of SAEs occurred during induction (75, 24.9%) and consolidation (64, 30.6%); there were 5 (6.3%) SAEs during maintenance. The most common AEs were pyrexia, nausea, diarrhea, and febrile neutropenia. Compared with younger pts, older pts had a higher frequency of grade ≥ 3 AEs (78.6% vs 90.8%) and SAEs (35.8% vs 51.4%), AEs leading to dose adjustment/interruption (30.2% vs 43%), and treatment-related AEs (73.6% vs 78.2%), SAEs (15.7% vs 23.9%), and those leading to discontinuation (6.9% vs 11.3%). Compared with younger pts, older pts had a higher frequency of certain grade ≥3 AEs, including severe infections (31.4% vs 45.1%), leukopenia (40.9% vs 49.3%), QT prolongation (3.1% vs 7.7%) , and pulmonary toxicity (3.8% vs 7.7%). There were 30 deaths (10%) reported during the study (7 younger pts, 23 older pts). Of pts who died, 19 were treated with idarubicin (all were older pts) and 11 were treated with daunorubicin for induction. Conclusions: Midostaurin plus CT resulted in high response rates regardless of pt age, sex, induction drug, or alternative CT regimen. The majority of pts received a 7+3 regimen regardless of age. The safety profile of midostaurin plus idarubicin or daunorubicin for induction was generally similar. The safety profile in older and younger pts was consistent with what has been previously reported, with no new safety signals identified. Disclosures Sierra: Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, 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; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griškevičius:Novartis: Research Funding. Cluzeau:Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy. Luppi:Gilead Sci: Consultancy, Speakers Bureau; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy; MSD: Consultancy; Novartis: Consultancy, Speakers Bureau; Sanofi: Consultancy. Farkas:Abbvie: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Johnson & Johnson: Honoraria. Bengoudifa:Novartis: Current Employment. Gilotti:Novartis: Current Employment. Hodzic:Novartis: Current Employment. Rambaldi:Roche: Honoraria; MSD: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Venditti:Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by chronic complement-mediated intravascular and extravascular hemolysis (IVH and EVH), and thrombosis. C5 inhibitors reduce IVH by inhibiting membrane attack complex formation and are the current standard of treatment for PNH. EVH persists in the presence of C5 inhibition. Pegcetacoplan is a C3 inhibitor targeted to control both IVH and EVH. The PADDOCK and PALOMINO studies assessed the safety and preliminary efficacy of pegcetacoplan in complement inhibitor-naïve patients. METHODS PADDOCK was a phase 1b, open-label, pilot study (NCT02588833) with 2 cohorts. Subjects in cohort 1 received pegcetacoplan at a suboptimal dose of 180 mg/day for 28 days; subjects in cohort 2 received pegcetacoplan 270 mg/day for up to 1 year. Subjects could participate in both cohorts. PALOMINO was a phase 2a, open-label, single-cohort study (NCT03593200) in which subjects received pegcetacoplan 270 mg/day for up to 1 year. Both studies enrolled subjects ≥18 years old diagnosed with PNH and no prior treatment with eculizumab. Primary efficacy endpoints in both studies were change from baseline in lactate dehydrogenase (LDH), haptoglobin, and hemoglobin. Secondary efficacy endpoints included change from baseline in reticulocyte count, total bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The number of packed red blood cell transfusions was also recorded. Primary safety endpoints were the incidence and severity of treatment emergent adverse events (TEAEs). RESULTS Three subjects were enrolled in PADDOCK cohort 1 and 20 in cohort 2; 1 subject was enrolled in both cohorts. PALOMINO enrolled 4 subjects. PADDOCK cohort 2 and PALOMINO efficacy data are shown in the Table. At baseline, mean LDH levels were >8× upper limit of normal in both studies. At day 365, mean LDH had decreased to CONCLUSIONS In PADDOCK and PALOMINO, pegcetacoplan improved hematological parameters by controlling both IVH and EVH in patients with PNH. Improvements in clinical parameters were also observed. Pegcetacoplan was shown to have an acceptable safety profile and was generally well tolerated in both studies. PADDOCK and PALOMINO demonstrate the therapeutic potential of pegcetacoplan in the treatment of PNH and support further evaluation in the ongoing phase 3 PRINCE trial (NCT04085601) in complement inhibitor-naïve patients. Disclosures Wong: Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sathar:Novo Nordisk: Honoraria; Bayer: Honoraria; Roche: Honoraria. Tse:MSD: Research Funding; Janssen: Research Funding. Roman:Alexion: Speakers Bureau; Novartis: Speakers Bureau. Amine:Acibadem City Clinic Tokuda Hospital: Current Employment. Tan:Apellis: Consultancy, Patents & Royalties. Di Casoli:Apellis: Current Employment, Current equity holder in private company. Deschatelets:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Francois:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Grossi:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Bogdanovic:Takeda (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Investigator fee in clinical trial; Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor approved in the US and EU either as single-agent therapy or in combination with rituximab for treatment of patients with Waldenström's macroglobulinemia (WM) across all lines of therapy. The open-label substudy of the phase 3 iNNOVATE trial (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was highly efficacious (90% overall response rate [ORR] per investigator) with improved responses over time in heavily pretreated, rituximab-refractory patients with WM (Buske Blood 2018). Here, we present results from the final analysis of the iNNOVATE open-label substudy. Methods : Patients with WM who failed to achieve at least a minor response (MR) or