Patients with cold agglutinin disease (CAD) experience fatigue and poor quality of life. However, previous CAD-related studies have not explored patient-reported outcomes such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Sutimlimab, a C1s complement inhibitor, has been shown to halt haemolysis in CAD. Here, we present 26-weeks’ patient-reported data from CARDINAL Part A (ClinicalTrials.gov, NCT03347396), which assessed efficacy and safety of sutimlimab in patients with CAD and recent history of transfusion. Aside from measuring changes in haemolytic markers, FACIT-Fatigue was measured at the treatment assessment timepoint (TAT; average of weeks 23, 25, and 26). Exploratory endpoints included the change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) and the 12-Item Short Form Health Survey (SF-12) at TAT, and Patient Global Impression of Change (PGIC), and Patient Global Impression of (fatigue) Severity (PGIS) at week 26. Mean (range) FACIT-Fatigue scores increased from 32.5 (14.0–47.0) at baseline (a score indicative of severe fatigue) to 44.3 (28.0–51.0) at TAT. Considerable improvements were reported for EQ-5D-5L at TAT, SF-12 scores at TAT, and PGIC and PGIS scores at week 26. Sutimlimab treatment resulted in sustained improvements in symptoms of fatigue and overall quality of life in patients with CAD. NCT03347396. Registered 20 November, 2017.

Background Cold agglutinin disease (CAD) is a rare, chronic form of autoimmune hemolytic anemia. Clinical manifestations can include classical complement pathway-mediated chronic hemolysis, anemia, and profound fatigue. Research has shown that patients with other anemias may develop anxiety and depression, but this has not been studied previously in patients with CAD. Methods CAD patients were identified in the Optum Claims-Clinical dataset (between January 1, 2006-June 30, 2016) and matched to comparison patients without CAD by patient factors. Adjusted Cox regression models estimated time to anxiety and depression, defined by three different outcomes: medication use, hospitalization, and therapy related to anxiety and depression. Subset analyses were performed for primary CAD. Patients were followed until they had anxiety and depression, they left the Optum system, death, or the study period ended (June 30, 2016). Results Patients with CAD (n = 384) were more likely to have medically attended anxiety and depression (adjusted hazard ratio [aHR]: 1.6; 95% confidence interval [CI]: 1.3-2.1), to be prescribed antidepressants or psychotherapy after their CAD diagnosis (aHR: 1.8; 95% CI: 1.2-2.9), or to be hospitalized for an anxiety and depression-related event along with medication or psychotherapy (aHR: 2.0; 95% CI: 1.4-2.9) relative to matched comparisons (n = 2789), during the follow-up period. Patients with primary CAD were at increased risk for medically attended anxiety and depression (aHR: 1.8; 95% CI: 1.4-2.4), with the highest risk for prescription medication or therapy (aHR: 2.7; 95% CI: 1.6-4.6). Conclusions Our study indicates that medically attended anxiety and depression manifest at a higher rate in CAD patients than in a matched non-CAD cohort. Study findings suggest that CAD patients may experience a greater burden on mental health that may negatively contribute to their overall quality of life. Further investigation on this topic is warranted.