who relapsed Results : Thirty-one patients with rituximab-refractory disease were enrolled; median age was 67 years (range 47-90), and median number of prior therapies was 4 (range 1-7). Median baseline Hgb was 103 g/L (range 64-146). Median baseline IgM was 39 g/L (range 9-107). Median follow-up was 58 months (range 9-61). Median PFS was 39 months (95% CI 25-NE); the PFS rate at 60 months was 40%. Median PFS was not reached (95% CI 27-NE) in patients with the MYD88L265P/CXCR4WT genotype and was 18 months (95% CI 3-28) in patients with the MYD88L265P/CXCR4WHIM genotype. ORR was 87%, with similar ORR observed across genetic subtypes (MYD88L265P/CXCR4WT, 88% [15/17]; MYD88L265P/CXCR4WHIM, 86% [6/7]); major response rates (≥PR) among these genotypes were 88% (15/17) and 71% (5/7), respectively (Figure 1A). Median OS was not reached in the full cohort of patients, regardless of number of prior therapies (1-2 vs ≥3). Improvements in IgM and Hgb were generally rapid and sustained (Figure 1B). Twenty-two patients (71%) had sustained improvement in Hgb, including 17/21 (81%) with baseline Hgb ≤110 g/L. Median change in IgM from baseline to nadir (month 54) was -37 g/L (range -75 to -5). Median duration of ibrutinib treatment was 41 months. The most common reason for discontinuing ibrutinib while on study was progressive disease (42%). At time of study closure, 14 patients (45%) remained on treatment; of these, 6 went on to receive ibrutinib in the commercial setting and 8 enrolled in a treatment extension study. Overall, 97% of patients experienced a treatment-emergent adverse event (TEAE), most commonly diarrhea (48%; grade ≥2, 13%) and pyrexia (35%; grade ≥2, 6%). Grade 3/4 TEAEs occurred in 81% of patients; the most common were neutropenia (16%), hypertension (10%), and anemia (10%). No deaths occurred due to AEs, and no patients died while on treatment. Ibrutinib dose was reduced in 5 patients (16%) due to an AE, and 2 patients (6%) discontinued treatment because of an AE. No patients experienced major hemorrhage or atrial fibrillation. Conclusions : In this final analysis of the open-label substudy of the iNNOVATE trial, single-agent ibrutinib continued to show sustained efficacy in patients who had heavily pretreated, rituximab-refractory WM. Responses to ibrutinib were consistent across genotypes, although subgroup numbers were small. Ibrutinib maintained a manageable safety profile, and no new safety signals were identified with over 5 years of overall follow-up. Disclosures Trotman: Celgene: Research Funding; PCYC: Research Funding; Takeda: Research Funding; BeiGene: Research Funding; F. Hoffmann-La Roche: Research Funding. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Matous:Celgene: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. MacDonald:Roche Canada: Consultancy, Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria. Tam:BeiGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Tournilhac:INNATE Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant. Ma:Genentech: Consultancy, Honoraria; Novartis: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Bioverativ: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Juno: Research Funding. Treon:Janssen: Consultancy, Other: Travel/accommodations/expenses; BeiGene: Consultancy; Bristol-Myers Squibb: Research Funding; BioGene: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel/accommodations/expenses, Research Funding. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ping:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Briso:Pharmacyclics GmbH, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Arango-Hisijara:Pharmacyclics LLC, an AbbVie Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Dimopoulos:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy.

Background:Joint damage is the most frequent and most debilitating comorbidity of haemophilia and can be prevented by adequate prophylactic treatment. Nevertheless, many causes and not only plasma levels of the factor affect joint damage in severe haemophilia (SH) patients. One to be considered is variability on fibrin polymerization capacity since it might influence the bleeding tendency and, consequently, would affect the joint condition in SH patients. To our knowledge, there are not enough studies about that. Aim:This work aimed to evaluate if there exists a relationship between fibrin capacity of polymerization and joint condition in SH patients. Methods:This is a prospective and transversal study that was approved by Ethics Committee from Hospital Universitario La Paz. Twenty eight SH patients (25 with SHA, 5 of them with inhibitors; 3 with SHB, 2 of them with inhibitor), median age [p25-p75]=41 [29.8-51.3] years old) were recruited. Joint condition was evaluated using the HEAD-US score. Plasma level of fibrinogen (Fib) was determined by Clauss method. Rotational thromboelastometry (ROTEM) was performed with fibTEM, an extrinsically activated test with tissue factor and the platelet inhibitor cytochalasin D. fibTEM results correlate well in many cases with the Clauss Fib assay, but is additionally influenced by fibrin polymerization ability which cannot reliably be detected with clotting tests. Fibrinogen capacity to increase the clot strength was evaluated by the ratio R= Fib/fibTEM maximum clot firmness (MCFfibTEM) which means the plasma concentration of Fib needed to increase maximum clot firmness in 1 mm. Data were analysed with GraphPrism Pad 6.0. Results:Median value of Fib was 306 [263-341] mg/dl, MCFfibTEM = 12 [10-15] mm and R= 25.0 [20.5-29.5] mg/dl/mm. Patients were classified taking into account the value of the 25th percentile of each variable (Fib, MCFfibTEM and R). Subjects with Fib ≤ 263 mg/dl were considered patients with low fibrinogen level, those with MCFfibTEM ≤ 10 mm were considered patients with low platelet independent maximum clot strength and subjects with a R < 20.5 mg/dl/mm were considered good responders to fibrinogen. Based on this analysis, neither Fib nor MCFfibTEM influenced the joint condition. However, patients with poor response to fibrinogen (R ≥ 20.6 mg/dl/mm) had a significantly greater joint damage than the good responders to fibrinogen (R < 20.6 mg/dl/mm) (Table 1). Poor responders to fibrinogen had frequently joint damage in ankles followed by elbows and knees being cartilage the most commonly affected joint compartment. Good responders to fibrinogen only presented milder joint alterations in elbows and ankles. Conclusions: Our results suggested that polymerization capacity of fibrin may be variable between patients with SH and might influence joint condition. More patients need to be recruited to confirm this finding. This work was supported by grants from FIS-FONDOS FEDER (PI19/00631 and PI19/00772). EMM holds a predoctoral fellowship from Fundación Española de Trombosis y Hemostasia (FETH-SETH). Disclosures Fernandez-Bello: Pfizer:Speakers Bureau;Novartis:Speakers Bureau;Stago:Speakers Bureau;Roche:Speakers Bureau;NovoNordisk:Current Employment, Research Funding, Speakers Bureau;Takeda:Research Funding, Speakers Bureau;SOBI,:Research Funding.de la Corte:Pfizer:Research Funding, Speakers Bureau;NovoNordisk:Research Funding, Speakers Bureau;Takeda:Speakers Bureau;Roche:Research Funding, Speakers Bureau;Sobi:Research Funding, Speakers Bureau;Bayer:Speakers Bureau.Alvarez Román:Novartis:Speakers Bureau;Bayer:Consultancy;Grifols:Research Funding;Pfizer,:Research Funding, Speakers Bureau;Roche:Speakers Bureau;NovoNordisk,:Research Funding, Speakers Bureau;Takeda:Research Funding, Speakers Bureau;SOBI,:Consultancy, Research Funding, Speakers Bureau.Martín:SOBI:Research Funding;NovoNordisk:Speakers Bureau;Novartis:Speakers Bureau;Roche:Speakers Bureau;Pfizer:Research Funding, Speakers Bureau.Rivas Pollmar:Pfizer:Speakers Bureau;Roche:Speakers Bureau;Novartis:Speakers Bureau.García Barcenilla:Novartis:Speakers Bureau;Bayer:Speakers Bureau;Roche:Speakers Bureau;Pfizer,:Speakers Bureau;Takeda:Research Funding, Speakers Bureau;NovoNordisk:Research Funding, Speakers Bureau.Canales:Janssen:Honoraria;Sandoz:Speakers Bureau;Takeda:Speakers Bureau;Karyopharm:Honoraria;Novartis:Honoraria;Celgene:Honoraria;Roche:Honoraria;Gilead:Honoraria;Sandoz:Honoraria;iQone:Honoraria;Janssen:Speakers Bureau;Janssen:Honoraria;Roche:Speakers Bureau;Karyopharm:Honoraria;Sandoz:Speakers Bureau;Novartis:Honoraria;Takeda:Speakers Bureau;Roche:Honoraria;Sandoz:Honoraria;Janssen:Speakers Bureau;Roche:Speakers Bureau.Butta:Takeda:Research Funding, Speakers Bureau;SOBI:Speakers Bureau;Pfizer:Speakers Bureau;ROCHE:Research Funding, Speakers Bureau;Novartis:Speakers Bureau;Grifols:Research Funding;NovoNordisk:Speakers Bureau.Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer:Consultancy;Grifols, Novo Nordisk, Takeda, Sobi, Pfizer:Research Funding;F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer:Honoraria.

Introduction Acute Myeloid Leukemia (AML) is a devastating disease with poor overall survival. Access to Precision Medicines is revolutionizing AML care and is driving an increase in Next Generation Sequencing (NGS) utilization to determine the genomic profile of patients with AML. Collaborative efforts to identify and promote emerging and established actionable biomarkers benefits all stakeholders in the patient diagnostic pathway and, ultimately, leads to more patients getting the right test for the right treatment. TP53 plays a central role in key cellular processes such as oncogenesis, cellular proliferation, and DNA repair.1 TP53 is commonly mutated in most cancers. However, a vast majority of AML patients harbor intact, wild-type TP53 in which TP53 pathway dysregulation is promoted by mechanisms such as FLT3 mutations and chromosomal translocations. TP53 mutations lead to clonal propagation and promotes leukemogenesis, and are associated with altered drug sensitivity, chemoresistance, and high risk of relapse.Thus, mutated TP53 is a powerful independent prognostic indicator of poor outcome in AML. TP53 mutations are common in AML cases characterized by increased genomic instability, relapse, and the elderly. Therefore, treating AML patients by directly targeting TP53 mutant AMLs, or leveraging wild-type TP53 AMLs with therapeutic strategies in combination with standard AML chemotherapy or other targeted therapies requires that all AML patients have their TP53 status tested.1 Methods We assessed the testing landscape for determining TP53 status in AML cancer using a data set of 7758 newly diagnosed and relapsed/refractory (R/R) AML patients in the US from Q1-2017 through Q2-2019 identified from Diaceutics' proprietary Global Diagnostic Index (GDI). An analysis of real-world TP53 and Next Generation Sequencing (NGS)-associated testing data and a laboratory profile mapping exercise of 806 US labs was carried out using Diaceutics' proprietary methods and data sources to evaluate TP53 testing rates, test availability, and testing methodology. AML biomarker testing rates were determined from 1176 patients and results available for 437 of them were used to obtain positivity rates. Results Overall, 95 labs performed in-house AML molecular biomarker testing. Of these, 50 performed TP53 testing, 65 performed IDH testing, and 84 performed FLT3 testing. Testing rates on bone marrow aspirates for TP53, IDH1/2, and FLT3 were 59%, 63% and 68%, respectively, with corresponding positivity rates of 15%, 9% (IDH1), 13% (IDH2), 17%, respectively. Simultaneous testing with cytogenetic markers occurred 77% of the time vs 23% of the time following the results from cytogenetic testing. A total of 43 labs included TP53 as part of comprehensive NGS panels, with 3 labs exclusively using Sanger Sequencing and 4 labs testing TP53 via single gene (Sanger and/or NGS) and comprehensive NGS panels. Co-mutation rates between mutated TP53 and FLT3 or IDH1 were 1.3% and 4.2%, respectively. Co-mutation rates between unmutated TP53 and FLT3 or IDH1 were 17.5% and 9.3%, respectively. Conclusion TP53 status is evolving from simply a poor prognostic indicator to an attractive actionable biomarker in newly diagnosed and R/R AML patients. Thus, TP53 status should always be properly tested in parallel with other actionable AML biomarkers. Stakeholder awareness should be increased and recommendations for TP53 clinical utility, preferred testing methods, gene regions to test, and results reporting should be updated, to advance standardization and harmonization that ultimately improves treatment outcomes for AML patients. Reference Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: Challenges and opportunities. Genes Chromosomes Cancer. 