Introduction CAD is a rare chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis, resulting in predominant extravascular red blood cell destruction in the liver, anemia, and fatigue. Patients with CAD have an increased risk of thromboembolism and early mortality. There are no approved pharmacologic treatments for CAD. Sutimlimab (formerly BIVV009) is a first-in-class humanized monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing CP activation, while leaving the lectin and alternative pathways intact. The aim of the Cardinal study (NCT03347396) is to assess efficacy and safety of sutimlimab in adults with CAD and a recent history of transfusion. The primary efficacy endpoint for the 26-week treatment period was met (Röth et al. Blood. 2019); interim results of the 1-year long-term follow-up (Week 53 study visit) are presented. Methods Cardinal is a Phase 3, open-label, single-arm, multicenter study with a 26-week treatment period (Part A) and an ongoing extension (Part B) for 2 years after the last patient completes Part A; interim data are available for Part B (minimum 1-year follow-up; data cut: January 16, 2020). Patients with confirmed CAD diagnosis were enrolled. Eligibility criteria included baseline hemoglobin (Hb) ≤10 g/dL and ≥1 blood transfusion in the prior 6 months. Sutimlimab was administered intravenously on Days 0 and 7, followed by biweekly infusions. Patients <75 kg or ≥75 kg received a 6.5 g or 7.5 g dose, respectively. The primary objectives of the interim Part B analysis are to evaluate long-term safety and tolerability of sutimlimab for ≥53 weeks; secondary objectives are to investigate the durability of response over time. Efficacy endpoints included change from baseline in hemolytic markers and the patient-reported outcome: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale. Outcomes were analyzed using descriptive statistics, frequency, or percentage. Results Twenty-four patients enrolled and 22 completed Part A (2 patients withdrew for reasons unrelated to the study drug). All patients who completed Part A entered Part B. The mean (standard deviation [SD]) age was 71.3 (8.2) years and 62.5% were female. In Part A, the mean (range) baseline Hb was 8.6 (4.9-11.1) g/dL. The median (range) number of transfusions <6 months prior to enrollment was 2 (1-19); 62.5% of patients had failed prior therapies. Hb improved rapidly after first sutimlimab dose and mean Hb was >11 g/dL from Week 5 (Part A) to Week 53 (Part B; Figure 1). Mean total bilirubin was normalized by Week 3 and remained <20 µmol/L to Week 53. Normalization of mean (SD) absolute reticulocyte count (baseline: 138 [68] ×109/L; Week 3: 65 [40] ×109/L) was observed alongside normalized haptoglobin levels and reductions in lactate dehydrogenase. Seventeen (70.8%) and 19 (86.4%) patients remained transfusion-free from Week 5 to Week 26 and Week 26 to Week 53, respectively. FACIT-F scores improved within 1 week and remained >40 from Week 3 to Week 51 at last data recording, consistent with a clinically meaningful improvement. Hb, bilirubin, and FACIT-F improvements correlated with the normalization of complement C4 (mean [SD] total C4 at baseline: 0.04 [0.07] g/L; Week 25: 0.29 [0.07] g/L) and near-complete inhibition of CP activity (mean [SD] CP at baseline: 20.0% [16.7]; Week 25: 3.0% [3.1]). From baseline to Week 53, all 24 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (50.0%) patients experienced a serious TEAE. One serious TEAE (viral infection) was associated with sutimlimab. Serious (including bacterial) infections were reported, but no meningococcal infections were identified. There was 1 TEAE of device-related thrombosis (assessed as unrelated to study drug) in Part B; there were no other vascular thromboembolic TEAEs. One patient died due to a progressive carcinoma (unrelated to study drug). Conclusions The 1-year interim follow-up results of the Phase 3 Cardinal study show that sutimlimab, a first-in-class selective CP inhibitor, has a sustained treatment effect in CAD; via long-term complement inhibition, sutimlimab maintains both Hb levels >11 g/dL and improved FACIT-F, with no new safety concerns identified. These positive results support sutimlimab use as an effective and well-tolerated long-term therapy for the management of chronic primary CAD. Disclosures Röth: Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Barcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Miyakawa:Bioverativ and Sanofi: Consultancy. Broome:Alexion: Honoraria; apellis: Honoraria; argenx: Honoraria; sanofi: Honoraria. Michel:Alexion Pharmaceuticals: Consultancy; Bioverativ: Consultancy; Rigel: Consultancy. Kuter:Kezar Life Sciences, Inc: Other, Research Funding; CRICO: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Shionogi: Consultancy; Protalex: Consultancy, Honoraria, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding. Jilma:Bioverativ: Consultancy, Other: reimbursement for travel costs for scientific presentations; True North Therapeutics: Consultancy, Other: reimbursement for travel costs for scientific presentations. Anderson Tvedt:Alexion Pharmaceuticals, Inc, Novartis, and Ablynx: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees. Weitz:Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau. Patel:Sanofi: Current Employment. Jiang:Sanofi: Current Employment. Reuter:Sanofi: Current Employment. Su:Sanofi: Current Employment. Shafer:Sanofi: Current Employment. Lee:Sanofi: Current Employment. Hobbs:Sanofi: Ended employment in the past 24 months. Berentsen:Mundipharma: Research Funding; Apellis Pharmaceuticals: Consultancy, Other: lecture honoraria; Bioverativ: Consultancy, Other: lecture honoraria; Janssen-Cilag: Other: lecture honoraria; Alexion Pharmaceuticals, Inc,: Other: lecture honoraria; Momenta Pharmaceuticals: Consultancy; True North Therapeutics: Other: lecture honoraria.

OBJECTIVES:Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia that may manifest in complement-mediated chronic hemolytic anemia, profound fatigue, and transient agglutination-mediated circulatory symptoms. This study compared the healthcare resource utilization (HRU) of patients with CAD with a matched non-CAD comparison cohort using national Danish health registry data. METHODS:All cases of CAD were identified from 1 January 1999 to 30 June 2016, in the Danish National Patient Registry using the International Classification of Diseases, Tenth Revision, discharge diagnosis codes. A subcohort of patients with primary CAD was identified based on the absence of secondary predisposing concomitant diseases. CAD cases were matched to individuals without CAD from the general population based on birth year, sex, and 19 disease categories of the Charlson Comorbidity Index. Comparative analyses assessed inpatient hospitalizations, outpatient clinic visits, emergency room visits, transfusion use, and expensive drug use between cohorts 6 months before and 12 months after the admission date of the first hospital visit with CAD diagnosis (index date). RESULTS:A total of 104 patients with CAD were matched to 1003 comparison cohort members. Throughout the 12 months after the index date, patients with CAD were more likely to have at least one inpatient hospitalization (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.5-6.0), outpatient clinic visit (OR, 17.2; 95% CI, 6.8-43.1), and blood transfusion (OR, 93.0; 95% CI, 33.3-259.8) than matched comparisons. HRU was similarly higher among patients with CAD than matched comparisons during the 6 months before the index date. Findings were similar among patients with primary CAD. CONCLUSIONS:Characterization of HRU among European patients with CAD has not previously been conducted. This study shows that patients with CAD utilize significant resources in Denmark. Increased HRU uses among patients with CAD before diagnosis presents opportunities for earlier diagnosis and management.