2019;58:875-888. https://doi.org/10.1002/gcc.2279 Disclosures Riccelli: Diaceutics: Current Employment, Current equity holder in publicly-traded company. Hoefsmit:Diaceutics: Current Employment, Current equity holder in publicly-traded company. Moore:Diaceutics: Current Employment. Idica:Diaceutics: Current Employment, Current equity holder in publicly-traded company. Sornkom:Diaceutics: Current Employment. Slifko:Diaceutics: Current Employment, Current equity holder in publicly-traded company. Delic:Diaceutics: Current Employment, Current equity holder in publicly-traded company. Entwistle:Diaceutics: Current Employment, Current equity holder in publicly-traded company. Munksted:Diaceutics: Current Employment, Current equity holder in publicly-traded company. Clark:Diaceutics: Current Employment, Current equity holder in publicly-traded company.

Background: Genomically instable (GI) chronic lymphocytic leukemia (CLL) is characterized by frequent alterations in DNA-damage response (DDR) genes (e.g. TP53, ATM) and related pathways. Conversely, pathogenic networks in CLL cases which maintain genomic integrity and operate with a functional DDR remain incompletely described. Methods: Molecular profiling was conducted on CD19 sorted samples derived from patients registered on the CLL8 study (1st-line, FC vs. FCR) for gene expression (GEP)(n=337, Exon 1.0 ST arrays, Affymetrix), copy number aberrations (CNAs) (n=309, SNP Arrays 6.0, Affymetrix) and mutation analyses/signature projections (n=171, whole exome sequencing, Illumina). FISH, IGHV and TP53 mutation analysis was conducted at trial enrolment. Results: Unsupervised consensus clustering (k=2-6) on variably expressed genes (SD>0.5) was used for class discovery. Two small, but highly differentiated clusters were identified, characterized through NRIP1 and EBF1/tri12. GSEA also segregated the remaining samples into four major clusters showing signatures of inflammation (I) and without inflammation (NI). These clusters were further segregated into GI-CLL clusters with increased “DNA-repair” or clusters with “epithelial-mesenchymal transition”-like signatures (EMT-L). Variability for del(17p)/TP53 mutation was found across clusters (p

Background Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the loss of endogenous complement regulators CD59 and CD55 on hematopoietic cells. Peripheral blood elements are susceptible to destruction by complement, resulting in intravascular hemolysis and thrombosis. Standard therapy is terminal complement inhibition with eculizumab, an anti-C5 monoclonal antibody. However, up to 3.5% of individuals of Asian descent carry polymorphisms in C5 that affect Arg885, which corresponds to the eculizumab and ravulizumab binding site (Nishimura et al. N Engl J Med. 2014). Patients with PNH who have these polymorphisms experience poor control of intravascular hemolysis with eculizumab, thus constituting a group with a high unmet medical need. Crovalimab is a novel anti-C5 monoclonal antibody that binds a distinct epitope on the beta subunit of C5. In vitro studies have demonstrated that crovalimab equally binds and inhibits the activity of wild-type and Arg885-mutant C5 (Fukuzawa et al. Sci Rep. 2017). Objectives The aim of the current report is to describe the response to crovalimab of PNH in patients with C5 polymorphism. Study Design and Methods Crovalimab is being evaluated in the ongoing Phase I/II COMPOSER study (NCT03157635) to establish its optimal dose, safety, and efficacy (Röth A, et al. Blood 2020). C5 inhibitor-naive or -experienced patients received an initial intravenous loading dose followed by an average subcutaneous maintenance dose of 680 mg every 4 weeks. Plasma concentration of crovalimab, lactate dehydrogenase (LDH), free and total C5, and complement activity were determined at every visit. Patients were followed up for occurrence of blood transfusions, breakthrough hemolytic events, and safety. Results Of the 59 patients enrolled in COMPOSER, 4 had the c.2654G->A nucleotide polymorphism predicting Arg885His substitution. The data cutoff was January 29, 2020. Follow-up ranged from 12.4 to 98.3 weeks. All 4 patients were male and had been diagnosed 44 to 734 weeks before enrollment with PNH granulocyte clone size ranging from 89% to 95%. At enrollment, 1 patient switched from ongoing therapy with eculizumab, while 3 had previously discontinued eculizumab. At enrollment, all patients had LDH > 3-fold the upper limit of normal (ULN), which declined rapidly and was maintained at < 1.5 × ULN throughout the follow-up period (Figure). One patient required transfusions after enrollment (12 red blood cell units over 6 months); this patient had an underlying diagnosis of aplastic anemia and required 198 units of red blood cells in the 12 months prior to enrollment. None of the 4 patients experienced a breakthrough hemolysis event. All 4 patients achieved complete terminal complement inhibition as measured by liposome immunoassay (LIA). LIA levels ranged from 32 to 42 U/mL at study entry, declined to < 10 U/mL (lower level of quantification) by day 2, and were maintained thereafter. Similarly, free C5 levels were maintained at < 0.5 µg/mL after week 6 (day 43). The safety profile in these patients was similar to that in the remainder of the participants. Three serious adverse events (SAEs) were reported, none of which were related to study treatment. One patient had 2 SAEs: bile duct stone and cholelithiasis. A second patient had an SAE of upper respiratory tract infection with admission to the hospital, which occurred after 20 months and resolved during treatment. Conclusions Crovalimab achieved complete and sustained terminal complement inhibition in patients with Arg885 polymorphism, consistent with previously reported outcomes for patients in the COMPOSER study. Crovalimab is a promising treatment for these individuals with high unmet medical need. Disclosures Nishimura: Chugai: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Alexion: Honoraria, Research Funding. Usuki:Alexion: Consultancy, Research Funding, Speakers Bureau; Chugai: Research Funding; Aperis: Research Funding; F. Hoffmann-La Roche. Ltd.: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. , Research Funding. Ramos:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Genentech, Inc: Current Employment, Other: Received fellowship support from Genentech, Inc.. Ichikawa:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. , Research Funding. Hernández-Sánchez:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Kiialainen:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Peffault De Latour:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paz-Priel:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.; Genentech, Inc: Current Employment. Röth:Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Yes, Crovalimab is an anti-C5 monoclonal antibody being evaluated as a therapy for paroxysmal nocturnal hemoglobinuria

Background: Hydroxyurea (HU) is an effective and common therapy for high-risk Polycythemia Vera (PV). Some patients may demonstrate resistance or intolerance to HU, but the consequences of these warrant further studies. Objective: Evaluate the clinical and economic implications of HU resistance/intolerance, in routine clinical practice in Israel. Methods: A retrospective analysis of Maccabi Health Services' (MHS) database was performed. MHS is a Non-for-Profit healthcare insurer and provider in Israel, with over 2.2 million members. Patients were included in the study if they had a recorded PV diagnosis or complete blood count indicative of PV, and had purchased HU for at least 3 months between 2000-2015. Enrolled patients were divided into 3 groups: A) Resistant to HU (patients prescribed 2g/day of HU); B) Intolerant of HU (patients who stopped HU, transitioned to another line of therapy or who developed HU related cytopenias); C) Stable on HU. A mid-time point was added to "Stable" to compensate for the time required for transition in the "Intolerant" group. Only patients who developed Intolerance within 5 years were included. Collected data pertained to demographics, clinical outcomes, resource utilization and expenditure data. Results: A total of 830 patients were identified. Only 3 met criteria for Resistance and were disregarded for further analysis, while 318 (38%) were defined as "Intolerant" and 509 (61%) as "Stable". At baseline, there were no significant differences between "Intolerant" and "Stable" groups, apart from platelet counts (431 vs. 495, respectively) and red cell distribution width (RDW) (18.4 vs. 17.6, respectively). Intolerance was determined based on HU-related cytopenias (n=144, 45% of Intolerant), transition to other treatment line (n=52, 16%) or stopping HU (n=122, 38%). These results indicate some patients continue HU treatment despite lack of disease control. "Intolerant" patients who had transitioned by 5 years from first HU purchase (N=173) and "Stable" patients who met the mid-point of time to transition (N=487) were eligible for comparison. Median follow up time was 4.9 and 5.5 years for "Intolerant" and "Stable" groups, respectively. Thrombotic events occurred in 8% of the "Intolerant" group compared with 3% of "Stable" (p=0.003) and event rate per 100 patient-years was 1.6 versus 0.5 (p During study follow up, hospitalization occurred in 84% versus 69% (p Treatment costs for an Intolerant patient in the first year after intolerance were 2.6-fold higher than those for a Stable patient, driven mainly by hospitalization costs being 3.6-fold higher (data available from 2010). Conclusions: The results of this analysis indicate that intolerance to HU treatment in PV patients is associated with serious clinical and economic implications, indicating a need for improved treatment for these patients. Disclosures Ellis: Novartis Pharma AG: Consultancy, Honoraria, Other: Institutional research grant; BMS: Consultancy, Other: Institutional research grant; Gilead: Other: Institutional research grant. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Chodick:Novartis Pharma AG: Other: Institutional grant. Yekutiel:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Other: Institutional grant. Sharf:Novartis Pharma AG: Consultancy, Other: Institutional Grant; Leukaemia Patient Advocates Foundation: Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; Israeli CML Patient Organisation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Other: Institutional grant; AbbVie: Consultancy, Other: Institutional Grant; Amgen: Consultancy, Other: Institutional grant; Bristol Mayers Squibb: Consultancy, Other: Institutional Grant; Celgene: Consultancy, Other: Institutional Grant; AOP Orphan: Other: Institutional grant; CTI: Other: Institutional grant; Medison: Other; Roche: Other; Jansseb: Other; Pfizer: Consultancy, Other; Takeda: Other; Gilead: Other. Feine:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Leef:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Ben Zvi:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Shavit:6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment.