In the May 2020 issue of Value in Health Regional Issues, Gordon Liu and colleagues reviewed the history of the development, current status, and trends in health technology assessment (HTA) in Asia.1 Using China, Japan, and South Korea as 3 case studies, the authors illustrated the complexity of HTA dynamics in the region. Academic research on HTA started much earlier than the actual HTA bodies appeared in various countries in Asia owing to the strong desire to provide adequate access to medical care in the region of the largest population in the world.

Abstract Introduction Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia in which red blood cells are bound by cold agglutinin autoantibodies. In addition to cold-induced symptoms, patients with CAD experience symptoms of chronic anemia and hemolysis including fatigue, weakness, and shortness of breath (Swiecicki PL et al. Blood 2013;122(7):1114-21). The objectives of this study were to identify disease-related symptoms and impacts most important to patients with CAD, and to evaluate whether existing patient-reported outcome (PRO) measures are appropriate to assess relevant CAD concepts. Methods As part of a larger study, qualitative concept elicitation (CE) interviews were conducted to better understand the disease burden of CAD from the patient perspective. The results from the first set of interviews were reported by Su J et al. Blood 2020;136(1):29-30. Based on the identified symptoms and impacts, standard survey methodological principles were used to develop a draft item pool to address concepts of interest. Items were refined and evaluated during the second set of interviews, which included 3 rounds of 60-minute phone interviews with patients with CAD using a semi-structured interview guide that included a CE section and cognitive debriefing. Pooled results from both sets of interviews were used to develop a conceptual model of the symptoms and impacts of CAD. Physician advisors were also invited to review the concepts identified in the interviews and to select those that they believed were most relevant as part of an advisory board. A PubMed review of literature published between 2010-2020 was also conducted to identify existing PRO measures used in the assessment of symptoms, impacts, and/or quality of life and patient experiences in adults with CAD or similar disease areas. Identified PRO measures were assessed to determine the extent to which they captured CAD-specific concepts identified in the CE interviews. Results In total, 37 participants diagnosed with primary or secondary CAD took part in the interviews (Set 1, n=16; Set 2, n=21). Overall, the mean age of participants was 67.2 years (range: 35-87), and the majority were female (73%). The most frequently reported symptom of CAD was reactions to cold environments (n=36; 97%), e.g., cold or numb feet/hands, and skin discoloration. Other reported symptoms included fatigue (n=35; 95%), shortness of breath (n=28; 76%), and trouble with thinking/concentration (n=21; 57%). The most frequently reported unfavorable impact of CAD was on day-to-day activities (n=32; 87%). Other negative impacts included effects on enjoyable activities (n=29; 78%) e.g., gardening, physical health/activities (n=28; 76%), social/leisure life (n=26; 70%); and mood/emotions (n=24; 65%). Most participants (n=30; 81%) reported they had made lifestyle/behavioral changes to help limit their CAD symptoms, such as wearing extra clothing in places that were likely to be cold. A conceptual model of the symptoms and impacts of CAD was developed based on these data (Figure 1). Physician advisors (n=7) agreed that the patient-reported symptoms and impacts identified during the interviews were relevant concepts to CAD. Following a literature review, no existing PRO measure was found to adequately address concepts deemed critical to CAD from the patient perspective. Owing to the lack of an existing fit-for-purpose measure, 14 concepts were identified from the interviews to develop an initial draft item pool. During the cognitive debriefing in the second set of interviews, participants (n=21: Round 1 n=8; Round 2 n=7; Round 3 n=6) evaluated these concepts. After 3 rounds of interviews, the new item set yielded 11 items relating to: fatigue; cold sensitivity; dyspnea; wearing extra clothing; limited physical, social, and enjoyable activities; difficulty with usual activities; mood; frustration; and anxiety/stress. Participants reported these items were comprehensive of their experiences with CAD, easy to understand, and would be relevant to gaining a better understanding of individuals' experiences with CAD. Conclusion These results support the need for a novel PRO measure(s) that adequately addresses concepts critical to the measurement of CAD symptoms and impacts from the patient perspective. Figure 1 Figure 1. Disclosures Joly: Sanofi: Current Employment. Dasmahapatra: Sanofi: Current Employment, Current equity holder in publicly-traded company. Su: Sanofi: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas US LLC: Current Employment. DiBenedetti: RTI Health Solutions: Current Employment, Other: Employee of RTI Health Solutions, funded by Sanofi Genzyme to conduct the original work which this abstract is based on. Kosa: RTI Health Solutions: Current Employment. Hill: Novartis: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Sanofi: Consultancy; ReAlta: Consultancy; Alexion: Honoraria; Amgen: Honoraria; Argenx: Consultancy; Apellis: Consultancy, Honoraria.