Introduction Extensive genomic characterization of multiple myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, less is known about the myeloma epigenome. One challenge that has hindered epigenetic studies are assays amenable to biobanked specimens. Here, we sought to determine whether ATAC-seq and RNA-seq of myeloma cells from cryopreserved bone marrow aspirates recapitulated those from fresh samples and used this approach to investigate enhancers of myeloma oncogenes. Methods Consent and collection of specimens followed approved Institutional Review Board protocols. Mononuclear cells were enrichment by Ficoll gradient centrifugation and were either cryopreserved in 10% DMSO and RPMI media with 10% FBS or used to isolate viable CD138+CD38+ myeloma cells. RNA-seq used the mRNA HyperPrep kit (Kapa Biosystems) with RNA from 50,000 cells. ATAC-seq used the Tn5 transposase (Illumina) on 20,000 cells. Sequencing was performed on an HiSeq 4000 (Illumina). Sequencing data were quality and adapter trimmed using Trim Galore! And mapped to the GRCh37 genome using STAR (RNA-seq) or bowtie2 (ATAC-seq). MACS2 was used to determine chromatin accessible regions and R was used for downstream analyses. H3K27ac ChIP-seq from Jin et al. (Blood, 2018) were downloaded from the European nucleotide archive (PRJEB25605). RNA-seq from CoMMpass (NCT01454297) were downloaded from dbGaP phs000748.v7.p4. Enhancer RNAs were interrogated in intergenic regions excluding 500 bp upstream of TSSs and 5 kb downstream of transcription termination sites to avoid contamination from exonic mRNAs or intronic pre-mRNAs. Results We compared RNA-seq and ATAC-seq data from myeloma cells isolated from fresh bone marrow aspirates to those cryopreserved for up to 6 months from the same aspirate. RNA-seq and ATAC-seq data from fresh and frozen samples from the same aspirate were highly correlated with each other but distinct from other samples as depicted by principal component analysis (Fig. A,B). Inspection of CCND1 showed high levels of RNA in two patients and this was consistent in both fresh and frozen specimens as well as with FISH results indicating a t(11;14) translocation in these samples (Fig. C). Similarly, fresh and frozen specimens from the same patient showed consistent expression for CCND2 and MYC and these data corresponded with chromatin accessibility found near these genes (Fig. D, see regions shaded in gray). Based on these results we expanded our analysis to include 8 biobanked specimens, which identified 91,632 regions of chromatin accessibility that were enriched around plasma cell lineage genes such as IRF4, CD38, SLAMF7, and IGH. Chromatin accessibility often predicted proximal gene expression and this was especially pronounced for regions enriched for histone 3 lysine 27 acetylation (H3K27ac) - a mark of enhancers. Active enhancers are sometimes demarcated by enhancer RNAs (eRNAs) observable in RNA-seq data, thus we queried intergenic regions marked by chromatin accessibility and H3K27ac for eRNAs using RNA-seq data on 768 myeloma specimens from the CoMMpass study. This identified transcription at 4,729 of 13,452 potential regions. eRNA expression was highly correlated with proximal gene expression. To illustrate this point, we performed t-SNE clustering based on mRNA and eRNA expression and color-coded each sample by myeloma gene expression subtype (Fig. E). Interestingly, this identified several regions highly correlated with oncogene expression between myeloma subtypes. For example, an enhancer ~154 kb upstream of CCND2 was uniquely transcribed in the MAF subtype (Fig. F) and this was highly correlated with CCND2 expression (Fig. G). Conclusions Cryopreservation of myeloma bone marrow aspirates allows isolation and analysis of biobanked samples that produce RNA-seq and ATAC-seq data that are highly congruent with those obtained from fresh samples and this represents a strategy for retrospective genomic and epigenomic studies. Chromatin accessibility analysis identified distinct enhancer elements regulating oncogenes in myeloma subtypes providing mechanistic insight into myeloma pathology. Figure 1 Disclosures Lin: Amgen: Current Employment, Current equity holder in publicly-traded company. Hofmeister:Bristol Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Nektar: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Oncopeptides: Honoraria; Oncolytics Biotech: Research Funding; Imbrium: Honoraria; Karyopharm: Honoraria, Research Funding. Nooka:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria. Lonial:GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Sanofi: Consultancy; Abbvie: Consultancy. Boise:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees.

Introduction: Among patients with MDS, it is estimated that 17-82% (median 60%) are transfusion dependent (Harnan S, et al. Acta Haematol 2016;136:23-42) and require ≥ 1 unit of red blood cells (RBCs) every 8 weeks. Sufficient blood supply is essential for the administration of RBC transfusions in patients with MDS, as shortage of blood supply may create unnecessary burden, such as treatment delay, worsened quality of life, or increased healthcare utilization. To our knowledge, no studies have examined the physicians' experience associated with shortage of blood supply and RBC transfusion delays in this patient population. Physicians' perspectives on the factors that impact clinical, economic, and humanistic outcomes of patients with MDS are also not well understood. The current study investigated physicians' understanding of these topics. Methods: Prior to data collection, interviews were conducted with physicians (3 each in France, Germany, Italy, Spain, and the UK) to pre-test and revise the questionnaire, a 40-minute web-based physician survey via the M3 Global Research physician panel, for relevance and understanding. All physicians took the survey in their native language and had to have been in practice for 2-35 years, spend ≥ 75% of their time in direct patient care, and have managed ≥ 15 patients with MDS in the past 3 months. Physicians answered questions regarding adequacy of blood supply related specifically to RBC transfusions for patients with MDS. Physicians identified the top 10 factors (from a list of 32) impacting the clinical, economic, and humanistic outcomes of patients with MDS. These factors were then weighted accordingly (assigned point values summing up to 100). Results were described descriptively in proportions for categorical/ordinal data and mean (standard error [SE])/95% confidence intervals [CI]) for continuous data. Results: A total of 244 hematologist/oncologists, 124 hematologists, and 10 oncologists completed the survey in France, Germany, Italy, Spain, and the UK (n = 75 [approx.] in each country; Table). On average, physicians were in clinical practice for 14.70 years (SE 0.32), 41.3% were aged 45-54 years, and 64.3% were male. Physicians spent 88.7% (SE 0.36%) of their professional time in patient care, and had seen an average of 54.5 (SE 2.26) patients with MDS in the past 3 months. Over 65% of physicians (range 54.7 [France]-73.7% [UK]) reported that their patients with MDS encountered RBC transfusion delays due to blood supply shortage (Table). On average this impacted 9.0% (95% CI 7.6-10.4) of all patients with MDS. However, among physicians who reported delays (n = 248), 13.8% (95% CI 11.9-15.7) of patients were impacted, ranging from 11.0% (Spain) to 19.4% (Italy). Physicians (17.2%; range 9.3 [Spain]-31.6% [Italy]) reported ≥ 25% of their patients with MDS requiring transfusions experienced transfusion delay due to blood supply shortage. On average, patients experienced a 4.2-day (95% CI 3.6-4.8) delay in receiving a transfusion due to blood supply shortage, and 16.7% (95% CI 14.3-19.1) of patients required additional healthcare provider visits due to blood supply shortages. The top 10 factors reported that impact clinical, economic, and humanistic outcomes of patients with MDS included: Eastern Cooperative Oncology Group performance status (ECOG PS) (74.6%); age (66.7%); hemoglobin level (66.7%); infections (61.1%); percentage bone marrow blasts at diagnosis (60.1%); comorbidities (59.5%); platelets (56.3%); cardiovascular comorbidity (52.9%); genetic abnormalities (50.3%); and white blood cell count (48.4%). Factors that had the greatest mean impact scores were ECOG PS (8.9, 95% CI 8.1-9.8); percentage bone marrow blasts at diagnosis (8.3, 95% CI 7.3-9.2); age (7.2, 95% CI 6.5-8.0); hemoglobin level (6.8, 95% CI 6.1-7.4); and comorbidities (6.6, 95% CI 5.9-7.3). Conclusions: Two thirds of physicians reported that shortage of blood supply resulted in a delay in RBC transfusions for patients with MDS. Almost 20% reported ≥ 25% of their patients with MDS requiring transfusions experienced a transfusion delay due to blood supply issues. ECOG PS, hemoglobin level, and age were the top factors reported to impact outcomes of patients with MDS. New treatment options should be explored to help reduce the number of RBC transfusions, which may also help improve clinical, economic, and humanistic outcomes of patients with MDS. Disclosures Gupta: Bristol Myers Squibb: Consultancy, Research Funding; Kantar: Current Employment. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Constantino:Kantar: Current Employment. Grisolano:Kantar: Current Employment; Bristol Myers Squibb: Consultancy. Tang:Bristol Myers Squibb: Current Employment; Asclepius Analytics: Current Employment. Jones:Bristol Myers Squibb: Current Employment. Tang:BMS: Current Employment, Current equity holder in publicly-traded company.