BACKGROUND:Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by immunoglobulin M autoantibodies that bind to the "I" antigen on erythrocytes. IgM binding results in either agglutination at ≤37°C, activation of the classical complement pathway, or both. Patients with CAD can have transient agglutination-mediated circulatory symptoms triggered by exposure to cold conditions. Separately, patients with CAD can experience complement-mediated symptoms such as anemia, hemolysis, and fatigue, but the effect of the season on these complement-mediated manifestations of CAD and clinical outcomes is not well understood.METHODS:Using data from the Optum® de-identified Electronic Health Record dataset, we compared hemoglobin, markers of hemolysis (bilirubin and lactate dehydrogenase [LDH]), and healthcare resource utilization (HRU) between seasons for 594 patients (62% female; 66% aged ≥65 years) with CAD (defined as having CAD-related terms in their clinical notes on ≥3 separate occasions between December 2008 and May 2016). Laboratory parameters and HRU were compared between seasons using multivariate regression models.RESULTS:Estimated median hemoglobin (9.87 g/dL in summer and 9.86 g/dL in winter; P = 0.944) and bilirubin (1.04 mg/dL in summer and 1.09 mg/dL in winter; P = 0.257) were similar in winter versus summer. While LDH was statistically significantly higher in winter compared with summer (P < 0.001), the estimated median value was above normal for both seasons (309 U/L in summer and 367 U/L in winter). HRU measures and transfusion and thromboembolism rates were similar across seasons.CONCLUSIONS:Patients with CAD had evidence of persistent chronic hemolysis, HRU, and thromboembolism risk year round.

Introduction CAD is a rare, chronic type of autoimmune hemolytic anemia, where hemolysis is driven by classical complement pathway (CP) activation. Complement activation assures rapid initiation of the complement cascade as part of an early immune response and inflammation. A proinflammatory state secondary to complement activation has been demonstrated in other hemolytic disease such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (Weitz et al. Thromb Res. 2012; Cofiell et al. Blood. 2015). Complement activation stimulates cytokine production (tumor necrosis factor, interleukin 6 [IL-6], IL-8, IL-17) via anaphylatoxins C3a and C5a and increases vascular inflammatory markers, consistent with complement-mediated inflammation (Landsem et al. Clin Exp Immunol. 2017; Cofiell et al. Blood. 2015). In patients with chronic fatigue syndrome, complement activation is associated with higher levels of fatigue (Sorensen et al. J Allergy Clin Immunol. 2003) and inflammatory cytokine activity correlates with the severity of fatigue symptoms (Montoya et al. PNAS. 2017). In addition, IL-6 plays a more dominant role in immune stimulation, particularly during chronic inflammation stress such as rheumatoid arthritis (Choy et al. Rheumatology. 2018). In CAD, CP activation and chronic inflammation may contribute to patient fatigue, apart from anemia. CP activation resulting in a proinflammatory state has not been formally studied in CAD. The interplay between complement-mediated inflammation and fatigue also has not been previously explored in patients with CAD. In the Cardinal study (NCT03347396), efficacy and safety of the humanized monoclonal anti-C1s antibody, sutimlimab (formerly BIVV009), was evaluated in patients with CAD and recent history of blood transfusion. Here we summarize the results of inflammatory cytokine expression for IL-6 and IL-10 and their relation to fatigue over the Part A 26-week treatment period of Cardinal. Methods In Cardinal Part A, patients with CAD received intravenous doses of sutimlimab on Days 0 and 7, and biweekly infusions thereafter. Patients weighing <75 kg and ≥75 kg received a 6.5 g and 7.5 g dose, respectively. Cytokine levels for IL-6 and IL-10 were assessed in patients with available serum samples. Cytokine profiles and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores were evaluated from baseline to follow-up time points at Weeks 1, 3, 5, and 25, as represented by the treatment assessment time point (TAT) after initiating sutimlimab treatment. Summary statistics describing IL-6, IL-10, and FACIT-F changes at each week were reported. Results Mean IL-6 level (mean pg/mL [standard error of the mean (SEM)]) steadily decreased from baseline (3.21 [0.958]; normal values IL-6 <3.2 pg/mL) to follow up at all time points after initiating sutimlimab treatment (Figure 1), showing rapid onset and durable pattern of decline as early as Week 1 (2.70 [0.839]). Mean IL-6 level was reduced by more than half by Week 3 (1.56 [0.297]), slightly rose at Week 5 (1.88 [0.383]), and was lowest at TAT (1.31 [0.201]). Mean IL-10 level (pg/mL [SEM]) also decreased in a time-dependent manner from baseline (1.36 [0.310]) initially at Week 1 (0.99 [0.250]). Mean IL-10 slightly increased at Week 3 (1.07 [0.306]), but dropped at Week 5 (0.83 [0.142]) and was lowest by TAT (0.82 [0.129]) with sutimlimab treatment (Figure 2). At baseline, mean (SEM) FACIT-F score was 32.5 (2.266) (Figures 1-2). Patient FACIT-F scores showed early and late improvements with mean score increases at Week 1 (39.67 [1.741]), Week 3 (40.70 [1.543]), Week 5 (43.75 [1.192]), and at TAT (41.86 [1.958]). Decreased inflammation, as demonstrated by IL-6 and IL-10 activity, occurred concurrently with FACIT-F score improvements over time. Conclusions In Cardinal Part A, decrease from baseline to TAT in mean proinflammatory cytokine IL-6 and regulatory cytokine IL-10 levels were observed during sutimlimab treatment, highlighting the influence of complement inhibition on inflammation in CAD. Improved FACIT-F scores are concurrent with sutimlimab treatment and inhibition of the CP. Concurrent inverse changes were noted between select inflammatory cytokines and improvements in patients' fatigue, suggesting complement-mediated inflammation may additionally contribute to manifestation of fatigue in patients with CAD. Disclosures Weitz: Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau. Ueda:Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria. Shafer:Sanofi: Current Employment. Su:Sanofi: Current Employment. Foster:Sanofi Genzyme: Current Employment. Storek:Sanofi: Current Employment. Patel:Sanofi: Current Employment.

Introduction Cold agglutinin disease (CAD) is a serious and rare autoimmune disorder associated with severe fatigue, weakness and other symptoms of chronic anemia and hemolysis. Prior studies have demonstrated that CAD is associated with substantial economic burden and healthcare resource use, including blood transfusions, and highlight an unmet need for novel treatments (Mullins M et al. Blood Adv 2017; Su J et al. J Med Econ 2019). In the pivotal CARDINAL study (Part A), sutimlimab (BIVV009), a monoclonal antibody that targets the underlying cause of hemolysis in CAD by selectively inhibiting complement C1s, provided clinically meaningful improvements with an acceptable safety profile in CAD patients (Röth A et al. Blood 2019). A post hoc analysis was conducted to describe the impact of sutimlimab treatment on healthcare resource utilization (HCRU) in CAD patients. Methods CARDINAL is a Phase 3 open-label, international, multicenter, single-arm study (NCT03347396), evaluating the efficacy, safety, and tolerability of sutimlimab in patients with primary CAD and a recent history of blood transfusion (defined as having ≥1 transfusion 6 months prior to enrollment). The study enrolled 24 patients who received an IV infusion of sutimlimab over approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter through Week 25. Post-hoc analysis of the full analysis set assessed hospitalizations and transfusions that occurred in the 6 month period pre- and post-administration of the first treatment dose. Distribution and descriptive statistics (mean, SD, median, min and max) were determined pre- and post-treatment periods and calculated for the differences between the pre- and post-treatment periods. Results The number of hospitalizations experienced by CAD patients in this post hoc analysis decreased 3.3-fold following sutimlimab treatment: from 10 patients (41.7%) in the pre-treatment period to 3 patients (12.5%) in the post-treatment period. Pre-treatment hospitalizations were the result of CAD-related symptoms or blood transfusion. Reasons for post-treatment hospitalizations included sepsis, infection and blood transfusion. The mean number of hospitalizations per patient decreased post-treatment compared with pre-treatment, but the mean duration of hospitalization per patient was similar between treatment periods (Table). During the post-treatment period, one patient was hospitalized for 18 days due to an infected hematoma following surgery, unrelated to sutimlimab treatment. Nine patients (37.5%) experienced fewer hospitalizations, shortened mean and total hospitalization duration following treatment. Similarly, blood transfusion use by CAD patients also decreased following sutimlimab treatment. Pre-treatment, all patients received ≥1 transfusion, decreasing to 41.7% patients post-treatment. This represented a total of 105 transfusions pre-treatment and 25 transfusions post-treatment, respectively (Table). Overall, 95.9% (23/24) patients received, at least, one less transfusion during the post-treatment versus pre-treatment period. The mean number of units transfused per transfusion was similar pre- and post-treatment; notably, the total number of units transfused decreased from 196 pre-treatment to 43 post-treatment (Table). Conclusion This post hoc analysis of HCRU data from the CARDINAL study provides evidence that CAD is a serious condition that can require hospitalization and blood transfusions. Sutimlimab treatment demonstrates substantial reductions in hospitalizations and blood transfusions. This results in a reduced HCRU impact and decreases the associated burden for hospitals, patients and payers. Disclosures Röth: Roche: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. Guillonneau:Sanofi: Current Employment, Current equity holder in publicly-traded company. Narcisse:Sanofi: Consultancy. Carita:Sanofi: Current Employment, Current equity holder in publicly-traded company. Su:Sanofi: Current Employment, Current equity holder in publicly-traded company. Joly:Sanofi: Current Employment, Current equity holder in publicly-traded company.

Aims: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia associated with increased thromboembolism risk and early mortality. Healthcare resource utilization (HRU) in CAD has not been reported. We aimed to compare HRU of patients with CAD with a matched non-CAD cohort in the United States. Materials and methods: Patients with CAD were identified from 2006 to 2016 in the Optum-Humedica database using CAD terms in clinical notes and hematologist review. Patients were required to have Integrated Delivery Network records and >= 6 months' follow-up before and after the first CAD mention date (index date). Patients with CAD were matched to a non-CAD cohort based on demographics. Multivariate analyses assessed inpatient hospitalizations, outpatient visits, emergency room visits, and transfusion use between cohorts 6 months before and 12 months after the index date. Results: Of 814 patients with CAD, 410 met inclusion criteria and were matched to 3,390 patients without CAD. Mean age of patients with CAD was 68.0 years; approximately 62% were female. In the 12 months after the index date, mean inpatient hospitalizations (0.83 vs. 0.25), outpatient visits (17.26 vs. 6.77), emergency room visits (0.55 vs. 0.32), and transfusion days (1.05 vs. 0.05) were higher for patients with CAD than the matched non-CAD cohort (all p < .0001). Similarly, in the 6 months before the index date, patients with CAD had higher HRU than matched patients without CAD for all measures evaluated. Limitations: Results of this study are based on patient information from the Optum-Humedica database, which is limited to commercially insured patients and may not represent the overall CAD population. Conclusions: CAD places a substantial burden on patients and healthcare systems. In addition, the high HRU for patients with CAD observed in the 6 months before diagnosis indicates that disease awareness and better diagnostic practices may be needed.

Introduction

We here present a primary solitary tumor of the lesser omentum that was found in a 71-yr-old woman. Differential diagnosis could not be made preoperatively; therefore, histopathological examination including immunohistochemical studies were performed to determine the nature of the tumor. The resected specimen, measuring 17 cm at the largest point, consisted of the outer solid part and the inner multiloculated cysts. Microscopically, the tumor was characterized by interlacing bundles of elongated spindle cells, with the nuclei focally showing a palisading pattern. However, skeinoid fibers were not observed anywhere. One to three mitoses per 50 high power fields were observed. Immunohistochemically, the tumor was negative for S-100 protein and smooth muscle–specific actin, but stained positive for CD34. The microscopic features were consistent with those of potentially malignant gastrointestinal stromal tumors. Stromal tumors that represent the differentiation toward neither typical leiomyomas or schwannomas rarely occur in the lesser omentum with only one such instance having been reported to date. Due to this rarity, it is difficult to make the differential diagnosis preoperatively, even with existing imaging techniques, and predicting the clinical behavior of such omental tumors is also often difficult. Therefore, complete resection should be performed when such tumors are encountered in daily practice.

Introduction Cold agglutinin disease (CAD) is a rare disorder (a prevalence of 16 cases per 1 million people), accounting for approximately 15%-25% of all autoimmune hemolytic anemias (Berentsen. Semin Hematol. 2018). Currently, there is no approved drug for the treatment of CAD. Debilitating fatigue that greatly affects quality of life is common among patients with CAD (Roth et al. Blood. 2019). The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale has recently been used to quantify fatigue in patients with CAD (Roth et al. Blood. 2019). However, the appropriateness of FACIT-F in these patients has not been assessed. In-depth individual interviews of adults with CAD were conducted primarily to identify the symptoms and effects of CAD reported as important by patients and to better understand their experiences with CAD. The secondary objective was to obtain patient feedback regarding the relevance and importance of the items on the FACIT-F. Methods Participants were identified and recruited from a proprietary panel of patients with CAD. Of 1,250 panel members, approximately 600 members from the United States (US) were invited to participate in an in-depth interview. Systematic random sampling was used to select every nth panel member from each of 4 US regions to receive an email invitation. A semi-structured interview guide was used to ensure consistent systematic collection of data pertaining to study objectives, while maintaining a conversational tone and encouraging spontaneity of answers. Results Twenty-two members expressed interest in participating; of these, 18 could be reached for screening and 16 were eligible for interview. The sample was 100% White and non-Hispanic, 62.5% female, and had an average age of 67.8 years. Participants resided in the West (37.5%), Midwest and South (both 25%), and Northeast (12.5%). The date of CAD diagnosis averaged 6 years before the interview, and 68.8% of patients had received their diagnosis within the last 1.5 years. Seven (43.8%) patients reported that they were not taking any prescription or over-the-counter (OTC) medication for CAD, whereas 9 (56.3%) were taking prescribed or OTC folic acid for CAD (of these, 4 also took prescription strength vitamin B12). In this sample, no patient reported current use of other prescription medications for CAD. A few patients spontaneously reported previous treatments for CAD (eg, transfusions and rituximab or other injections). However, previous CAD treatment was not systematically collected for all subjects and is a limitation of the study. Concept-elicitation of symptoms The most frequently reported symptoms were fatigue/tiredness/lack of energy (93.8%), reaction to cold environments (93.8%), breathlessness (68.8%), and trouble thinking/concentrating (68.8%). When probed, 43.8% of patients reported sleep disturbances (Figure 1A). Concept-elicitation of effects Most participants (68.8%) reported lifestyle or behavioral changes to help treat CAD symptoms (eg, taking gloves/extra clothing to places that may be cold). Others reported giving up/limiting enjoyable or outdoor activities and making major changes (eg, discontinuing outdoor activities, restricting travel). Other CAD-related effects included impairment in daily activities, overall health/physical activities, and social/leisure activities/relationships (Figure 1B). For the evaluation of the FACIT-F in this CAD population, participants reported that FACIT-F instructions and items were clear and easy to understand, response options were distinct from each other, and they could recall their fatigue over the previous 7 days. They reported that FACIT-F measured one or more concepts personally important to them and important concepts were not missing. This provides support for the content validity of the FACIT-F in patients with CAD. Conclusions Patients with CAD experienced negative effects on daily activities, physical health/activities, social/ leisure activities/relationships, the ability to concentrate/recall, and mood/emotions mostly owing to fatigue/lack of energy and reactions to cold environments. Most patients required modifying their lifestyle/behavior to manage CAD symptoms. FACIT-F measured concepts important to patients with CAD, which supports its content validity and use in this patient population. Disclosures Su: Sanofi: Current Employment. Kosa:Sanofi: Other: RTI Health Solutions was contracted by Sanofi to conduct this work; RTI Health Solutions: Current Employment. DiBenedetti:Sanofi: Other: RTI Health Solutions was contracted by Sanofi to conduct this work; RTI Health Solutions: Current Employment, Other.

Introduction Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA) accounting for 20% of all cases, with no approved therapies and limited management options for patients. CAD is characterized by immunoglobulin M-mediated erythrocyte agglutination, which triggers activation of the classical complement pathway leading to hemolysis and subsequent anemia. Red blood cell (RBC) transfusions are used as a supportive treatment in CAD to temporarily alleviate anemia, although the transfusion practices are variable among providers treating patients with CAD. Recent RBC transfusion guidelines from the AABB (formerly the American Association of Blood Banks) recommend that transfusions be administered with a restrictive threshold in most clinical scenarios (ie, transfusion is not indicated until hemoglobin [Hb] reaches 7-8 g/dL and/or patients exhibit anemia-related symptoms) to avoid associated complications such as acute reactions, alloantibody development, and hemochromatosis (Carson et al, JAMA, 2016; Carson et al, N Engl J Med, 2017). Because of the dearth of information available regarding trends in RBC transfusion practices among US hematologists, the objective of this longitudinal, retrospective, observational assessment of an electronic medical record database was to evaluate transfusion practices applied to patients with CAD in the US. Methods Patients were retrospectively identified from Optum® de-identified Electronic Health Record (EHR) dataset. Adult patients with ≥1 AIHA-related medical encounter between January 2007 and September 2018 (study period) and ≥3 mentions of CAD-related terms from physician notes ("cold agglutinin disease," "cold autoimmune hemolytic anemia," or "cold agglutinin hemoglobinuria") were included (Broome et al, Blood, 2017). The index date for each patient was the date of first mention of CAD during the study period. The baseline period was defined as the interval from the start of medical activity in the EHR database or study period (whichever occurred later) to the index date, and the follow-up period was defined as the interval from the index date to the end of the study period, end of medical activity, or death (whichever occurred earlier). The study sample was categorized into 2 study groups, the transfusion group (patients with CAD with ≥1 RBC transfusion after the index date) and the non-transfusion group (patients with CAD without any transfusions during the study period). Patients were further grouped based on the following Hb levels (g/dL): <8, ≥8 to ≤10, and >10 to ≤12. The closest Hb level prior to the most recent transfusion (within the prior 15 days and the lowest level) was used for the transfusion group and the lowest Hb level during the study period was used for the non-transfusion group. Descriptive statistics included mean, standard deviation, and median values for continuous variables and frequency (n and percent) for categorical variables. No adjustment was made for this descriptive analysis. Results A total of 903 patients with CAD were identified from the Optum EHR database; most patients were white (n=760 [84%]) and female (n=560 [62%]). Baseline demographics and clinical characteristics of each group can be found in the Table. Of the patients with CAD, 548 (61%) did not receive transfusions and 355 (39%) received ≥1 RBC transfusion. Among patients with CAD who received transfusions, 84% (n=297) had ≥2 RBC transfusions. Out of the 903 patients with CAD, 864 had Hb levels reported and 752 had Hb levels ≤12 g/dL. Forty-four percent (n=329/752) of those CAD patients received ≥1 RBC transfusion. When separated by Hb levels, 18% of patients with Hb >10 to ≤12 g/dL (n=19/108); 41% (n=88/216) of patients with Hb ≥8 to ≤10 g/dL; and 52% (n=222/428) of patients with Hb <8 g/dL received ≥1 RBC transfusion. Of the 423 (56%) patients with CAD and Hb levels ≤12 g/dL who did not receive RBC transfusions, 21% (n=89/423) had Hb levels >10 to ≤12 g/dL; 30% (n=128/423) had Hb levels ≥8 to ≤10 g/dL; and 49% (n=206/423) had Hb levels <8 g/dL. Conclusions Overall, patients with CAD are not a heavily transfused population. Even in those with a significantly decreased Hb (<8 g/dL), approximately half of them (49%) did not receive RBC transfusions. This suggests that the use of transfusions in patients with CAD may not reflect disease severity. Further prospective studies are needed to fully understand the impact of transfusions on patients with CAD. Disclosures Su: Sanofi Genzyme: Employment, Equity Ownership. Punekar:Sanofi: Employment, Equity Ownership. Morales Arias:Sanofi: Employment, Equity Ownership. Jain:Sanofi Genzyme: Employment, Equity Ownership.

Introduction Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA). It is characterized by both IgM-mediated agglutination of erythrocytes and hemolysis mediated by activation of the classical complement pathway. Recent studies have shown an increased risk of thromboembolic events (TE) in CAD patients. In addition, a recent analysis using the Danish National Patient Registry demonstrated a significant increase in mortality for CAD patients compared with matched individuals from the general population in Denmark (Bylsma et al, HemaSphere, 2018). Mortality among CAD patients has not been assessed in a US population. This study evaluated mortality risk in the largest cohort of CAD patients in the US. Methods Patients were retrospectively identified from the Optum® de-identified EHR dataset. Between January 2007 and September 2018 (study period), patients with ≥1 AIHA-related medical encounter and ≥3 mentions from physician notes of CAD-related terms ("cold agglutinin disease," "cold autoimmune hemolytic anemia," or "cold agglutinin hemoglobinuria") were included in the CAD cohort ("case"). For this cohort, the first mention of CAD terms was set as the index date. Patients without an AIHA-related medical encounter were included in the non-CAD cohort ("control"). For the control cohort, the index date was assigned based on the average occurrence of index date in the CAD population for the duration in the EHR database. For both cohorts, the baseline period was defined as the interval from the start of the medical activity in the EHR database or study period (whichever occurs later) to the index date, and the follow-up period was defined as the interval from the index date to the end of the study period, the end of medical activity, or death (whichever occurs earlier). The case and control cohorts were matched by age, gender, race, region, index year, and follow-up period using 1:5 nearest neighbor matching. Both cohorts were stratified according to the presence or absence of ≥1 TE during the study period. Mortality rate per 100,000 patients was calculated as the number of patients who died in each cohort divided by the number of patients in each cohort, from 2007 to 2018, multiplied by 100,000. Mortality rate was compared between matched cohorts using a Poisson test. An independent t-test was used to compare age at death between matched CAD and control groups; and time to death (starting from the index date) was analyzed using Kaplan-Meier curves and compared between matched cohorts using log-rank P test. Results In total, 651 CAD patients and 3,255 matched non-CAD controls were identified. Of these, 35% (n=228) of CAD patients and 20% (n=641) of non-CAD patients experienced ≥1 TE (P<0.001). Median age at index date for both cohorts was 72 years. Most patients were female (CAD 64%; non-CAD 65%) and Caucasian (CAD 85%; non-CAD 85%). Median follow-up duration was 42 months for the CAD cohort and 51 months for the control cohort. Mean (standard deviation [SD]) Elixhauser Comorbidity Index Score was 8.0 (4.9) for CAD patients and 4.5 (4.1) for matched controls. The overall mortality rate was significantly higher for the CAD cohort than the matched-control cohort (CAD: 17,512 vs non-CAD: 11,306; P<0.001). For patients that experienced ≥1 TE during the study period, the mortality rate in the CAD cohort was 23,684 compared with 15,913 in the matched-control cohort (P<0.001; Table 1). During the study period, 114 CAD patients and 368 matched non-CAD patients died. The mean (SD) age at death in the CAD cohort (77 [12] years) was lower compared with the matched controls (82 [8] years; P<0.001). For patients with ≥1 TE, mean (SD) age at death was 77 (13) years vs 82 (7) years for the CAD and control cohorts, respectively (P<0.001; Table 1). A Kaplan-Meier analysis demonstrated a significantly decreased survival probability among CAD patients compared with matched controls (P<0.001; Figure 1). In addition, CAD patients with ≥1 TE also had a significant decrease in survival when compared with matched controls with ≥1 TE (P<0.001). Conclusions CAD patients in the US have an increased mortality risk compared with a matched non-CAD population. The associated increased TE risk observed among CAD patients may be a contributing factor to this mortality. Further studies are needed to better define this association and elucidate other potential contributors to mortality in these patients. Disclosures Hill: Apellis: Honoraria; Novartis: Speakers Bureau; Bioverativ, a Sanofi company: Honoraria; Alexion: Research Funding. Punekar:Sanofi: Employment, Equity Ownership. Morales Arias:Sanofi: Employment, Equity Ownership. Broome:Cellphire: Research Funding; Alexion: Honoraria, Research Funding; Sanofi Genzyme: Honoraria, Research Funding; Incyte: Research Funding; Rigel: Research Funding. Su:Sanofi Genzyme: Employment, Equity Ownership.

A study (Step2quit, Parkes et al. BMJ 2008) of current smokers randomized to assessment and communication of “lung age” vs no assessment found 13.6% of intervention vs 6.4% of controls smoke-free at 1 year. Our objective was to expand on Step2quit using a model to estimate the impact of a lung health intervention (LHI) consisting of spirometry and lung age assessment on lifetime effects of COPD diagnosis, progression, costs, and cost per quality-adjusted life-year (QALY) gained vs usual care (UC). The model was estimated from US population surveys and published studies. Target population was US smokers aged ≥35 years, stratified by COPD severity (GOLD stage) and diagnosis receiving LHI vs UC at a routine office visit. Post-visit COPD diagnosis and smoking cessation differ by receipt of LHI. Depending on GOLD stage, diagnosed patients may receive SABA, anticholinergics (AC), LABA+ICS, or AC+SABA. Costs and outcomes were modeled with Markov health states defined by smoking status, GOLD Stage and diagnosis. Transition to more severe GOLD stage depends on treatment received and smoking status. Lifetime costs (in $2009) and outcomes were discounted at 3%/year. Results show that LHI leads to more lifetime diagnosis (72% LHI vs 51% UC) and less progression to severe/very severe COPD (10.1% LHI vs 12.4% UC). Lifetime per-person COPD costs are $52,789 for LHI vs $51,182 for UC, with higher LHI costs of intervention ($57) and treatment ($3,731) partially offset by lower COPD management costs (-$2,181). LHI provides additional QALYS at $10,064/QALY gained. Using conventional willingness-to-pay threshold values, LHI is a cost-effective intervention in COPD.