Introduction: Peripheral T-cell lymphomas (PTCL) are a rare subset of non-Hodgkin lymphomas with an overall response rate to CHOP-based therapy of 80% but 5-year survival ranges between 20-40%. (Ellin et al Blood 2014) While response by PET/CT is prognostic (Mehta-Shah Blood Advances 2019), the high rate of relapse after complete response suggests that more sensitive determinants of minimal residual disease may have prognostic and even therapeutic importance. T-cell receptor gene rearrangement (TCR) by next generation sequencing is able to detect a known TCR clonotype at 10-5. (Shah et al AMP 2017) Therefore, in a prospective multi-institutional study, we sought to evaluate the utility of peripheral blood TCR by next generation sequencing in quantifying minimal residual disease in peripheral T-cell lymphoma. (NCT03297697) Here we report the results of TCR evaluation at the end of CHOP-based therapy. Methods: Patients with previously untreated PTCL (PTCL-NOS: peripheral T-cell lymphoma, NOS; angioimmunoblastic T-cell lymphoma: AITL; anaplastic large cell lymphoma: ALCL;, monomorphic epitheliotropic intestinal T-cell lymphoma: MEITL) treated with anthracycline based therapy for curative intent were eligible for the study. TCR (TCR gamma, TRG, or TCR beta, TRB) clonotype was established from baseline diagnostic tumor tissue. Peripheral blood (10cc) was collected in Streck tubes for TCR clonotype at each cycle of therapy, after completion of CHOP-based therapy, every 6 months for two years, at progression and in the stem cell product (if collected). TCR clonality was assessed and tracked using the LymphoTrack® TRG/TRB Assays-MiSeq® (Invivoscribe, San Diego, CA). Results: 39 patients were enrolled in the study (16 PTCL-NOS, 10 AITL, 7 ALK- ALCL, 5 ALK+ ALCL, 1 MEITL). One patient was enrolled with PTCL-NOS but was withdrawn after confirming a diagnosis of T-ALL. One patient with ALK- ALCL withdrew consent prior to sample collection. 19 patients have completed frontline therapy and have end of treatment TCR analysis available. The remaining 18 patients either have not yet completed treatment or did not have samples analyzed at the time of submission. Patients received CHOEP (n=10), BV-CHP (n=4), CHOP (n=32), CEOP (n=1) and CHOP+azacitidine (n=1). Median age was 61 (range: 22-80). Sixteen completed 6 cycles of therapy and of these, 7 underwent consolidation with an autologous transplant. One stopped due to intolerance after 5 cycles and remains in complete remission. 2 had progression of disease prior to completion of 6 cycles of therapy. At end of treatment evaluation by PET/CT, 13/19 (68%) had complete remission, 1/19 (5%) had partial remission and 5/19 (26%) had progressive disease. Of the 19 patients, 15 (78.9%), including 1 with leukemic disease, had TCR clonotype identifiable in the baseline diagnostic tissue, and 4 (21.1%) did not have a TCR clonotype identified (3 PTCL NOS, 1 ALK+ ALCL) in tumor tissues at baseline. Two of 15 patients had undetectable TCR clonotype in the blood at end of treatment and neither of them has relapsed. Thirteen of the 15 patients had detectable TCR clonotype at end of treatment. Of the 10 patients in complete remission by PET/CT at the end of treatment with known clonotype, 8 had a detectable TCR clonotype and 2 had undetectable TCR at the end of CHOP-based therapy. Five of 6 patients with PD or PR at end of treatment had detectable TCR clonotype in the blood and 1 lacked clonotype in baseline samples. At a median follow up of 13.1 months, only one patient has relapsed and this patient had positive peripheral blood TCR at end of treatment despite PET CR. We will present the end of treatment evaluation for all patients on the study at the time of the meeting. Conclusions: Measurement of peripheral blood TCR at the end of treatment is feasible in PTCL using next generation sequencing with a known tumor clonotype. Lack of radiographic CR was highly correlated with detectable TCR, but detectable TCR was also frequently seen in complete remission by PET/CT. Longer follow up, including analysis of TCR following autologous transplant, is required to determine if TCR clonotype at the end of CHOP-based therapy predicts likelihood of relapse and to evaluate the dynamics of TCR clonotype during and after completion of treatment. This study was supported by the Lymphoma Research Foundation and T-cell Leukemia/Lymphoma Society. Disclosures Mehta-Shah: Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding; Innate Pharmaceuticals: Research Funding; Genetech/Roche: Research Funding. Fehniger:Indapta: Consultancy; Nkarta: Consultancy; Kiadis: Consultancy; HCW Biologics: Research Funding; Compass Therapeutics: Research Funding; ImmunityBio: Research Funding; Orca Biosystems: Consultancy; Wugen: Consultancy. Jacobsen:Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; Merck: Consultancy; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Kahl:AbbVie: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Laboratories Inc: Consultancy; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; BTG: Consultancy; Janssen: Research Funding; BMS/Celgene: Research Funding; Immune Design: Research Funding; Kite, a Gilead Company: Research Funding; Forty Seven: Research Funding; ADC Therapeutics: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Roche/Genentech: Consultancy, Research Funding; Autolus: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; WuGen: Consultancy; EUSA: Consultancy; Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy. Huang:Invivoscribe: Current Employment. Hutt:Invivoscribe: Current Employment. Vigil:Invivoscribe: Current Employment. Olson:Invivoscribe: Current Employment. Jacobsen:Invivoscribe: Current Employment. Horwitz:GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; Myeloid Therapeutics: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Affirmed: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; C4 Therapeutics: Consultancy.

Background. The majority of PV patients are iron deficient at diagnosis [Ginzburg Leukemia 2018]. PV patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels 70% within 12 hours and the effect persists for 3-7 days. In a phase 2 trial in β-thalassemia, PTG-300 also decreased serum iron and TSAT but did not demonstrate off-target effects. The current study aims to compare the iron status in frequent TP-requiring PV patients before, during, and after treatment with PTG-300. Methods. Polycythemia patients who met 2016 WHO criteria for diagnosis were enrolled in the 28-week dose finding part of a Phase 2 trial. All patients required ≥3 phlebotomies with or without concurrent cytoreductive therapy over 6 months prior to enrollment. Patients were given PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly in individualized adjustment to maintain hematocrit Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 on concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. All subjects-maintained hematocrit Conclusions. The current results indicate that PTG-300 is an effective agent for the controlling hematocrit and reversing iron deficiency. The effect of PTG-300 on PV-related symptoms and those of iron deficiency, are also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Kuykendall:Novartis: Research Funding; Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding. Yacoub:Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Hoffman:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Forbius: Consultancy; Protagonist: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; CTI Biopharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding.