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Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count 20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post–SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: Age ≥18;Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);failure of ≥1 prior treatment for wAIHA;Haptoglobin ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to Exclusion Criteria include: Presence of other forms of AIHA;Uncontrolled or insufficiently controlled hypertension;Neutrophil count 1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy; duration of hemoglobin response; and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patients have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. Figure Disclosures Cooper: Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Tong:Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter:Incyte: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Shionogi: Consultancy; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, 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; Protalex: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria.

Approximately 80% of adult patients with immune thrombocytopenia (ITP) have treatment failure with corticosteroids or become dependent on them and require second-line therapy. Several new and effective therapies have been introduced during the past decade and our understanding of disease burden and its effect on quality of life has expanded. It is now recommended that splenectomy, the standard second-line therapy for decades, be delayed for at least 12 to 24 months, allowing for more patients to achieve remission on medical therapies before considering surgery. It is highly recommended that medical therapies be used that have abundant clinical trial evidence, such as the thrombopoietin receptor agonists (TPO-RAs) rituximab and fostamatinib. Unfortunately, there are no reliable biomarkers that help in treatment selection. These therapeutic medical options have variable efficacy, safety profiles, mechanisms of action, and modes of administration. This enables and mandates an individualized approach to treatment, where patient involvement, preferences and values have become central to the process of choosing the appropriate therapy. Both TPO-RAs and fostamatinib are maintenance therapies, whereas rituximab is given for a limited number of doses. Although the response is usually maintained while receiving a TPO-RA or fostamatinib therapy, half of rituximab responders will no longer respond 1 to 2 years after administration and require retreatment or other therapy.

Introduction: Coronavirus disease 2019 (COVID-19) may cause a hypercoagulable state. The D-dimer is frequently elevated in COVID-19, but other markers of coagulation activation, including the prothrombin fragment 1.2 (PF1.2) are poorly described. Given the near universal D-dimer elevation in critically ill patients with COVID-19, the PF1.2 may be a more specific marker to identify thrombotic complications. Methods: We studied hospitalized adults with COVID-19 and PF1.2 measurement performed at any point during hospitalization. We evaluated the relationship between PF1.2 and synchronously measured D-dimer. We utilized receiver operating characteristic (ROC) analysis to evaluate optimal thresholds for diagnosing thrombosis and multivariable logistic regression to evaluate association with thrombosis. Thresholds for each assay for multivariable regression were determined from ROC analysis. To avoid confounding of therapeutic anticoagulation on PF1.2 or D-dimer measurement, patients receiving therapeutic anticoagulation at the time of assay measurement were excluded from these analyses. Results: Patients and Thrombotic Events. 115 hospitalized patients with COVID-19 were included [110 (95.7%) critically ill], encompassing 3318 patient-days (474 patient-weeks) analyzed for thrombotic and critical illness complications. At the data cutoff date, 74 patients (64.3%) had been discharged from the hospital alive, 24 patients (20.9%) died in the hospital, and 17 patients (14.8%) remained hospitalized, having been hospitalized for a median of 44 (range, 30-62) days. Over a median follow-up of 29 (range, 2-62) hospital days, 26 patients developed radiographically-confirmed VTE (22.6%, a rate of 5.49 per 100 patient-weeks); including arterial, extracorporeal circuit, and recurrent line thrombosis, 56 patients (48.7%) developed a thrombotic complication. At the time of PF1.2 and synchronous D-dimer measurement, 37 patients (32.1%) were receiving therapeutic anticoagulation, 77 patients (67.0%) were receiving prophylactic anticoagulation, and 1 patient (0.9%) was not receiving pharmacologic thromboprophylaxis. Association of PF1.2 with D-dimer. Synchronously measured PF1.2 and D-dimer were moderately positively correlated (r=0.542, P Association of PF1.2 with Hypercoagulability. Median PF1.2 levels were higher in patients with thrombosis than those without (611 vs. 374 pmol/L, P=0.006, Figure 2). Therapeutic anticoagulation suppressed median PF1.2 levels: median (IQR) PF1.2 in patients not receiving therapeutic anticoagulation (N=29) was 611 pmol/L (333-1148 pmol/L), significantly higher than the median (IQR) PF1.2 in patients receiving therapeutic anticoagulation (N=27) of 347 pmol/L (195-506 pmol/L), P=0.0017. ROC and Multivariable Regression Analyses. In ROC analysis, PF1.2 had superior specificity and conferred a higher positive likelihood ratio in identifying patients with thrombosis than did the D-dimer (PF1.2 threshold of >523 pmol/L: 69.2% sensitivity, 67.7% specificity; >924 pmol/L: 37.9% sensitivity, 87.8% specificity, Figure 3). In multivariable analysis controlling for age, sex, and BMI, a PF1.2 >500 pmol/L was significantly associated with VTE [adjusted odds ratio (OR) 4.26, 95% CI, 1.12-16.21, P=0.034] and any thrombotic manifestation (adjusted OR 3.85, 95% CI, 1.39-10.65, P=0.010); conversely, synchronously measured D-dimer >2,500 ng/mL was not significantly associated with VTE (OR 5.91, 95% CI, 0.69-50.56, P=0.11) or any thrombotic manifestation (OR 2.47, 95% CI, 0.78-7.78, P=0.12). The vast majority (90.6%) of patients with a non-elevated PF1.2 result did not develop VTE and 75% did not develop any thrombotic complication. Conclusions: When measured at any point during hospitalization in patients not receiving therapeutic anticoagulation, PF1.2 was more specific than synchronously measured D-dimer in identifying patients who experienced thrombosis and was significantly associated with thrombotic manifestations in multivariable analyses while the D-dimer was not. PF1.2 may be a useful assay, and potentially more discriminant than D-dimer, in identifying thrombotic manifestations in hospitalized patients with COVID-19. Disclosures Al-Samkari: Rigel: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding. Kuter:Caremark: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; CRICO: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Shionogi: Consultancy; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding; Protalex: Consultancy, Honoraria, 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; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Kezar Life Sciences, Inc: Other, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Dova: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding. Rosovsky:Bristol-Myers Squibb, Dova, Janssen, Portola: Consultancy; Bristol-Myers Squibb, Janssen: Research Funding.

Introduction: Iron deficiency anemia (IDA) is the most common cause of anemia worldwide and is frequently untreated or undertreated (Kesselbaum et al. 2014). The association of thrombocytosis with IDA is well-recognized, with recent work elucidating its underlying physiology (Xavier-Ferrucio et al. 2018). Thrombocytosis in IDA may predispose to thrombotic complications, as described in many case reports. Given that IDA is ubiquitous, even minor increases in thrombotic risk due to thrombocytosis have dramatic public health implications. Data describing the rate, predictors, and risk of thrombotic complications are limited. This study characterizes these features of thrombocytosis in IDA. Methods: We queried a large institutional patient data repository containing comprehensive chart data for over 5.8 million patients to identify patients with IDA with and without thrombocytosis and thrombotic events over a 40-year time period (1979 to 2019). Demographic information, hematological parameters, thrombosis history, and other medical history were collected at time of peak thrombocytosis, time of IDA diagnosis, and clinical baseline (before IDA diagnosis or after resolution). The fidelity of query data was assessed by performing detailed manual chart review of 700 total patients. Clinical diagnoses of IDA were verified by confirming ferritin values Results: Our queries identified 36,327 IDA cases and 15,022 IDA with thrombocytosis cases. Query fidelity rates were 95% and 75%, respectively, yielding a true thrombocytosis rate of 32.6% in patients with IDA. After excluding cases with other causes of thrombocytosis, we calculated a 7.8% rate of thrombosis in patients with IDA and a 15.8% rate of thrombosis in patients with reactive thrombocytosis secondary to IDA (Table 1, Figure). The odds ratio for thrombosis in IDA with thrombocytosis vs IDA alone was 2.23 (2.09-2.38, p Among patients with IDA and thrombocytosis, ferritin and hemoglobin (Hgb) were both moderately negatively correlated with platelet count (Plt) (Table 2). Platelet mass index (Plt x MPV) at time of IDA diagnosis and peak thrombocytosis was significantly higher than baseline. Platelet mass index and Hgb were strongly negatively correlated at peak thrombocytosis. Multivariate regression including age, sex, WBC count, Hgb, Plt, and MCV demonstrated a significant predictive relation between decreasing Hgb and increasing Plt at peak thrombocytosis. Conclusions: In this large retrospective analysis, we describe the rate and predictors of thrombocytosis in IDA in addition to rates of thrombosis in IDA patients with and without reactive thrombocytosis. Combining queries of a massive clinical database with manual chart review to ensure data validity, we found a 32.6% rate of thrombocytosis in IDA, negative correlations between both Hgb/ferritin and Plt, and a 2-fold increased thrombotic risk in patients with thrombocytosis reactive to IDA relative to IDA alone. We also found increased total body platelet mass in IDA patients with thrombocytosis, which may contribute to this increased thrombotic risk. Thrombosis rates overall were high, possibly due to database inclusion of more morbid inpatients in addition to outpatients. Given the global burden of untreated and undertreated IDA, our findings suggest that adequate IDA treatment may reduce thrombotic complications and associated morbidity and mortality. Acknowledgements: A. Song is the recipient of the American Society of Hematology HONORS Award (provides research support). Disclosures Kuter: Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kezar: Research Funding; Principia: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Shinogi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy.

Publisher's Note: There is a Blood Commentary on this article in this issue., Key Points In addition to thrombotic complications, bleeding is a significant cause of morbidity in patients with COVID-19. D-dimer elevation at admission was predictive of bleeding, thrombosis, critical illness, and death in patients with COVID-19., Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients., Visual Abstract

Introduction : Thrombopoietin receptor agonists (TPO-RAs) are used to treat immune thrombocytopenia (ITP), but predicting clinical response to TPO-RAs before initiation is not possible. As ITP is both a disorder of increased platelet destruction and inadequate platelet production and because endogenous thrombopoietin (TPO) levels are typically normal or only slightly elevated in ITP patients (Makar et al, 2013), we hypothesized an inverse relation between baseline endogenous TPO level and probability of response to TPO-RAs. If a relation exists, obtaining TPO levels prior to TPO-RA therapy would be highly clinically useful in the treatment planning of patients with ITP given that the baseline platelet count, receipt of treatment, and disease duration do not significantly affect TPO level in ITP patients (Mukai et al, 1996, Makar et al, 2013). To determine whether endogenous thrombopoietin (TPO) levels predict treatment response to TPO-RAs we performed a retrospective analysis of ITP patients with known baseline TPO levels who received TPO-RAs. Methods : TPO-RA treatment and disease-related data were collected for ITP patients with a baseline TPO level treated with eltrombopag or romiplostim. Response fraction (RF) (proportion of platelet counts on therapy that were ≥50×109/L and least 20×109/L higher than pretreatment baseline) was determined for each patient. Multiple logistic regression was used to model the probability of three classes of treatment response [overall (RF>0.0), moderate (RF≥0.5), and superior (RF≥0.8)] based on TPO level. A generalized linear model with logit transformation was used to predict RF based on TPO level. All models controlled for duration of disease, number of prior therapies, and splenectomy status. Receiver operating characteristic (ROC) analysis was performed to identify optimal TPO thresholds for response and correlations between TPO level and various response characteristics were analyzed. Results : 67 patients (37 receiving eltrombopag and 46 receiving romiplostim; 16 patients had discrete treatment episodes with each drug) were included. Baseline patient characteristics are summarized in Table 1. Logistic regression models demonstrated a significant predictive relation between TPO level and probability of all classes of treatment response as illustrated in Figure 1 and Figure 2. TPO level was significantly inversely correlated with all response classes; correlation coefficients and odds ratios for each class of response (per 10 pg/mL TPO increase) are given in Table 2. Generalized linear modeling demonstrated a significant predictive relationship between TPO level and response fraction for both romiplostim (P Conclusions : TPO levels predict response to eltrombopag and romiplostim in ITP patients, with lower levels predicting improved probability and magnitude of response. ITP patients with normal TPO levels are likely to clinically respond to either eltrombopag or romiplostim, those with modest elevations of TPO are more likely to respond to romiplostim than eltrombopag, and those with extreme elevations in TPO are unlikely to respond to either agent. Therefore, obtaining a baseline serum TPO level in any ITP patient in whom TPO-RA agonist therapy is anticipated may be clinically useful. Disclosures Al-Samkari: Agios: Consultancy. Kuter:Bioverativ: Consultancy, Research Funding; Principia: Research Funding; Amgen Inc.: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protalex: Research Funding; ONO: Consultancy; Novartis: Consultancy; Syntimmune: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; BMS: Research Funding.

Introduction: Cases of de novo immune thrombocytopenia (ITP), including a fatality following SARS-CoV-2 vaccination in a previously healthy recipient, led to studying its impact in pre-existing ITP. Published reports are limited but suggest that most patients with ITP tolerate the COVID-19 vaccines well without frequent ITP exacerbations (Kuter, BJH, 2021). Data regarding risk factors for exacerbation and relationship of response to first dose to that of second dose are limited. Methods: Data for patients with pre-existing ITP were obtained via 3 sources. First, via a ten-center retrospective study of adults with ITP who received a SARS-CoV-2 vaccine between December 2020 and March 2021 and had a post-vaccination platelet count (n=117); 9 centers were in the United States. Eighty-nine percent of patients received mRNA-based vaccines. The second and third sources of data were surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom ITP Support Association. A 'stable platelet count' was defined as a post-vaccination platelet count within 20% of the pre-vaccination level. ITP exacerbation was defined as any one or more of: platelet decrease ≥ 50% compared to pre-vaccination baseline, platelet decrease by >20% compared to pre-vaccination baseline with platelet nadir < 30x10 9/L, receipt of rescue therapy for ITP. Continuous variables were described as mean ±SD or median [interquartile range]; categorical variables were described as n (%). Relative risks and 95% confidence interval were calculated to estimate strength of association. Results: Among 117 patients with pre-existing ITP from 10 centers who received a SARS-CoV-2 vaccine, mean age was 63±17 years, 62% were female, with median 12 [4-23] years since diagnosis of ITP; patients had received a median of 3 [2-4] prior medical treatments. Sixty-nine patients were on ITP treatment at the time of vaccination (Table 1). There was an almost even distribution of platelet count response following each vaccine dose. In 109 patients with data for dose 1, platelet counts increased in 32 (29%), were stable in 43 (39%), and decreased in 34 (31%); in 70 patients following dose 2, platelet counts increased in 24 (34%), were stable in 25 (36%), and decreased in 21 (30%) (Figure 1). Nineteen (17%) patients experienced an ITP exacerbation following the first dose and 14 (20%) of 70 after a second dose. In total, fifteen patients received and responded to rescue treatments (n = 6 after dose 1, n = 8 after dose 2, n = 1 after both doses). Of 7 patients who received rescue treatment after dose 1, 5 received dose 2 and only 1/5 received rescue treatment again. Rescue consisted of increased dose of ongoing medication, steroids, IVIG, and rituximab. Splenectomized persons and those who received 5 or more prior lines of medical therapy were at highest risk of ITP exacerbation. Only 1 of 47 patients who had neither undergone splenectomy nor received 5 or more lines of therapy developed ITP exacerbation after dose 1. There were 14 patients off-treatment at the time of dose 1 and 7 patients at time of dose 2; 1 patient in each group developed ITP exacerbation with both these having had normal counts prior to vaccination and having undergone splenectomy. In 43 patients whose platelet counts were stable or increased after dose 1 and received dose 2, only 6 (14%) had platelet decreases to Conclusions: Thrombocytopenia may worsen in pre-existing ITP post-SARS-CoV2-vaccination but when ITP exacerbation occurred, it responded well to rescue treatment. No serious bleeding events were noted. Rescue treatment was needed in 13% of patients. Proactive vaccination surveillance of patients with known ITP, especially those post-splenectomy and with more refractory disease, is indicated. These findings should encourage patients with ITP to not only be vaccinated, but to receive the second dose when applicable to ensure optimal immunization. Rituximab interferes with vaccination response and ideally would be held until a minimum of 2 weeks after completion of vaccination. Figure 1 Figure 1. Disclosures Lee: Principia Biopharma: Consultancy. Beltrami Moreira: Kadmon: Other: Spouse current employer; Jounce Therapeutics: Other: Spouse employment ended in the past 24 months. Al-Samkari: Amgen: Research Funding; Argenx: Consultancy; Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Rigel: Consultancy; Sobi: Consultancy; Novartis: Consultancy. Cuker: Novo Nordisk: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Novartis: Research Funding; UpToDate: Patents & Royalties; Alexion: Research Funding; Spark Therapeutics: Research Funding; Synergy: Consultancy. MacWhirter - DiRaimo: JD has not personally received any payment personally, but PDSA has received grants and consultancy fees from Novartis, grant and honorarium from Amgen, grant and consultancy fees from Pfizer and UCB, and grants from Argenx, Principia, Rigel, and CSL Behr: Consultancy, Honoraria, Other. Gernsheimer: Cellphire: Consultancy; Rigel: Research Funding; Principia: Research Funding; Novartis: Honoraria; Amgen: Honoraria; Dova: Consultancy; Sanofi: Consultancy. Kruse: Alex has not personally received any payment but reports that PDSA received grants and consultancy fees from Novartis, grant and honorarium from Amgen, grant and consultancy fees from Pfizer and UCB, and grants from Argenx, Principia, Rigel, and CSL Behri: Consultancy, Honoraria, Other. Kessler: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: 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; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Kruse: CK has not personally received payment but reports that PDSA received grants and consultancy fees from Novartis, grant and honorarium from Amgen, grant and consultancy fees from Pfizer and UCB, and grants from Argenx, Principia, Rigel, and CSL Behring: Consultancy, Honoraria, Other. Leavitt: Pfizer: Research Funding; Merck: Consultancy; CSL DOVA: Consultancy; Catalys: Consultancy; Behring: Consultancy; BPL: Consultancy; HEMA Biologics: Consultancy; Rigel: Consultancy; Syntimmune: Research Funding; Sangamo Therapeutics: Research Funding; BioMarin: Consultancy, Research Funding. Liebman: Sanofi/Genzyme: Research Funding; Novartis: Consultancy, Research Funding; Argenx: Research Funding; Amgen: Consultancy; Dova: Consultancy, Honoraria; Pfizer: Consultancy. Newland: Novartis: Consultancy, Research Funding, Speakers Bureau; UCB Biosciences: Consultancy; Roche: Speakers Bureau; Octapharma: Research Funding; GSK: Consultancy, Research Funding, Speakers Bureau; BMS: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Argenx: Consultancy, Speakers Bureau; Angle: Consultancy; Grifols: Consultancy, Speakers Bureau. Tarantino: Pfizer: Research Funding; Novo Nordisk: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; UCB: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau; Principia: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioMarin: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Thachil: Amgen: Speakers Bureau; Novartis: Speakers Bureau. Kuter: Up-to-Date: Patents & Royalties: Up-To-Date; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding; Rubius: Current equity holder in publicly-traded company. Cines: Dova: Consultancy; Rigel: Consultancy; Treeline: Consultancy; Arch Oncol: Consultancy; Jannsen: Consultancy; Taventa: Consultancy; Principia: Other: Data Safety Monitoring Board. Bussel: CSL: Other: DSMB; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION: Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer therapy. Due to the lack of FDA-approved therapies for CIT and clear limitations of platelet transfusions, clinicians often must choose between reducing dose intensity, delaying treatment, switching to an alternative regimen less prone to thrombocytopenia, or even discontinuing therapy altogether. Lower overall survival in CIT is associated with bleeding complications in patients proceeding with chemotherapy as well as patients managed with reductions in relative dose intensity of chemotherapy due to dose reduction and/or treatment delay. Although there are no current FDA-approved therapies for CIT, evidence has emerged supporting use of romiplostim to treat CIT. However, predicting clinical response to romiplostim before initiation is not currently possible due to the lack of a known predictive biomarker. Baseline endogenous TPO levels may, however, be a predictive biomarker for response to thrombopoietin receptor agonists. Prior studies have demonstrated the utility of baseline TPO level to predict romiplostim response in ITP and avatrombopag response in thrombocytopenia of chronic liver disease. Because measurement of TPO level prior to romiplostim treatment of CIT is standard at our institution, we investigated the utility of baseline TPO level to predict romiplostim response in CIT. METHODS: We performed an observational study of patients age ≥18 years who had TPO levels measured and received romiplostim for the treatment of CIT. For each weekly on-romiplostim platelet (Plt) count assessment, clinical response was defined as Plt ≥75×10 9/L and ≥30×10 9/L above pretreatment baseline. Overall, moderate, and superior classes of treatment response were defined based on response fraction (RF) of weekly Plt assessments meeting clinical response criteria (RF >0, ≥ 0.6, and ≥ 0.8, respectively). Median TPO levels were compared in those patients with and without a moderate response or a superior response using the Mann-Whitney U test. A generalized linear model was used to model the logit transformation of RF to predict response fraction based on TPO level. Receiver operating characteristic (ROC) analysis was performed to identify TPO level thresholds for optimal discrimination of those who achieved moderate and superior responses from those who did not. RESULTS: Patients: 63 patients met inclusion criteria. Baseline patient characteristics are detailed in TABLE 1. Relation of TPO Level and Romiplostim Response: Median (IQR) TPO level was lower in patients who achieved a moderate response to romiplostim versus those who did not, 234 (135-1085) pg/mL versus 665 (244-1970) pg/mL (P=0.034) and lower still in patients who achieved a superior response versus those who did not, 212 (91-690) pg/mL versus 559 (173-1851) pg/mL (P=0.023) (FIGURE 1). A generalized linear model demonstrated a significantly higher predicted response fraction as TPO level declined (P=0.036, Figure 2). TPO level was significantly correlated with lowest effective romiplostim dose (r=0.27, P=0.049). Optimal TPO Thresholds for Predicting Response: Utilizing Youden's index, the optimally discriminant TPO level threshold for moderate response to romiplostim was ≤457 pg/mL, which predicted a 61% probability of response in those with a TPO level ≤457 pg/mL and a 65% probability of non-response in those with a TPO level >457 pg/mL (Figure 3A). The optimally discriminant TPO level threshold for superior response to romiplostim was ≤260 pg/mL, which predicted a 59% probability of response in those with a TPO level ≤260 pg/mL and a 70% probability of non-response in those with a TPO level >260 pg/mL (Figure 3B). A near trivial response rate was associated with extreme TPO elevations (e.g., 7% for TPO level >1978 pg/mL, Figure 3). CONCLUSION: Lower TPO levels predict for a higher likelihood and depth of response to romiplostim in CIT, extreme TPO elevations predict strongly for non-response, and higher doses of romiplostim may be needed in patients with moderate TPO elevations to achieve a response. Considering the significant impact of CIT on patient outcomes as a result of treatment delays and dose reductions, baseline serum TPO level in patients with CIT may be a clinically useful biomarker in predicting response to romiplostim, and therefore potentially useful in guiding patient selection and dosing. Figure 1 Figure 1. Disclosures Kuter: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Up-to-Date: Patents & Royalties: Up-To-Date; Rubius: Current equity holder in publicly-traded company; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding. Al-Samkari: Novartis: Consultancy; Rigel: Consultancy; Moderna: Consultancy; Argenx: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding. OffLabel Disclosure: Romiplostim is a thrombopoietin-receptor agonist (TPO-RA) used off-label for chemotherapy-induced thrombocytopenia. TPO-RAs are well-established in the treatment of numerous etiologies of thrombocytopenia, including immune thrombocytopenia (ITP), aplastic anemia, and thrombocytopenia of chronic liver disease.

Background: The autoimmune disorder immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired production, leading to a predisposition to bleeding and diminished quality of life. Although initially responsive to standard therapy, most patients do not attain durable remission or are challenged by long-term tolerability. Rilzabrutinib is the first oral, reversible Bruton tyrosine kinase (BTK) inhibitor that targets mechanisms driving ITP without effects on normal platelet aggregation. Preclinical studies showed simultaneous rapid anti-inflammatory effects of rilzabrutinib and neutralization and prevention of autoantibody signaling (Langrish J Immunol 2021). In an ongoing phase I/II study, the optimal dose of 400 mg bid rilzabrutinib (± concomitant ITP therapy) was well tolerated and resulted in rapid and durable platelet response across several subgroups of patients and with extended treatment. Study Design and Methods: LUNA3 is the first randomized, multicenter, phase III study evaluating the efficacy and safety of rilzabrutinib vs placebo with open-label extension in adult and adolescent patients with persistent or chronic ITP (NCT04562766; EudraCT 2020-002063-60). Eligible patients must have primary ITP for >6 months if aged 12-17 years or >3 months if aged ≥18 years and an average of 2 platelet counts 35×10 9/L) within 2 weeks prior to study treatment. Additionally, patients should have a previous response (platelet count ≥50×10 9/L) to corticosteroids or intravenous immunoglobulin/anti-D that was insufficient or not sustained, or documented intolerance or insufficient response to any appropriate courses of standard-of-care ITP therapy. Randomization is carried out separately for the 2 age groups (12-17 years and ≥18 years), and then patients are stratified by splenectomy status (yes/no) and thrombocytopenia severity (platelet counts Figure 1 Figure 1. Disclosures Kuter: Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Up-to-Date: Patents & Royalties: Up-To-Date; Rubius: Current equity holder in publicly-traded company; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding. Bussel: CSL: Other: DSMB; UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cooper: Principia and Sanofi: Consultancy; Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses. Gernsheimer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: personal fees ; Amgen: Honoraria; Cellphire: Consultancy; Dova: Consultancy, Honoraria; Principia: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; NHLBI: Research Funding. Lambert: Dova: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PDSA: Research Funding; ClinGen, ISTH, ASH, GW University: Honoraria; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Bayer: Consultancy; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Liebman: Sanofi, Momenta: Research Funding; Alexion, Novartis, Dova: Consultancy. Tarantino: Grifols: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding; Pfizer: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: 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, Speakers Bureau; UCB: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioMarin: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Bandman: Sanofi: Ended employment in the past 24 months. Arora: Principia Biopharma Inc, a Sanofi Company: Ended employment in the past 24 months. Neale: Principia Biopharma: Divested equity in a private or publicly-traded company in the past 24 months; Principia Biopharma/Sanofi: Ended employment in the past 24 months. Burns: Sanofi: Ended employment in the past 24 months. Yao: Sanofi: Current Employment. Ghanima: Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy; Bayer, BMS/Pfizer: Research Funding; Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

Introduction: Key characteristics of immune thrombocytopenia (ITP) include immune-mediated platelet destruction/impaired production, with resultant thrombocytopenia and increased bleeding risk. Durable response to current therapies remains an unmet need, particularly in the relapsed/refractory setting. Rilzabrutinib is the first oral, reversible, covalent inhibitor of Bruton tyrosine kinase designed to target immune-mediated pathways in ITP without inhibiting normal platelet aggregation. Initial phase I/II results in ITP demonstrated rapid and durable efficacy with rilzabrutinib that was well-tolerated at all dose levels, including the optimal 400 mg bid dose. Interim results on rilzabrutinib effects in patients with relapsed/refractory ITP were previously reported. Here we present long-term data from a larger group of patients who initiated rilzabrutinib at 400 mg bid and are continuing in the long-term extension (LTE) period. Methods: This ongoing, global phase I/II study (NCT03395210) enrolled adult patients from 8 countries with relapsed or refractory ITP who previously responded to ≥1 prior ITP therapy. Eligible patients with 2 baseline platelet counts of Results: As of June 1, 2021 in 60 patients, 45 patients initiated rilzabrutinib 400 mg bid and to date, 16 patients with durable, stable response proceeded to LTE at 400 mg bid. At enrollment for patients initiating rilzabrutinib 400 mg bid, median age was 49 y (range, 19-74), median duration of ITP was 6.1 y (range, 0.4-52.5), and median platelet count was 15×10 9/L (range, 2-33×10 9/L). Patients were heavily pretreated with a median of 6 prior treatment events (range, 1-53), including 24% with prior splenectomy. Overall, 18/45 patients (40%) achieved the primary endpoint. In primary responders, platelet counts of ≥30×10 9/L, ≥30×10 9/L with ≥20×10 9/L above baseline, and ≥50×10 9/L were maintained for a median of 95%, 86%, and 72% of weeks, respectively. Median time to first platelet counts of ≥30×10 9/L, ≥30×10 9/L with ≥20×10 9/L above baseline, and ≥50×10 9/L were 8.5 (7-134), 11.5 (7-134), and 12.5 (8-142) days, respectively. According to subgroup analyses, primary platelet responses were consistently >30% irrespective of baseline platelet counts, the use of concomitant therapy, duration of ITP, or number of prior therapies (Table). LTE patients received rilzabrutinib for an overall median duration of 462 days (range, 303-764). At LTE entry, patients had a median platelet count of 87×10 9/L (range, 16-321×10 9/L). In addition to all LTE patients achieving the primary endpoint during the main treatment period, these patients maintained platelet counts of ≥30×10 9/L, ≥30×10 9/L with ≥20×10 9/L above baseline, and ≥50×10 9/L, for a median of 100%, 96%, and 90%, of weeks, respectively, during the LTE period (Figure). Treatment-related treatment-emergent adverse events (TEAEs; all grade 1/2) were reported in 27/45 patients (60%); the most common were 36% diarrhea and 31% nausea, and all others were Conclusion: Oral rilzabrutinib 400 mg bid was well-tolerated and had durable, clinically significant platelet responses across subgroups and with extended treatment in patients with heavily pretreated ITP. Continued study in the ongoing, randomized phase III LUNA3 trial (NCT04562766) will further assess the magnitude and durability of rilzabrutinib's clinical benefit in ITP. Figure 1 Figure 1. Disclosures Kuter: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding; Up-to-Date: Patents & Royalties: Up-To-Date; Rubius: Current equity holder in publicly-traded company; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees. Mayer: Principia: Research Funding. Jansen: 3SBIO, Novartis: Other: Travel, accomodations, expenses; Advisory Board Novartis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Other: Travel, Accommodations, Expenses. McDonald: Bayer, Sobi, Novartis, Amgen, argenx: Honoraria; Grifols: Research Funding. Baker: Roche, Janssen-Celeg: Membership on an entity's Board of Directors or advisory committees; Bayer, Takeda, Pfizer, Daiichi Sankyo, CSL Behring, Roche, Amgen, Celgene, Rigel Pharmaceuticals, Abbvie, Sanofi, MorphoSys AG, Acerta Pharma, Jansen-Cileg, Bristol-Myers Squibb, Boehringer Ingelheim, Portola, Technoclone, Alexion: Research Funding. Bird: Novartis, Amgen: Speakers Bureau. Garg: Amgen Janssen Novartis Sanofi Takeda: Honoraria; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; University Hospital Leicester: Current Employment. Gernsheimer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: personal fees ; Amgen: Honoraria; Cellphire: Consultancy; Dova: Consultancy, Honoraria; Principia: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; NHLBI: Research Funding. Ghanima: Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy; Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria; Bayer, BMS/Pfizer: Research Funding. Bandman: Sanofi: Ended employment in the past 24 months. Arora: Principia Biopharma Inc, a Sanofi Company: Ended employment in the past 24 months. Burns: Sanofi: Ended employment in the past 24 months. Yao: Sanofi: Current Employment. Daak: Sanofi: Current Employment. Sourdille: Sanofi: Current Employment. Thomas: Chinook and Equillium Biopharma: Current holder of individual stocks in a privately-held company; Chinook: Membership on an entity's Board of Directors or advisory committees; Equillium Biopharma: Current Employment; Principia, a Sanofi Company: Ended employment in the past 24 months; Equillium Biopharma: Current equity holder in publicly-traded company. Neale: Principia Biopharma/Sanofi: Ended employment in the past 24 months; Principia Biopharma: Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses; Principia and Sanofi: Consultancy. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD.

Introduction Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet (plt) destruction and/or impaired production. Some patients with ITP are refractory or have inadequate responses to existing therapy. In vitro data have demonstrated that the sera of ~50% of patients with ITP can activate the classical complement pathway (CP) and/or fix complement on plt surfaces. We hypothesized that a primary mechanism of thrombocytopenia in a subset of patients with ITP is CP-dependent, and that CP inhibition with sutimlimab (formerly BIVV009), a humanized monoclonal antibody that selectively inhibits activation of the CP by binding to C1s, should improve thrombocytopenia. Interim results on sutimlimab use in patients with chronic ITP were previously reported. Here we present long-term data from a larger group of patients. Methods Adults with chronic (duration >1 year) severe ITP (plt count ≤30×109/L at screening) with an inadequate response to ≥2 prior therapies were enrolled in an open-label Phase 1 trial. Concomitant ITP medications were allowed if the patient was receiving a stable dose for the last month and unable to sustain plts ≥30×109/L without bleeds. In Part A, patients received sutimlimab on Days 0 and 7, then biweekly for up to 21 weeks, followed by a scheduled 9-week washout to evaluate relapse and eligibility to be re-treated in a long-term extension phase (Part B). Eligibility for Part B included a clinically meaningful response to sutimlimab and no rescue ITP therapy after Dose 2. Results Interim results are as of April 9, 2020. Twelve patients (mean [range] age, 45 [27-66] years; 75% [n=9] female) received ≥1 dose of sutimlimab. Median (range) disease duration at screening was 5 (2-36) years and 4 patients had prior splenectomy. Median (range) prior ITP medications was 4 (2-10). Eight patients had insufficient response to rituximab and 9 had insufficient response to thrombopoietin receptor agonists. Seven patients completed Part A including protocol washout (mean [range] washout time, 3 [0-7] weeks) and 4 were removed early due to the need for rescue therapy or unresponsiveness. Six patients enrolled in Part B (mean [range] duration, 55 [8-83] weeks). In Part A, mean (standard deviation [SD]) plt count increased from 25×109/L (16.9) at baseline to 54×109/L (60.2) 24 hours after sutimlimab initiation and to 139×109/L (157.3) at Day 7 (Figure 1). Mean plt count was maintained at >50×109/L in Part A and 5 (42%) patients achieved overall response (plt count ≥50×109/L and >2-fold increase from baseline on 2 consecutive occasions >7 days apart). Median time to first plt count ≥50×109/L was 2 days. Four (33%) patients achieved complete response (plt count ≥100×109/L on 2 consecutive occasions >7 days apart). Five (42%) patients achieved durable response (plt count ≥50×109/L in ≥50% of visits from Week 5 to 21 and did not use rescue ITP therapy after the second dose until Week 21). Plt responses correlated with changes in CP activity (Figure 1), consistent with CP inhibition. Seven patients fulfilled criteria for Part B. In Part B, mean (SD) baseline plt count before re-treatment was 22×109/L (19.2) and increased to 65×109/L (56.6) at Day 4 and to 126×109/L (155.5) at Day 7 (Figure 1). As of April 9, 2020, in Part A, 9 patients experienced a total of 62 treatment-emergent adverse events (TEAE) and 2 patients experienced a total of 3 treatment-emergent serious adverse events (TESAE), of which 1 TESAE (migraine) was assessed as possibly related to sutimlimab by the investigator. In Part B, 6 patients experienced a total of 51 TEAEs and 1 patient with a history of diverticulitis experienced 1 TESAE of diverticulitis assessed as not related to sutimlimab by the investigator. There were no deaths or thromboembolic events during the study, and no discontinuation of study drug due to an AE. Conclusions Sutimlimab therapy results in a rapid and durable response in plt count in a subset of patients with chronic ITP who had inadequate responses to multiple prior therapies. The response is sustained after more than 1 year of therapy with an acceptable safety profile. This is continued clinical evidence that the complement pathway plays a role in thrombocytopenia in a subset of patients with ITP. These sustained responses suggest ≥1 additional pathophysiologic explanation for the clinical heterogeneity of ITP and provide a strong platform for continued evaluation of CP inhibition in ITP treatment. Disclosures Broome: Alexion Pharmaceuticals, Inc: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding; Cellphire: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Rigel: Honoraria, Research Funding; Sanofi Genzyme: Honoraria, Research Funding. 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. Kuter:Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Shionogi: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; CRICO: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; Protalix Biotherapeutics: Consultancy; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Dova: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Incyte: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Scully:Takeda: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Smith:Bioverativ: Honoraria; Alnylam: Honoraria. Wang:Sanofi: Current Employment. Jiang:Sanofi: Current Employment. Reuter:Pediatric Infectious Disease Society: Other: Member of the vaccine advocacy and social media committees; Sanofi: Current Employment. Daak:Sanofi: Current Employment, Current equity holder in publicly-traded company. Hobbs:Sanofi: Ended employment in the past 24 months.

Background: Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder characterized by a low thrombocyte count, increased risk of bleeding, and fatigue. Immunoglobulin G (IgG) autoantibodies directed against platelet surface antigens can be detected in most patients with ITP. These autoantibodies accelerate platelet clearance, can inhibit platelet production, and may impair platelet function. Current ITP therapies include non-specific immunosuppression (steroids and rituximab), inhibition of platelet clearance (splenectomy, intravenous [IV] immunoglobulins, anti-D globulins, and syk inhibition) or stimulation of platelet production (thrombopoietin receptor agonists). However, steroids have known side effects, such as hypertension and fluid retention. Splenectomy provides sustained remission for a high proportion of patients, but has surgical and infection risks. IgG homeostasis is regulated by the neonatal Fc receptor (FcRn). Efgartigimod, a human IgG1 antibody Fc-fragment, is a natural ligand of the FcRn engineered to competitively bind to FcRn and prevent the recycling of endogenous IgG. In a Phase 2 trial in 38 patients with primary ITP, efgartigimod 5 mg/kg or 10 mg/kg given in 4 weekly IV infusions was well tolerated compared to placebo (Newland AC. Am J Hematol. 2020;95:178-187. NCT03102593). Efgartigimod induced a rapid reduction of total IgG levels associated with clinically relevant increases in platelet counts (up to 63.7% mean change from baseline 3 days after the fourth infusion), and a decreased proportion of patients with bleeding, compared with placebo. Platelet counts ≥50×109/L for >10 cumulative days were observed in 38% of efgartigimod patients and 0 placebo patients. Platelet counts ≥100×109/L were observed in 46% and 39% of patients receiving efgartigimod 5 mg/kg or 10 mg/kg and 1 (8%) patient receiving placebo. These results suggest that targeted IgG reduction with efgartigimod is a potential new treatment modality in primary ITP warranting longer-term Phase 3 evaluation. Study Design and Methods: ADVANCE, a Phase 3, multicenter, randomized, double-blinded, placebo-controlled trial (NCT04188379), will evaluate the efficacy and safety of efgartigimod in adults with persistent or chronic primary ITP. Eligible patients must have a mean platelet count Recruitment: ADVANCE recruitment is ongoing with a target of ~117 patients with chronic primary ITP and up to 39 patients with persistent primary ITP across approximately 80 sites in Europe, Japan, and the US. Trial participants will be eligible for continuation into ADVANCE+, a long-term open-label extension trial (NCT04225156). Figure Disclosures Newland: Sobi: Other: Ad Board; Novartis: Other: Ad Board, Research Funding, Speakers Bureau; Dova Pharmaeceuticals: Other: Ad Board; Grifols: Other: Ad Board; argenx: Other: Ad Board; Amgen: Other: Ad Board, Research Funding, Speakers Bureau; GSK: Research Funding. Liebman:Dova: Consultancy; Pfizer: Consultancy; Rigel: Consultancy; Novartis: Consultancy; argenx: Consultancy; Bristol-Myers: Research Funding; Janssen: Research Funding. McDonald:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Michel:Rigel: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Miyakawa:argenx: Consultancy; Kyowa Kirin: Consultancy; Zenyaku Kogyo: Consultancy; UCB: Consultancy. Parys:argenx: Current Employment. De Haard:argenx: Current Employment. Ulrichts:argenx: Current Employment. Godar:argenx: Current Employment. De Beuf:argenx: Current Employment. Ayguasanosa:argenx: Current Employment. Broome:Alexion: Honoraria; argenx: Honoraria; apellis: Honoraria; sanofi: Honoraria. Kuter:Rigel: Consultancy, Honoraria, Other, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; CRICO: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Shionogi: Consultancy; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Zafgen: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria.

Introduction: Rilzabrutinib is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase (BTK) that targets underlying disease mechanisms of platelet destruction without inhibiting platelet aggregation (common with ibrutinib). The mechanisms of BTK inhibition provide a new approach for treating patients with immune thrombocytopenia (ITP). Completion of dose-escalation study phase determined that the minimally-effective dose was rilzabrutinib 400 mg given twice daily (BID; Kuter. ASH 2019). Methods: This open-label phase I/II study evaluated rilzabrutinib in adults with relapsed ITP who had at least two platelet counts Results: As of May 5, 2020, 32 patients initiated treatment with rilzabrutinib 400 mg BID. The median baseline age was 50 years (range, 21-74) and 97% were classified as having primary ITP. Patients had a median baseline platelet count of 13×109/L, had ITP for a median duration of 7.3 y (range, 0.4-52.5), and were heavily pretreated with a median of 6 prior therapies (range, 1-53; 28% prior splenectomy). Median duration of rilzabrutinib 400 mg BID treatment was 18.0 wk (range, 1.4-24.6). Overall, 14/32 patients (44%) achieved the primary endpoint, and responders maintained platelet counts ≥50×109/L for a median of 71% (range, 33%-100%) of weekly counts. Primary endpoint responses were achieved despite prior splenectomy or lack of response to prior ITP therapies (Table). Independent of the primary response, 67% of all patients were able to achieve clinically meaningful benefit of platelet counts ≥30×109/L. Nine patients continued rilzabrutinib 400 mg BID into the LTE period for an additional median of 20 wk (range, 4-36) of treatment. Four of these LTE patients were on rilzabrutinib monotherapy and 5 on rilzabrutinib with concomitant ITP therapy (n=3 corticosteroids, n=2 romiplostim). Baseline characteristics for the 9 LTE patients were a median duration of ITP of 2.6 y (1.2-14.3) and a median of 5 prior therapies (range, 1-8; 1 patient had a prior splenectomy). Platelet counts of ≥50×109/L in the LTE period were maintained for a median of 100% (range, 36%-100%) of weekly counts (Figure). Treatment-related, treatment-emergent adverse events (TEAEs) were all grade 1/2 in patients initiating rilzabrutinib 400 mg BID; 1 patient each experienced grade 1 diarrhea and grade 1 hypophosphatemia in the LTE period. Conclusions: Oral rilzabrutinib treatment achieved clinically significant platelet responses (≥50×109/L) in patients with heavily pretreated ITP irrespective of splenectomy or lack of response to prior ITP therapy, and maintained responses for the majority of time. In addition, most patients (67%) achieved a clinically meaningful response (platelet counts ≥30×109/L). In patients treated beyond 6 months in the LTE, responses remained consistently reliable (median 100% of weeks). Rilzabrutinib was well tolerated with only grade 1/2 treatment-related TEAEs overall, with only 2 related grade 1 events observed in the LTE period. Continued study is warranted to further demonstrate the magnitude and durability of rilzabrutinib's clinical benefit. Disclosures Kuter: Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Principia: Consultancy, Research Funding; Momenta: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria. Efraim:UMHAT"ST.MARINA": Consultancy, Current Employment, Current equity holder in private company. Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. McDonald:Bayer: Consultancy, Honoraria; Rigel: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Consultancy, Honoraria, Other: Travel Expenses. Bird:Sanofi: Consultancy, Other: (pls note personal honoraria declined for ad board); Principia Biopharma: Other: investigator in clinical studies; Amgen: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Novartis: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Rigel: Other: investigator in clinical studies; CSL-Behring: Other: investigator in clinical studies; Bristol-Myers Squibb Company: Other: investigator in clinical studies; Ablynx: Other: investigator in clinical studies. Regenbogen:Roche: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Garg:Takeda: Consultancy. Kaplan:Celgene: Honoraria; Novartis: Honoraria. Bandman:Principia Biopharma: Current Employment. Burns:Principia Biopharma: Current Employment. Neale:Principia Biopharma: Current Employment. Thomas:Principia Biopharma: Current Employment, Current equity holder in publicly-traded company. Cooper:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Principia: Consultancy, Honoraria. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

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 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 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 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.

Synchrotron radiation micro-X-ray fluorescence (SR-μXRF) is a powerful elemental mapping technique that has been used to map tungsten and zinc distribution in bone tissue. However, the heterogeneity of the bone samples along with overlap of the tungsten L-edge with the zinc K-edge signals complicates SR-μXRF data analysis, introduces minor artefacts into the resulting element maps, and decreases image sensitivity and resolution. To confirm and more carefully delineate these SR-μXRF results, we have employed laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to untangle the problem created by the K/L-edge overlap of the tungsten/zinc pair. While the overall elemental distribution results are consistent between the two techniques, LA-ICP-MS provides significantly higher sensitivity and image resolution compared with SR-μXRF measurements in bone. These improvements reveal tissue-specific distribution patterns of tungsten and zinc in bone, not observed using SR-μXRF. We conclude that probing elemental distribution in bone is best achieved using LA-ICP-MS, though SR-μXRF retains the advantage of being a non-destructive method with the capability of being paired with X-ray techniques, which determine speciation in situ. Since tungsten is an emerging contaminant recently found to accumulate in bone, accurately determining its distribution and speciation in situ is essential for directing toxicological studies and informing treatment regimes. Graphical abstract Tungsten and zinc localization and uptake in mouse femurs were imaged by synchrotron radiation, left, and by laser ablation ICP-MS, right. The increased resolution of the LA-ICP-MS technique resolves the problem of the overlap in tungsten's L-edge and zinc's K-edge.

Introduction Immune thrombocytopenia (ITP) is characterized by platelet (plt) destruction and impaired plt production related to multiple humoral and cell-mediated processes. The heterogeneity of ITP pathogenesis is highlighted by clinical experience that shows up to 20% of patients with ITP have an inadequate response to current therapy and remain at risk of life-threatening bleeds and substantially impaired quality of life. Evidence of activation of the classical complement pathway (CP) by plt autoantibodies has long been recognized in ITP. In vitro studies showed sera from approximately 50% of patients with ITP activated the CP and/or fixed complement on plt surfaces. Inhibition of the CP in vitro with TNT003, a monoclonal C1s antibody, decreases deposition of C3b and C5b-9 on plts when exposed to ITP patient sera. Sutimlimab (formerly BIVV009) is a humanized, monoclonal antibody that selectively inhibits C1s, the proximal mediator of the CP, and has shown clinical activity in other CP-mediated disorders, such as cold agglutinin disease. We hypothesized that a primary mechanism of thrombocytopenia in a subset of patients with ITP is CP dependent, and that CP inhibition with sutimlimab should improve thrombocytopenia. Methods Adult patients with chronic (>1 year of duration), severe ITP with inadequate response to ≥2 prior therapies (plt count [ct] ≤30 × 109/L at screening) were enrolled in an open-label Phase 1 trial. Patients could receive concomitant ITP medication if on a stable dose for the prior month and were unable to sustain plt cts ≥30 × 109/L in the absence of bleeds. Patients received sutimlimab on Day 0, 7, and then biweekly for up to 21 weeks (Part A) followed by a scheduled washout to evaluate relapse and re-treatment response in a re-treatment/continuation arm (Part B) for an additional year. Results All results are presented as of a data cutoff of 14 December 2018. Seven patients received at least 1 dose of sutimlimab. At screening for Part A, mean (range) age was 44.9 (28-65) years and 85.7% (n=6) of patients were female. The mean (range) baseline plt ct for Part A was 27.9 × 109/L (8-57). The mean (range) plt ct 24 hours post-initial dose of sutimlimab was 81.3 × 109/L (1-209). The mean (range) plt ct on Day 7 was 206.3 × 109/L (25-435). Mean plt ct was maintained at >50 × 109/L throughout Part A. Response defined as a plt ct >50 × 109/L measured on 2 separate occasions more than 7 days apart was achieved by 57% (n=4) of patients by Day 14 (Figure). One additional patient achieved a stable plt ct 20-50 × 109/L. The mean (range) C4 level increased from 27.6 (15-45) mg/dL at baseline to 37.3 (26-50) mg/dL at Day 7 after the initial sutimlimab treatment. Four patients completed the protocol washout/re-treatment at the end of Part A and entered Part B. In all of these patients, sutimlimab washout resulted in reoccurrence of thrombocytopenia. Mean (range) time in washout was 4.1 (3-7) weeks. These 4 patients were re-treated in Part B. The mean (range) baseline plt ct at re-treatment was 16.0 × 109/L (5-26). Re-treatment efficacy was observed in patients in Part B. Safety data is available from Part A as of the 14 December 2018 data cutoff. Six patients experienced a total of 30 treatment-emergent adverse events. No patients discontinued Part A early due to an adverse event. Two patients experienced a total of 3 treatment-emergent serious adverse events (SAE), of which 1 SAE of migraine was assessed as possibly related to sutimlimab. There were no thrombotic events. The benefit-risk remained positive for continued investigational use of sutimlimab in ITP. Conclusions In a preliminary analysis of interim data, sutimlimab resulted in a rapid ( Disclosures Broome: Sanofi Genzyme: Honoraria, Research Funding; Cellphire: Research Funding; Rigel: Research Funding; Incyte: Research Funding; Alexion: Honoraria, Research Funding. Röth:Bioverativ: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, 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, Research Funding. Kuter:Daiichi Sankyo: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Principia: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Shire: Consultancy, Honoraria; UCB: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Momenta: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Kezar: Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Scully:Shire/Takeda: Consultancy; Shire: Research Funding; Ablynx/Sanofi: Consultancy; Novartis: Consultancy; Alexion: Consultancy. Smith:Alnylam: Honoraria; Bioverativ: Honoraria. Wang:Sanofi: Employment. Reuter:Pediatric Infectious Disease Society: Other: Social Media Committee, Vaccine Advocacy Committee; Sanofi: Employment. Hobbs:Sanofi-Genzyme: Employment.

The interaction of chloroquine (CQ) and the μ-oxo dimer of iron(III) protoporphyrin IX (ferriheme) in aqueous solution was modeled using molecular dynamics (MD) simulations. Two models of the CQ-(μ-oxo ferriheme) complex were investigated, one involving CQ π-stacked with an unligated porphyrin face of μ-oxo ferriheme and the other in which CQ was docked between the two porphyrin rings. The feasibility of both models was tested by fitting computed structures to the experimental extended X-ray absorption fine structure (EXAFS) spectrum of the CQ-(μ-oxo ferriheme) complex in frozen aqueous solution. The docked model produced better agreement with experimental data, suggesting that this is the more likely structure in aqueous solution. The EXAFS fit indicated a longer than expected Fe-O bond of 1.87Å, accounting for the higher than expected magnetic moment of the complex. As a consequence, the asymmetric Fe-O-Fe stretch shifts much lower in frequency and was identified in the precipitated solid at 744cm(-1) with the aid of the O(18) isomer shift. Three important CQ-ferriheme interactions were identified in the docked structure. These were a hydrogen bond between the oxide bridge of μ-oxo ferriheme and the protonated quinolinium nitrogen atom of CQ; π-stacking between the quinoline ring of CQ and the porphyrin rings; and a close contact between the 7-chloro substituent of CQ and the porphyrin methyl hydrogen atoms. These interactions can be used to rationalize previously observed structure-activity relationships for quinoline-ferriheme association.

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, leads to accumulation of heme intermediates, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) that may result in neurovisceral attacks. ENVISION (NCT03338816) is an ongoing study, evaluating efficacy and safety of givosiran in symptomatic AHP patients in a 6-month double blind (DB) period and a 30-month open label extension (OLE) period. While the efficacy and safety profile of givosiran has previously been reported in the DB period, here its effect through Month 18 of the OLE period is reported. Methods: ENVISION is an ongoing Phase 3 global, randomized, placebo-controlled study. Exploratory efficacy outcome measures in the OLE included composite porphyria attacks (i.e. those requiring hospitalization, urgent care, or IV-hemin at home), ALA/PBG levels and hemin use. In addition, quality of life assessments (Physical Component Summary Short Form-12 [PCS SF-12], EuroQoL Visual analog scale [EQ-VAS]), the Porphyria Patient Experience Questionnaire (PPEQ), and missed days of work were assessed. Analyses were descriptive and represent the timepoint after which all patients completed at least their Month 18 visit (01/10/2020). Results: As of January 10, 2020, 94 patients completed the DB period and 93 patients entered the OLE (placebo/givosiran=46; givosiran/givosiran=47). Mean exposure to givosiran at data cutoff was 12.97 [SD=3.6] months for placebo/givosiran and 18.86 [3.6] months for givosiran/givosiran, with maximum exposure of 25.1 months. Continued treatment in givosiran/givosiran patients led to a median annualized attack rate (AAR) of 0.58 (range: 0-16.2) through Month 18. Patients in the placebo/givosiran group had an AAR of 1.62 (range: 0-11.8) after receiving givosiran for ≥12 months during the OLE period, compared with 10.65 (range: 0-51.6) whilst receiving placebo during the 6-month DB period. The average number of attacks per patient over time following givosiran treatment continued to decline during the OLE period for both groups (Figure 1). Sustained ALA/PBG lowering during the OLE was accompanied by sustained reductions in hemin use, and more than half of the placebo/givosiran patients experienced 0 days of hemin use. Improvements in PCS SF-12 scores at Month 6 (mean change from baseline=+5.1 [SD=9.0]) were maintained at Month 18 (mean change from baseline=+7.0 [7.0]) for givosiran/givosiran patients, with similar improvements observed in placebo/givosiran patients at Month 18 (mean change from baseline=+9.9 [8.2]). Continued givosiran treatment in givosiran/givosiran patients led to further improvements in EQ VAS compared with DB period (mean change from baseline 5.2 at completion of the DB period [SD=22.2] and 13.7 [22.5] at Month 18 during the OLE period), with placebo/givosiran patients also showing improvements at Month 18 (mean change from baseline 8.3 [SD=18.5]). Placebo/givosiran patients reported improvements in PPEQ scores (traveling, social activities, planning future events, household chores, exercise, and treatment satisfaction) since initiating givosiran, comparable to the improvement observed in the givosiran group during the DB period. Additionally there was a decrease in the number of work days missed due to porphyria in the past 4 weeks at Month 6 (mean=6.7 days [SD=7.8], n=20/46) compared with Month 18 (2.5 [5.1], n=23/46), for patients in the placebo/givosiran group who were able to work. The most common related adverse events (AEs) occurring during givosiran treatment were injection site reactions, nausea and fatigue. Hepatic and renal events were both reported in 17% of patients each during givosiran treatment. No new safety concerns occurred in the OLE compared with DB period. Conclusion: In the ongoing OLE period of the ENVISION study, patients receiving long-term treatment with givosiran demonstrated a durable response in clinical efficacy, across a wide range of clinical parameters. Following the initial 6 months of givosiran treatment during the OLE, placebo/givosiran patients had a similar clinical response to that observed in givosiran/givosiran patients in the OLE period through Month 18. The safety profile of givosiran remained acceptable and consistent with that previously observed. Disclosures Kuter: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Dova: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding; Shire: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Rees:AstraZeneca: Other: Data monitoring committee membership; Novartis: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring; Alnylam Pharmaceuticals: Consultancy, Honoraria; Emmanus Medical: Consultancy, Honoraria. Ventura:Alnylam Pharmaceuticals: Consultancy, Honoraria; Recordati Rare Diseases: Consultancy, Honoraria. Balwani:Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording; Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding. Gouya:Alnylam Pharmaceuticals: Consultancy, Honoraria, Other: Scientific meeting. Simon:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Liu:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ko:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Rhyee:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silver:Alnylam Pharmaceuticals: Other: Travel reimbursement, Research Funding; Blue Care Network: Consultancy; Oncology Business Review: Speakers Bureau.

Introduction Epidural and spinal hematoma are rare but potentially devastating complications of neuraxial anesthesia. Individuals with pre-existing bleeding disorders and tendencies are likely at higher risk of these feared complications, however there are currently no comprehensive recommendations to direct the use of neuraxial anesthesia in these patients. Objective Our objectives were to create a set of consensus recommendations to advise clinicians on appropriate treatment thresholds prior to neuraxial anesthesia for patients with a variety of common and uncommon bleeding disorders and tendencies, and to propose safe hemostatic thresholds for administration and removal of neuraxial anesthetics in these individuals. Materials and Methods A steering committee comprised of 14 hematologists, anesthesiologists and methodologists created and refined a set of Delphi statements regarding the use of neuraxial anesthesia in the following pre-existing bleeding disorders and tendencies: von Willebrand disease, immune thrombocytopenia, gestational thrombocytopenia, platelet function disorders, thrombocytopenia associated with hypertensive disorders of pregnancy, coagulation factor deficiencies and fibrinogen disorders. Statements were developed using data obtained from a previously conducted scoping review of existing literature supplemented with the expert opinion of the steering committee in areas where there are minimal published data. Statements include varying hemostatic laboratory parameters in the context of high or low bleeding risk as measured by either a validated bleeding assessment tool (BAT) or pre-defined criteria for excessive bleeding. We plan to recruit approximately 30 international panelists from the fields of hematology and anesthesiology to participate in a modified (i.e. electronic) Delphi technique. Three Delphi rounds will be conducted, during which we will ask panelists to rate their agreement with each Delphi statement on a 5-point Likert scale. Results will be analyzed for statistical consensus, defined as a Cronbach's alpha value of greater than or equal to 0.70. Statements that achieve consensus will be included in the final recommendations. Results Results of the modified Delphi study are pending. Conclusions Administration of neuraxial anesthesia in patients with pre-existing bleeding disorders and tendencies continues to present a significant management challenge for clinicians. We anticipate that the resultant recommendations will become a helpful tool for the future management of neuraxial anesthesia in these patients. Disclosures Martin: Borden Ladner Gervais LLP:Consultancy.Carvalho:Gauss Surgical:Consultancy.Kuter:Dova:Consultancy, Honoraria;Daiichi Sankyo:Consultancy, Honoraria;Actelion (Syntimmune):Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Principia Biopharma:Consultancy, Honoraria, Other, Research Funding;Protalix Biotherapeutics:Consultancy;Shionogi:Consultancy;Protalex:Consultancy, Honoraria, Research Funding;Kezar Life Sciences, Inc:Other, Research Funding;CRICO:Consultancy, Honoraria;Genzyme:Consultancy, Honoraria;Principia:Consultancy, Research Funding;Shire:Consultancy, Honoraria;Shionogi:Consultancy, Honoraria;Sanofi (Genzyme):Consultancy, Honoraria;Incyte:Consultancy, Honoraria;Immunovant:Consultancy, Honoraria;Kyowa-Kirin:Consultancy, Honoraria;Merck Sharp Dohme:Consultancy, Honoraria;Momenta:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;Pfizer:Consultancy, Honoraria;Zafgen:Consultancy, Honoraria;Up-To-Date:Consultancy, Honoraria, Patents & Royalties;UCB:Consultancy, Honoraria;Platelet Disorder Support Association:Consultancy, Honoraria;Argenx:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Bristol-Myers Squibb:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Caremark:Consultancy, Honoraria;Immunovant:Other: Travel Expenses, Research Funding;Alnylam:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Agios:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Amgen:Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Takeda (Bioverativ):Consultancy, Honoraria, Other, Research Funding;Rigel:Consultancy, Honoraria, Other, Research Funding;Protalex:Consultancy, Honoraria, Other, Research Funding.Lavin:Tremeau Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Siemens Healthineers:Other: Speaker's fees;Takeda:Research Funding;Shire:Research Funding.Sholzberg:Takeda:Honoraria, Other: Scientific Advisory Board, Research Funding;Novartis:Honoraria, Other: Scientific Advisory Board;NovoNordisk:Honoraria, Other: Scientific Advisory Board;Octapharma:Honoraria, Other: Scientific Advisory Board, Research Funding;Amgen:Honoraria, Other: Scientific Advisory Board, Research Funding.

Taliglucerase alfa, an enzyme replacement therapy (ERT) approved in several countries for the treatment of adult and pediatric patients with Type 1 Gaucher disease, is the first FDA-approved plant cell-expressed recombinant therapeutic protein for humans. PB-06-004 (NCT00962260) was a multicenter, open-label, expanded access study designed to follow the safety of taliglucerase alfa in patients with Gaucher disease who required ERT and who were previously treated with imiglucerase but had a dose reduction or discontinued due to a shortage of imiglucerase. Eligible patients (aged ≥18 years) with Type 1 Gaucher disease received taliglucerase alfa every 2 weeks for ³9 months at a dose equivalent to their previous imiglucerase dose, before it was reduced or discontinued (Part A), and had the option of continuing treatment for up to 33 months (Part B); a later amendment allowed treatment-naïve patients. Fifty-eight patients received treatment (55.2% male, mean age 46.1 years, mean bi-weekly dose 35.2 U/kg, mean duration 17.8 months); 51 patients previously received ERT, 7 were treatment-naïve. Thirty-six patients completed the study. Hemoglobin concentration and platelet counts were also explored. Most adverse events (AEs) were mild or moderate in severity and not related to taliglucerase alfa; treatment-related AEs were mild and transient in nature. In previously treated patients, mean (SE) hemoglobin concentration was 13.0 (0.3) g/dL at baseline, 13.4 (0.2) g/dL at 9 months, and 13.4 (0.2) g/dL at last follow-up; mean (SE) platelet count was 179,242 (15,344)/mm3 at baseline, 209,727 (17,157)/mm3 at 9 months, and 215,242 (17,867)/mm3 at last follow-up. In treatment-naïve patients, mean hemoglobin concentration and platelet counts increased. In conclusion, taliglucerase alfa was well tolerated for up to 33 months of treatment and demonstrated a durable therapeutic effect, as evidenced by stable or improved hemoglobin concentration and platelet counts in this expanded access study. Disclosures Kuter: BMS: Research Funding; Bioverativ: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Protalex: Research Funding; Novartis: Consultancy; Principia: Research Funding; Amgen Inc.: Consultancy; Argenx: Consultancy; ONO: Consultancy; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wajnrajch:Pfizer Inc: Employment. Hernandez:Pfizer Inc: Employment. Wang:Pfizer Inc: Employment. Chertkoff:Protalix Biotherapeutics: Employment. Zimran:Pfizer Inc: Honoraria; Shire: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

Introduction : Hereditary hemorrhagic telangiectasia (HHT) is a rare hereditary multisystem vascular disorder causing visceral arteriovenous malformations (AVMs) and mucocutaneous bleeding. Chronic gastrointestinal bleeding and epistaxis frequently produce profound iron deficiency anemia refractory to conventional treatment. Patients with HHT have elevations in vascular endothelial growth factor (VEGF), so the anti-VEGF agent bevacizumab, a recombinant, humanized monoclonal IgG1 antibody that binds to and neutralizes circulating VEGF, is a promising systemic HHT therapy. Currently, data pertaining to the efficacy of bevacizumab for the treatment of HHT is limited to case reports and retrospective studies that do not describe the effect of bevacizumab on objective hematologic parameters (Guilhem et al 2017, Iyer et al 2018). As our institution is an HHT center that has developed a pathway for the use of bevacizumab in HHT patients, we performed a retrospective analysis assessing the efficacy of bevacizumab to alleviate chronic bleeding as measured by improvement in hemoglobin concentration, need for red cell transfusions and iron infusions, and epistaxis control. Management of bleeding in HHT patients is an off-label use of bevacizumab. Methods : All HHT patients treated with systemic bevacizumab for chronic bleeding were selected for retrospective analysis. Data was collected for each patient over a 14-month course, divided into a pretreatment period (six months), induction period (two months), and maintenance period (six months) and included demographics, baseline HHT characteristics, epistaxis grade, surgical interventions, bevacizumab dosing, adverse events, hemoglobin, red cell transfusions, intravenous iron infusions, and other anemia and/or bleeding-directed therapies. Additionally, the peak hemoglobin on bevacizumab over the course of all available follow-up was collected for each patient. Our institution's bevacizumab treatment pathway began with an induction phase (5 mg/kg of IV bevacizumab every two weeks for four treatments) followed by a maintenance phase (5 mg/kg administered monthly thereafter). Statistical tests used in data analysis included the paired t-test, Wilcoxon signed rank test, and Fisher's exact test. Results : 13 HHT patients were treated with bevacizumab for chronic bleeding for a median of 13.9 (range, 4.9-30.1) months. Baseline patient characteristics are shown in Table 1 and hematologic parameters during the pretreatment, induction, and maintenance periods are shown in Table 2. Compared with pretreatment values, bevacizumab treatment increased the mean hemoglobin by 4.0 g/dL (95% CI, 2.6-5.3 g/dL) [mean (95% CI) hemoglobin 8.5 (7.8, 9.9) g/dL versus 12.5 (11.2, 13.7) g/dL, p Conclusions : Systemic bevacizumab was highly effective to treat chronic bleeding and iron deficiency anemia in HHT. This study is the first to demonstrate the impact of bevacizumab on objective hematologic parameters, such as hemoglobin and iron infusion requirements. Further study is needed to confirm the benefit magnitude and define optimal dosing, treatment duration, and long-term safety. Disclosures Al-Samkari: Agios: Consultancy. Kuter:Protalex: Research Funding; Rigel: Consultancy, Research Funding; Novartis: Consultancy; Amgen Inc.: Consultancy; Argenx: Consultancy; Bioverativ: Consultancy, Research Funding; BMS: Research Funding; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia: Research Funding; ONO: Consultancy.

Tungsten accumulates in bone but is neither labile nor inert once absorbed. Tungsten’s relatively high cytosolic solubility and availability are problematic given its association with childhood lymphocytic leukemia. In light of tungsten’s technological prevalence, and the increased concern of regulatory agencies, here we characterize the chemical form and localization in mice exposed to tungsten through drinking water. Using X-ray fluorescence spectroscopy, we report accumulation of tungsten in bone tissue with some sites having ~10-fold greater intensities than background levels. The long bone tissue studied includes cortical, cancellous and bone marrow. Persistence of tungsten in cortical bone tissue following removal of the source indicates that it is retained in an insoluble form. The X-ray absorption near-edge structure spectra for tungsten in these tissues indicate that it is no longer in the originally administered form, orthotungstate, but rather resembles the heteropolytungsate species, phosphotungstate. Tungstate accumulates in bone and can be resistant to chelation therapies typically used to remove heavy metals in vivo. Here, tungstate is shown to accumulate in mouse bone tissue in a persistent, insoluble form proposed to be condensed polytungstate.

Carbon monoxide (CO) has long been known as the “silent killer” owing to its ability to form carboxyhemoglobin—the main cause of CO poisoning in humans. Its role as an endogenous neurotransmitter, however, was suggested in the early 1990s. Since then, the biological activity of CO has been widely examined via both the direct administration of CO and in the form of so-called “carbon monoxide releasing molecules (CORMs).” This overview will explore the general physiological effects and potential therapeutic applications of CO when delivered in the form of CORMs.

Interaction of the antimalarial chloroquine (CQ) with ferriprotoporphyrin IX, Fe(III)PPIX, was investigated in aqueous solution (pH 7.4) and as a precipitate from aqueous medium at pH 5.0. In solution, spectrophotometric titrations indicated strong association (logKobs 13.3 ± 0.2) and a Job plot gave a stoichiometry of 1:2 CQ:Fe(III)PPIX. UV–visible absorbance and magnetic circular dichroism spectra of the complex were compared to various Fe(III)PPIX species. Close similarity to the spectra of the μ-oxo dimer, μ-[Fe(III)PPIX]2O, was revealed. The induction of this species by CQ was confirmed by magnetic susceptibility measurements using the Evans NMR method. The observed low-magnetic moment (2.25 ± 0.02 μB) could only be attributed to antiferromagnetically coupled Fe(III) centers. The value was comparable to that of μ-[Fe(III)PPIX]2O (2.0 ± 0.1 μB). In the solid-state, mass spectrometry confirmed the presence of CQ in the complex. Dissolution of this solid in aqueous solution (pH 7.4) resulted in a solution with a UV–visible spectrum consistent with the same 1:2 stoichiometry observed in the Job plot. Magnetic susceptibility measurements made on the solid using an Evans balance produced a magnetic moment (2.3 ± 0.1 μB) consistent with that in solution. Diffusion coefficients of CQ and its complex with Fe(III)PPIX were measured in aqueous solution (3.3 ± 0.3 and 0.6 ± 0.2 × 10− 10 m2·s− 1, respectively). The latter was used in conjunction with an empirical relationship between diffusion coefficient and molar volume to estimate the degree of aggregation. The findings suggest the formation of a 2:4 CQ:Fe(III)PPIX complex in aqueous solution at pH 7.4.

Introduction CAD is a rare autoimmune hemolytic anemia with an estimated prevalence of 16 per 1 million. Hemolysis is driven by activation of the classical complement pathway (CP), resulting in erythrocyte opsonization with predominant extravascular destruction and ensuing anemia. Patients with CAD have an increased early mortality and risk of thromboembolism. There are no approved treatments. 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 alternative and lectin pathways intact. The objective of the Cardinal study (NCT03347396) is to assess efficacy and safety of sutimlimab in adults with CAD who have a recent history of transfusion. Methods Cardinal is a pivotal Phase 3, open-label, single-arm, multicenter study of 26 weeks' duration (Part A) with an ongoing extension (Part B). Data is available from Part A. Patients with confirmed diagnosis of CAD were enrolled. Eligibility criteria included baseline hemoglobin (Hb) ≤10 g/dL, total bilirubin level above normal, and ≥1 blood transfusion in the prior 6 months. Sutimlimab was administered intravenously on Days 0 and 7, followed by biweekly infusions. Patients weighing The primary efficacy endpoint was response rate based on a composite of Hb increase ≥2 g/dL or Hb ≥12 g/dL at treatment assessment (average from Weeks 23, 25, and 26) and transfusion avoidance from Weeks 5 to 26. Secondary efficacy endpoints included change from baseline in hemolytic markers (eg, bilirubin) and quality of life (QOL) measured by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale. The proportion of responders for analysis of the primary endpoint was calculated with a 95% exact Clopper-Pearson confidence interval (CI). All secondary endpoints were analyzed using descriptive statistics, frequency, percentage, or CIs. Results Twenty-four patients enrolled and received ≥1 dose of sutimlimab. The mean (standard deviation) age was 71.3 (8.2) years with 62.5% females. Mean (range) baseline Hb was 8.6 (4.9-11.1) g/dL. The median (range) number of transfusions within 6 months prior to enrollment was 2 (1-19) and 62.5% of patients had failed prior therapies. Out of 24 patients, 22 completed Part A; 2 patients were withdrawn early for reasons unrelated to the study drug. The estimated mean (standard error [SE]) Hb increase at treatment assessment time point was 2.6 (0.4) g/dL. Hb improved rapidly after the first dose of sutimlimab with 1.2 g/dL and 2.3 g/dL increases by Weeks 1 and 3, respectively. Mean overall Hb was maintained above 11 g/dL after Week 3 (Figure 1A). Twenty (83.3%) patients had a mean Hb increase ≥1 g/dL. Mean total bilirubin was normalized by Week 3. Seventeen (70.8%) patients remained free of transfusions from Weeks 5 to 26. FACIT-F scores improved within 1 week, peaking by Week 5, and remained stable through Week 26. The estimated mean (SE) FACIT-F score increase at the treatment assessment time point was 10.9 (1.4), consistent with a clinically meaningful response. Hb, bilirubin, and FACIT-F improvements correlated with rapid normalization of complement C4 and near-complete inhibition of CP activity (Figure 1B). The prespecified primary endpoint was met (13 [54.2%] patients). Twenty-two (91.7%) patients experienced ≥1 treatment-emergent adverse event (TEAE), with 7 (29.2%) patients experiencing a serious TEAE (TESAE). There were no TESAEs assessed as related to sutimlimab. There was 1 death in a patient with hepatic cancer that was assessed as unrelated to the study drug. Serious infections were reported, but no meningococcal infections were identified. There were no thromboembolisms and decreases in mean D-dimer and thrombin-antithrombin III complex thrombotic markers were observed. All 22 patients that completed Part A enrolled in Part B. Conclusions The Phase 3 Cardinal study shows that sutimlimab, a first-in-class selective inhibitor of the CP, has a rapid and sustained treatment effect in CAD by preventing hemolysis, significantly increasing Hb, and improving QOL (FACIT-F). These results demonstrate that targeting the CP represents a novel, effective therapeutic approach for the management of CAD and indicate that sutimlimab has the potential to change treatment practices for patients with this condition. Disclosures Röth: Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. D'Sa:Janssen: Honoraria, Research Funding. Miyakawa:Bioverativ: Consultancy; Sanofi: Consultancy. Broome:Cellphire: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Bioverativ a Sanofi Company: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Rigel: Honoraria, Research Funding; Sanofi Genzyme: Honoraria, Research Funding. Michel:Bioverativ: Consultancy; Alexion: Consultancy; Rigel: Consultancy. Kuter:Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Massachusetts General Hospital: Employment; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; UCB: Consultancy, Honoraria. Jilma:TrueNorth a Bioverativ company, a Sanofi company: Consultancy, Research Funding. Tvedt:Ablynx, alexion and novartis: Consultancy. Lin:Sanofi: Employment. Jiang:Sanofi: Employment. Reuter:Pediatric Infectious Disease Society: Other: Social Media Committee, Vaccine Advocacy Committee; Sanofi: Employment. Hobbs:Sanofi-Genzyme: Employment. Berentsen:Apellis: Consultancy, Honoraria; Alexion: Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Mundipharma: Research Funding; True North Therapeutics: Consultancy, Honoraria.

Background: Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impairment of platelet production, leading to downstream thrombocytopenia, a predisposition to bleeding, and adverse impact on patient quality of life. Unmet needs in relapsed or refractory ITP are to improve remission rates and durability through targeting underlying disease mechanisms. PRN1008 is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase (BTK) that modulates immune-mediated processes in ITP. Preclinical PRN1008 data showed inhibition of B-cell receptor-mediated activation of human B cells, Fc receptor (Fc-gamma and Fc-epsilon)-mediated activation of immune cells, and dose-dependent reduction in platelet loss in a mouse ITP model. In platelets from normal healthy volunteer and ITP patients, clinically-relevant concentrations of PRN1008 showed no platelet aggregation or interference with other platelet agonists, in contrast to ibrutinib (Langrish et al. ASH 2017:1052). Methods: This is an ongoing open-label, adaptive, intra-patient dose-escalation, phase I/II study of PRN1008 in adult patients with relapsed or refractory ITP (primary or secondary) who previously responded to ≥ 1 prior ITP therapy and have no available therapeutic options (NCT03395210). Eligible patients have two platelet counts < 30,000/µL within 15 days prior to treatment. Oral PRN1008 starting doses were 200 mg QD, 400 mg QD, 300 mg BID (total 600 mg daily), and 400 mg BID (total 800 mg daily), with intra-patient dose escalation allowed every 4 weeks (maximum 400 mg BID) as needed for efficacy. Stable doses of concomitant corticosteroids and thrombopoietin-receptor agonists (TPO-RA) are permitted. The primary end point is the proportion of patients with ≥ 2 consecutive platelet counts (separated by ≥ 5 days) of ≥ 50,000/µL and increased by ≥ 20,000/µL from baseline without requiring rescue medication. Results: A total of 21 patients have been enrolled to date at starting doses of 200 mg QD (n=9), 400 mg QD (n=1), 300 mg BID (n=5), and 400 mg BID (n=6). As of 15 July 2019 data cut-off, 11 patients were receiving ongoing treatment, 4 completed the study, and 6 patients withdrew (2 due to patient decision, 2 from non-treatment-related adverse events [AEs], 1 erroneously enrolled, and 1 because of rescue medication use). Patients had a median age of 54 y (range, 30-65), 4 (19%) had a prior splenectomy, 19 (90%) were diagnosed with primary ITP, and 2 (10%) with secondary ITP. Patients had ITP for a median of 8.3 years (range, 0.5-42.4) and had received a median of 4 prior ITP therapies. Median platelet count at study entry was 14,173/µL (range, 2,670-27,000/µL). During the study, 6 (29%) patients received PRN1008 monotherapy; 15 (71%) patients were on ≥ 1 concomitant ITP medication. Related treatment-emergent AEs (TEAEs) were reported by 4 (19%) patients; all were grade 1 or 2. The most frequent related TEAEs were nausea, diarrhea, and abdominal distension. There were no treatment-related bleeding or thrombotic events, and no significant changes in the ITP-BAT bleeding scale between baseline and the last visit. There were no dose limiting toxicities (DLT). Patients had received treatment for a median of 10.1 weeks (range, 0.1-31.0). Overall, 7 (33%) patients achieved the primary endpoint across all doses (Table). Patient responses were improved at the 2 higher doses. In 10 patients who had reached ≥ 12 weeks of treatment, ≥ 50% of patients had platelet counts of ≥ 50,000/µL and ≥ 20,000/µL increases from baseline. Conclusion: Overall, PRN1008 was active in 33% of ITP patients who were refractory to multiple treatments with no alternative therapeutic options. This result was demonstrated despite the limited duration of treatment and including patients at all dose levels. In addition, patients treated for longer periods of time have substantially improved response rates that support continued interest in this ongoing study. The safety profile was tolerable at all studied doses whether given as a monotherapy or with allowed concomitant ITP therapy. Importantly, TEAEs were grade 1 or 2 with no thrombotic events. The dose-escalation portion of the study is complete; enrollment is expanding at the 400 mg BID starting dose for a duration of 24 weeks to further characterize treatment benefit and for continued treatment beyond 24 weeks in patients who have responded. Disclosures Kuter: Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Boccia:AstraZeneca: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; AMAG: Consultancy; Genentech: Speakers Bureau; DSI: Speakers Bureau. Lee:Weill Cornell Medical College: Employment. Tzvetkov:UMHAT Georgi Stranski: Employment; DCC Pleven: Consultancy. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Kostal:Novartis: Honoraria; AOP: Honoraria; University Hospital in Hradec Kralove, Czech Republic: Employment. 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; AbbVie: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; PharmaMar: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. McDonald:Bayer: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Bandman:Principia Biopharma: Employment, Equity Ownership, Patents & Royalties: Institutional with Incyte and Portola, no royalties. Burns:Principia BioPharma: Employment. Neale:Principia BioPharma: Employment, Equity Ownership. Thomas:Principia Biopharma: Employment, Equity Ownership; BMS: Equity Ownership; Pfizer: Equity Ownership. Cooper:Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Disclosure: Yes, this was an investigational clinical phase I/II study of PRN1008 in patients with relapsed/refractory ITP. Phase I dose escalation phase is now complete and expanded phase II studies ongoing.

Introduction. wAIHA is a rare and often serious disease in which red blood cells (RBCs) coated with autoantibodies bind to Fcγ receptor-bearing macrophages, triggering a spleen tyrosine kinase (SYK) dependent signaling pathway that leads to RBC phagocytosis. Fostamatinib is a potent SYK inhibitor administered orally that was approved by the US FDA for the treatment of chronic ITP in adults. A phase 2, multicenter, open-label study (the SOAR study; NCT02612558) evaluated the response to fostamatinib in adult patients with wAIHA. We report the final results of the initial 24-week treatment period and the extension period of the phase 2 study. Methods. The study included adult patients with primary or secondary wAIHA, documented by IgG positive direct antiglobulin test (DAT), who had: failed ≥1 prior treatment for wAIHA, hemoglobin (Hgb) ULN (upper limit of normal). Patients were initiated on fostamatinib at 150mg BID with dose reduction permitted based on tolerability. Patients were seen every 2 weeks for 12 weeks, then every 3 weeks for 12 weeks, and every 6 weeks thereafter. The primary efficacy endpoint was achieving Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion. Patients who responded or showed clinical benefit were allowed to enter the extension period as long as they were tolerating the study drug. Results. The study included 25 evaluable patients (15 women) with median age 61 (range 27-88) years, median duration of wAIHA of 2 years ( Eleven of 25 (44%) achieved the primary efficacy endpoint by Week 24 plus 1 late responder at Week 30 (total of 12 responders [48%]). Increases in median Hgb were generally detected at Week 2 (first visit) and sustained over time, with 24% achieving the primary endpoint by Week 2 (Figure). Median Hgb of responders increased by >2.0 g/dL from baseline by Week 4 vs. no change for nonresponders. 13 eligible patients entered the extension period of the study, including 9 of 11 responders, 1 late responder, and 3 patients with a beneficial trend. Seven patients are still on treatment, and 6 discontinued the study, including 3 who withdrew, 1 was lost to follow up, and 2 had a loss of response (1 of whom also had increased alanine aminotransferase). Overall, adverse events (AE) were manageable and consistent with the fostamatinib safety database of >3500 patients across all disease programs. No new safety signals were detected. The most common AEs during the initial treatment period were diarrhea in 9, fatigue in 8, hypertension in 7, and dizziness in 6. AEs were mostly mild to moderate. Seven patients had serious AEs, including anemia, acute myocardial infarction, fall, Hgb decreased, inappropriate secretion of antidiuretic hormone, infection, pneumonia, rhabdomyolysis, sepsis, skin necrosis, and systemic inflammatory response syndrome. Two patients had AEs leading to death: one had infection with skin necrosis and calciphylaxis; the other had pneumonia. Neither were considered related to treatment, and both patients were immunosuppressed due to steroids. Six subjects (24%) received rescue therapy, including RBC transfusion, prednisone and/or immunoglobulins. Conclusions. In this phase 2, multicenter, open-label study, fostamatinib markedly improved Hgb levels in 48% of 25 evaluable patients with wAIHA. Adverse events were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure Disclosures Rogers: Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Boxer:Arizona Oncology: Employment; Incyte: Speakers Bureau; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau; Gerson Lerman: Consultancy; Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Arnold:Novartis: Honoraria, Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy; Bristol-Myers Squibb: Research Funding. Broome:Cellphire: Research Funding; Alexion: Honoraria, Research Funding; Incyte: Research Funding; Sanofi Genzyme: Honoraria, Research Funding; Rigel: Research Funding. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Murakhovskaya:Momenta: Membership on an entity's Board of Directors or advisory committees. Chow:Rigel: Employment, Equity Ownership. Numerof:Rigel: Employment, Equity Ownership. Zheng:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Kuter:Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Kezar: Research Funding; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of fostamatinib in other diseases is off-label.

Introduction : Complement activation contributes to platelet destruction in immune thrombocytopenia (ITP). Autoantibodies bound to platelets fix complement (Naiaoui et al. 2011) and ITP platelets have increased cell surface-bound C3 and C4 (Kurata et al. 1985). Despite this known pathophysiology there is very little published data describing serum complement levels in ITP patients and no data describing a possible relation of complement levels to disease characteristics. Therapeutics targeting the complement system are now emerging for the treatment of ITP, including an ongoing clinical trial of the C1 esterase inhibitor sutimlimab (BIVV009). ITP patients with major complement-mediated platelet destruction as revealed by low serum complement levels may be more likely to respond to anti-complement therapies. With this background, we aimed to characterize the serum complement levels of C3, C4, and total hemolytic complement (CH50) in a large cohort of ITP patients and explore the relation of these levels to clinical features in 108 adults with ITP. Complement measurements from 120 healthy adult subjects were used for comparison. ITP patient data was collected retrospectively as standard clinical serum complement evaluation has been a routine part of initial patient evaluation at our ITP center for the past two years. Methods : Serum C3, C4, and CH50 were measured using a commercially-available turbidimetric assay (Optilite System, Binding Site, Birmingham, UK). Reference ranges were: C3, 81.1-157.0 mg/dL; C4, 12.9-39.2 mg/dL; CH50, 41.7-95.1 U/mL. Data collected for analysis included dates and results of complement testing (including disease status and platelet count at time of testing), patient demographics, and disease characteristics. Satisfaction of the 2011 American Society of Hematology (ASH) ITP diagnostic criteria were required for ITP patient inclusion and ASH ITP guideline definitions of disease severity and treatment response were used. Patients with other disorders known to reduce complement (e.g. systemic lupus) were excluded. Wilcoxon rank-sum tests and t-tests were used to compare groups. Multivariate logistic regression was used to model the probability of low complement levels based on disease severity and platelet count as well as model the probability of treatment response based on complement levels. Results : A total of 98 C3 assays, 97 C4 assays, and 102 CH50 assays from 108 ITP patients (92 patients had all three assays performed) were collected and compared with results from 120 healthy subjects obtained from the assay manufacturer. Of ITP patients, mean (range) age was 53 (18-89) years, 54% were female, 16% were splenectomized, and 52% were receiving ITP-directed treatment at the time of complement testing. 32% of patients had levels of one or more complement assay below the reference range and 10% had low levels of all three assays. Mean serum C3, C4 and CH50 were significantly lower in ITP patients relative to healthy subjects (Table 1, Figure). On subgroup analysis, patients requiring treatment for ITP had significantly lower serum C4 and CH50 and splenectomized patients had significantly higher serum C3 (Table 2). Multivariate logistic regression analyses including age, sex, splenectomy status, disease severity, platelet count at time of complement assay, and results of complement testing demonstrated a relation between low C4 levels and presence of severe or refractory disease (relative to non-severe disease, OR for severe/refractory disease 6.28, 95% CI 0.75 to 52.54, P=0.090) and low C3 levels and platelet count (odds ratio (OR) for low C3 per 10×109/L reduction in platelet count, 1.04, 95% CI, 0.99 to 1.08, P=0.057). Multivariate logistic regression models including age, sex, splenectomy status, platelet count, treatment response, and results of complement testing did not demonstrate a relation between complement levels and response to corticosteroids, IVIG, or thrombopoietin receptor agonists. Conclusions : ITP patients have significantly lower serum C3, C4, and CH50 than healthy subjects, with the overall difference driven by the one-third of ITP patients with substantial reductions. We observed a relation between low C4 and more severe disease and low C3 and reduced platelet counts. Patients requiring treatment had significantly lower C4 and CH50 relative to those not requiring treatment, and splenectomized patients had significantly higher C3. Disclosures Kuter: Protalix: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kezar: Research Funding; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding. Al-Samkari:Moderna: Consultancy; Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Introduction : Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare hereditary multisystem vascular disease of disordered angiogenesis. Pathologic elevations in vascular endothelial growth factor (VEGF) result in fragile, abnormal vessels in nasal and gastrointestinal (GI) mucosa causing recurrent epistaxis, chronic GI bleeding, and anemia that is often transfusion-dependent. Bevacizumab is a monoclonal IgG1 antibody that neutralizes circulating VEGF and is a potential targeted anti-angiogenic treatment in HHT, which has no FDA-approved therapy. Data for use of intravenous (IV) bevacizumab in HHT is currently limited to case reports and small single-center retrospective case series. The International HHT Intravenous Bevacizumab Investigative Team study of Bleeding (InHIBIT-Bleed) is an international collaboration of HHT Centers seeking to more definitively describe the safety and effectiveness of systemic bevacizumab to treat chronic bleeding and anemia in HHT. Methods : The following data was retrospectively collected at each participating center for all HHT patients treated for at least 3 months with off-label systemic bevacizumab for chronic bleeding: demographics, baseline HHT characteristics, epistaxis severity score (ESS, a validated 10-point scale to evaluate epistaxis in HHT), bevacizumab dosing, treatment-emergent adverse events (TEAEs), hemoglobin (Hgb), red blood cell (RBC) transfusions, and IV iron infusions. Hgb and ESS at baseline were compared with post-bevacizumab values at 3, 6, 9, and 12 months with the paired t-test. RBC transfusion and iron infusion requirements before and after bevacizumab treatment were compared with the Wilcoxon signed rank test. Results : 140 HHT patients were treated with IV bevacizumab for chronic bleeding for a median of 23 (range, 3-96) months with a median of 12 (range, 2-74) total infusions. Bevacizumab was dosed at 5 mg/kg every 2 weeks for the first 2 months, then monthly for 4 months; following this, maintenance dosing practices varied depending on center. Baseline patient characteristics are given in Table 1. After bevacizumab initiation, patients with baseline anemia (Hgb Conclusions : We present results of IV bevacizumab treatment of chronic bleeding and anemia in a large cohort of 140 HHT patients, demonstrating that bevacizumab was highly effective, with an improvement in mean Hgb of 3.9 g/dL, dramatic reduction in ESS, and decrease in RBC transfusion and iron infusion requirements by 86% and 66%, respectively. Effectiveness was maintained over time. Safety analysis included a total of 194 patient-years of IV bevacizumab administration to HHT patients and had low TEAE rates with only 4% discontinuing treatment due to TEAEs. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Moderna: Consultancy; Dova: Consultancy, Research Funding. Kuter:Caremark: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Agios: Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kezar: Research Funding; Shire: Consultancy, Honoraria; Kezar: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Momenta: Consultancy, Honoraria. OffLabel Disclosure: The presentation will discuss off-label use of systemic bevacizumab for the treatment of chronic bleeding and anemia in hereditary hemorrhagic telangiectasia.

Background Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count ( Methods After a 2-week screening period, patients were randomized 1:1:1 to receive 4 weekly intravenous infusions of either placebo or efgartigimod at a dose of 5 mg/kg or 10 mg/kg. Following periods included 8-week follow-up, up to 13 weeks extended follow-up, and a 1-year open-label extension (OLE) where patients could be treated with efgartigimod 10 mg/kg (Figure 1). Patients aged 18 to 85 years with confirmed primary ITP, and an average of 2 platelet counts ˂30×109/L during screening (with no single reading >35×109/L), were recruited. Oral corticosteroids, oral immunosuppressants, and/or thrombopoietin receptor agonists at stable doses were permitted. The primary endpoint was safety. Secondary endpoints included pharmacodynamic (PD) markers, pharmacokinetic (PK) parameters, presence of anti-drug antibodies (ADA) and autoantibodies, and efficacy. Data for all endpoints were summarized by group using descriptive statistics. Data until the last visit of the first treatment cycle of the OLE period are reported. Results Thirty-eight patients (placebo [N=12], efgartigimod at a dose of 5 mg/kg [N=13] or 10 mg/kg [N=13]), mostly with longstanding ITP (median disease duration 4.8 [0.1-47.8] years) who had insufficient response to prior ITP therapy or failed splenectomy (N=6), were randomized. Twenty (52.6%) patients had a baseline platelet count Efgartigimod was well tolerated with no dose-related safety observations and the safety profile was consistent with previous observations in healthy volunteers. No increased risk of infection was apparent. Low positive pre- and post-dose ADA titers were measured in all groups and did not have an apparent effect on PK/PD parameters. Treatment with efgartigimod resulted in a rapid reduction of total IgG (up to 63.7% mean change from baseline) and all IgG subtypes in all treated patients. Autoantibodies were identified in all patients and were reduced following efgartigimod treatment. Efgartigimod-treated groups achieved a higher maximum mean platelet count change from baseline compared to the placebo group. A higher proportion of efgartigimod-treated patients achieved a platelet count of ≥50×109/L and ≥100×109/L at any time compared to the placebo group (Figure 2). Forty-six percent patients on efgartigimod vs. 25% on placebo achieved a platelet count of ≥50×109/L on at least 2 occasions and 38% vs. 0% achieved ≥50×109/L for at least 10 cumulative days. A decreased incidence of bleeding, measured using WHO and ITP-BAT scales, was observed in both efgartigimod-treated groups. In the OLE period, in which 12 patients received efgartigimod 10 mg/kg, 8 (66.7%) patients achieved platelet count ≥50×109/L on at least 2 occasions. Conclusion A short 3-week treatment cycle of efgartigimod in patients with ITP predominantly refractory to previous lines of ITP therapy was well tolerated, markedly reduced IgG levels, was associated with clinically relevant increases in platelet counts, and reduced the proportion of patients with bleeding (Figure 3). This suggests that targeted IgG reduction with efgartigimod is a potential new treatment modality in primary ITP, and warrants evaluation of longer-term treatment in a larger Phase 3 study. Disclosures Newland: Novartis: Consultancy, Honoraria, Research Funding; Angle: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria; Dova: Consultancy, Honoraria. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Godar:Argenx: Employment. Verschueren:Argenx: Consultancy. Gandini:Argenx: Employment, Equity Ownership. Ulrichts:Argenx: Employment. Beauchamp:Argenx: Employment. Dreier:Argenx: Employment. Ward:Argenx: Equity Ownership, Honoraria, Research Funding. Michel:Rigel: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Liebman:Pfizer: Consultancy; Dova: Consultancy; Bristol-Myers: Research Funding; Argenx: Consultancy; Rigel: Consultancy; Janssen: Research Funding; Novartis: Consultancy. De Haard:Argenx: Employment, Equity Ownership, Patents & Royalties. Leupin:Argenx: Employment, Equity Ownership, Patents & Royalties. Kuter:Dova: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Kezar: Research Funding; Kezar: Research Funding; Shire: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Shinogi: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; UCB: Consultancy, Honoraria.

BACKGROUND: Myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and polycythemia vera (PV) are commonly diagnosed in the sixth decade, but as many as 20% of patients are younger than 40. This introduces the possibility of pregnancy and need for specialized management. ET/PV patients have a higher risk of pregnancy complications, with a reported 68.5% live birth rate (LBR), and 1.8% and 2.4% risk of major thrombotic and bleeding events respectively. Risk factors for pregnancy complications are conflicting, and further contemporary studies are needed. METHODS: We retrospectively analyzed 130 pregnancies in 58 ET/PV women seen at 3 affiliate hospitals from 1995-2019. Patients were identified using ICD-9/10 codes in the electronic medical record. We analyzed 12 input variables as risk factors associated with first pregnancy complications after MPN diagnosis by univariate logistic regression (α=0.1, type I error rate; Table 1a). Variables with p RESULTS: The analysis included 53 ET patients and 5 PV patients. Driver mutation status for JAK2, CALR, or MPL was available in 79% of all patients: 60.3% were JAK2+ and 12.1% were CALR+. 2 patients were high-risk by International Prognostic Score of thrombosis (IPSET). Median maternal age was 34, median year of delivery was 2010, and median time between MPN diagnosis and index pregnancy was 3 years. There were no complications in 46% of pregnancies. The LBR was 70%. Aspirin (ASA) and interferon were used in 58.5% and 1.5% of pregnancies, respectively. In the pregnancies that resulted in live birth, postpartum low-molecular-weight heparin (LMWH) was used in 23.5% of cases. Antepartum LMWH was used in 6.9% of cases. PV patients were more likely to be treated with ASA (p=0.039) or postpartum LMWH (p=0.013) compared to ET patients. The most common complication was spontaneous abortion (SAB), defined as fetal loss On univariate analysis, only history of miscarriage prior to MPN diagnosis (13.2% of women) and ASA use during pregnancy were significantly associated with outcomes. On multivariate analysis, history of prior miscarriage remained statistically significant (OR 8.82, p=0.023), while ASA use during pregnancy trended toward improved outcomes (OR 0.33, p=0.12). All other variables were not significantly associated with pregnancy outcomes (Table 1a). Cell counts throughout pregnancy were available in 53 ET patients (Figure 1). There was a significant decline in platelets (p CONCLUSIONS: In this contemporary analysis of pregnancy outcomes in 130 ET/PV women, we demonstrate that overall prognosis is good, with a LBR of 70%. However, pregnant ET/PV patients remain at high risk, with SAB and complication rates of 24.6% and 54%, and maternal thrombosis and hemorrhage occurring in 2.3% and 6.9% of pregnancies. We show for the first time that prior miscarriage is a significant predictor of pregnancy complication in MPN patients (OR 8.82). Cell counts have never been systematically evaluated in MPN patients throughout pregnancy. We found that platelet counts decrease dramatically, often to normal, in ET. Platelet recovery occurs quickly in the postpartum period, with most patients returning to 75% of their baseline platelet count by one month postpartum. The observed 43% platelet nadir from starting counts to the day of delivery is greater than the expected 20% platelet decrease in the normal pregnant population. This decrease is unlikely to be explained by hemodilution, as the observed Hg decrease in ET patients approximates that seen in normal women. While we found no effect of JAK2 or CALR mutation status on pregnancy complications, it is possible that changes in allele burden influence platelet trends and outcomes. Measuring these changes in available women is the next step in our investigation. Disclosures Bustoros, MD: Takeda: Honoraria. Connell:Michael H. Flanagan Foundation: Membership on an entity's Board of Directors or advisory committees. Connors:Bristol Myer-Squibb: Consultancy, Other: Scientific Ad boards; Portola: Other: scientific ad boards; Abbott: Consultancy; Eli Lilly: Consultancy. Kuter:Argenx: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kezar: Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Kezar: Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; UCB: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding. Mullally:Janssen: Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Zwicker:Daiichi: Consultancy; Quercegen: Research Funding; Parexel: Consultancy; Portola: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy; Bayer: Consultancy. Hobbs:Jazz pharmaceuticals: Consultancy; Bayer: Research Funding; Merck: Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Agios: Consultancy.

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and potentially serious disease in which autoantibodies bind to red blood cells (RBCs), leading to phagocytosis by Fc receptor-bearing macrophages via a spleen tyrosine kinase (SYK) dependent signaling pathway. Fostamatinib is a potent SYK inhibitor that is orally administered and was approved for the treatment of chronic ITP in April 2018 by the US FDA and has demonstrated activity in patients with wAIHA. A phase 2, open-label, multicenter study (NCT02612558) showed that 11 of 25 (44%) patients with wAIHA had markedly improved hemoglobin (Hgb) levels after treatment with fostamatinib. Adverse events (AEs) from the phase 2 studies in wAIHA were manageable and consistent with those in the fostamatinib safety database of >3500 patients across multiple disease states. Therefore, the phase 2 results support the conduct of a phase 3 study in wAIHA. A phase 3, randomized, double-blind, placebo-controlled global study (NCT03764618) to investigate the safety and efficacy of fostamatinib in subjects with wAIHA is currently enrolling patients. The study intends to enroll approximately 80 patients at 109 sites in 19 countries across North America, Europe and Australia. This is the first randomized, double-blind, placebo-controlled study to explore the effect of a SYK inhibitor in the treatment of wAIHA. Study Design and Methods Inclusion Criteria: Eligible adult patients must have: primary or secondary wAIHA, documented by IgG or IgA positive direct antiglobulin test (DAT); failed ≥1 prior treatment for AIHA; haptoglobin ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN; and baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to Exclusion Criteria: Patients should not have other types of AIHA, uncontrolled or poorly controlled hypertension, a neutrophil count 1.5 x ULN. Treatment: Patients will be randomized 1:1 to receive fostamatinib or placebo for 24 weeks. Patients will receive an initial dose of 100 mg BID which will be increased to 150 mg BID at Week 4, based on patient tolerability. In the event of dose-limiting AEs, the dose may be reduced at any time. Randomization will be stratified by concomitant steroid use at baseline and severity of anemia at screening. All patients will be allowed to continue concurrent steroid therapy and other selected wAIHA therapy (maximum of 2) throughout the 24-week study. A rescue medication protocol is allowed as needed. A steroid taper protocol allows reduced used of steroids in responsive patients. Patients who complete the phase 3 study will be encouraged to enroll in an open-label extension study to receive fostamatinib. Endpoints: Efficacy endpoints will include hemoglobin response, defined as a hemoglobin level >10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue medication; duration of hemoglobin response; and use of wAIHA rescue therapy. Safety endpoints include the incidence of adverse events. Patients will be evaluated at clinic visits approximately every two weeks for safety assessments and measurement of hemoglobin levels. Statistics: Based on results of the phase 2 study, a sample size of 80 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05. The response rate will be compared between groups using a chi-square test adjusting for randomization stratification factors. Figure Disclosures Cooper: Amgen: Consultancy, Honoraria, 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; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gorham:Rigel: Employment, Equity Ownership. Lowe:Rigel: Consultancy. Numerof:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Kuter:Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Shinogi: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Pfizer: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Momenta: Consultancy, Honoraria; Kezar: Research Funding; Pfizer: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Shire: Consultancy, Honoraria. OffLabel Disclosure: Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of fostamatinib in other diseases is off-label.

In order to better understand the interaction of antimalarial compounds with ferriprotoporphyrin IX (Fe(III)PPIX), association constants of pyridines, imidazoles, amines and phenolates with Fe(III)PPIX and protoporphyrin IX (PPIX) have been measured spectrophotometrically in 40% (v/v) aq. DMSO at pH 7.4. The pH independent log association constants for coordination of nitrogen donor ligands exhibit a linear free energy relationship (LFER) with the pKa of the donor atom. Association through π-stacking interactions (log Kπ) with PPIX and Fe(III)PPIX increases with the number of π-electrons in the aromatic ring system. These findings indicate that in the aqueous milieu of the malaria parasite digestive vacuole, coordination to the Fe(III) center of the porphyrin is necessarily very weak, while π-stacking interactions will be much stronger. On the other hand, in environments in which proton competition is absent, coordination will dominate, with the most basic donor atoms forming the strongest complexes with Fe(III)PPIX. The lipid nanospheres within the digestive vacuole which are now known to be the location of conversion of Fe(III)PPIX to hemozoin could possibly be such an environment, making both types of interaction relevant to the design of new hemozoin inhibitors.

Introduction : Antiplatelet antibody (APA) testing is considered an adjunct laboratory test in the diagnosis of immune thrombocytopenia (ITP). While it is not routinely obtained owing to inconsistent sensitivity and specificity in prior studies (Neunert et al, 2011), the definition of ITP used in these studies was not standardized. Additionally, potential clinical utility of this testing beyond diagnosis has been suggested, such as correlations between certain serologic patterns and response to IVIG (Peng et al, 2014). In consideration of these prior findings, we undertook a retrospective analysis of APA testing [glycoprotein-specific testing done by the commercial PakAuto assay (Immucor, Brookfield, WI), a monoclonal antibody immobilization of platelet antigens (MAIPA) assay, with all testing performed by the same laboratory] utilizing standardized ITP and Evans syndrome (ES) diagnostic criteria for patient inclusion. We examined serologic evolution over time and relation of antibody positivity to disease severity and response to therapies. Methods : Data collected for analysis included dates and results of APA testing (including disease status and platelet count at time of testing), patient demographics, and disease characteristics. Satisfaction of the 2011 American Society of Hematology (ASH) ITP diagnostic criteria were required for ITP patient inclusion and standard definitions of disease severity and response to treatment from the ASH guidelines were used in analysis. Logistic regression was used to model the probability of disease severity (non-severe, severe, or refractory) and treatment response (to corticosteroids or IVIG) based on serologic findings. Longitudinal serologic evolution in patients with multiple APA assays were analyzed. Results : A total of 214 APA assays from 115 ITP patients and 12 ES patients were collected; results from eluate testing (direct assay) only were used in analysis. Baseline patient characteristics are listed in Table 1. Of 7 possible positive test serologic patterns, only 4 were seen (Figure 1); antibodies against both GPIIb/IIIa and GPIb/IX were required for the presence of antibodies against GPIa/IIa. A multinomial logistic regression model including disease severity, age, sex, duration of disease, and platelet count at time of APA assay found a statistically significant predictive relationship between an increasing number of positive antibodies and disease severity [relative to non-severe ITP, relative risk ratio for severe ITP and refractory ITP was 1.89 (P=0.001) and 2.38 (P=0.004), respectively, per one additional positive antibody, Figure 2]. Multiple logistic regression models including antibody positivity to each platelet glycoprotein (GPIIb/IIIa, GPIb/IX, or GPIa/IIa), age, sex, disease duration and splenectomy status found a significant predictive relation between presence of anti-GPIa/IIa and non-response to corticosteroid treatment (odds ratio, 0.082, P=0.008). No significant relation was found between an antibody and non-response to IVIG. Fifty patients had multiple (2 to 5) APA assays performed over months to years. In evaluation of serologic evolution over time, all 7 patients who entered clinical remission also converted from a positive to a negative serology; 22 patients had stable serologic findings over time; 5 patients had a reduction in number of positive antibodies; and 18 patients demonstrated evidence for epitope spreading, with an increase in the number of positive antibodies (Figure 3). The sensitivity of a positive APA assay for the presence of active ITP was 91%. The sensitivity and specificity of a negative APA assay for remission in a patient with previously confirmed ITP (N=40 assays in patients with clinical remission in the study) were 88% and 91%, respectively. Conclusions : The MAIPA-based direct APA assay is sensitive for the presence of active ITP in patients satisfying 2011 ASH diagnostic criteria. To our knowledge, this is the first study demonstrating that a higher number of positive glycoprotein-specific antibodies may predict for more severe disease as defined by 2011 ASH disease severity criteria. Anti-GPIa/IIa antibodies only occur in the setting of pre-existing positivity for both anti-GPIIb/IIIa and anti-GPIb/IX antibodies, possibly due to a distinctive sequence of epitope spreading. Serologic testing typically turns negative when a patient enters clinical remission. Disclosures Al-Samkari: Agios: Consultancy. Kuter:Novartis: Consultancy; Pfizer: Consultancy; Syntimmune: Consultancy; Argenx: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; ONO: Consultancy; Amgen Inc.: Consultancy; Bioverativ: Consultancy, Research Funding; Principia: Research Funding; Rigel: Consultancy, Research Funding; BMS: Research Funding; Protalex: Research Funding.

Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing. Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted. Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result. Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2). Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO. Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs. Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy. Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. Disclosures Barger: Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: Research Funding.

Background: Avatrombopag (AVA) is an oral, thrombopoietin receptor agonist approved by FDA for the treatment of thrombocytopenia in patients with chronic liver disease scheduled to undergo a procedure. AVA is also being developed for other indications including chronic immune thrombocytopenia (cITP) (Bussel et al, Blood, 2014; Wojciech et al, Br J Haematol, in press 2018). In repeated-dose studies in mice, rats and cynomolgus monkeys, there were AVA dose, concentration, and duration-dependent histologic changes in gastric fundic glands that reversed by 4 weeks after dosing was stopped. This was associated with decreased gastric acid production, hypergastrinemia, and increased intragastric pH in all species. The NOAEL in 2-year toxicology studies was defined at exposures 4 to 21-fold the recommended human AVA dose. Hypergastrinemia and parietal cell hyperplasia have also been reported with proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RA). These findings may be secondary to suppression of gastric acid production, and, in rodents, may lead to gastric carcinoids. Findings of hypergastrinemia-related gastric hyperplasia in rodents have a low risk/relevance to humans. To further evaluate the preclinical findings and screen for atrophic gastritis, gastric biomarkers (gastrin, gastrin-17, and pepsinogen I/II [PG-I/PG-II]) were measured in 2 Phase 3 trials with chronic AVA dosing. These multicenter, randomized, controlled Phase 3 trials were conducted in patients with cITP, and assessed clinical safety and efficacy of AVA versus placebo (PBO) (Study 1- NCT01438840) or eltrombopag (ELT) (Study 2- NCT01433978); Study 2 was terminated early due to enrollment challenges. Methods: Both Phase 3 trials enrolled adults (≥18 years) with chronic ITP (Baseline platelet count (PC) Patients with Baseline fasting gastrin-17 levels greater than upper limit of normal (ULN) were excluded from the study, as were patients taking PPIs or H2RAs if not on a stable dose or if gastrin-17 levels were >1.5 times the ULN. Safety analyses included adverse event (AE) monitoring and laboratory testing, including fasting gastric biomarkers. Patients who developed 2 consecutive fasting gastrin-17 levels >2.5 times the ULN or low serum PG-I levels or low PG-I/PG-II ratio (with low fasting gastrin-17 levels) were to be discontinued from the trials. Patients with elevations >5 times the ULN were to undergo endoscopy to assess the gastric mucosa. Results: A total of 64 patients were treated with AVA across the two trials (Study 1 n=47; Study 2 n=17); the majority were white (92.2%) and female (64.1%), with a mean age of 46.6 years. The median duration of exposure to AVA was 35.1 weeks, with a mean daily dose of 24.6 mg; 75% of subjects received AVA doses between 5 and 40 mg for ≥20 weeks. AVA was shown to be superior to PBO in the median cumulative number of weeks of platelet response (PC ≥50×109/L in the absence of rescue therapy) in Study 1 (12.4 vs. 0.0 weeks, respectively; p Of the AVA-treated patients, no significant changes in the mean fasting gastrin, gastrin-17, PG-I, PG-II, or the PG-I/PG-II ratio were observed from Baseline over the course of the trial (Figure 1). In addition, no patients met the gastric biomarker change criteria for discontinuation or to undergo endoscopy. Common AEs in Study 1 included headache, contusion and upper respiratory tract infections, with 4 cases of thromboembolic events. Conclusions: In Phase 3 trials, AVA was shown to be effective and well tolerated in the treatment of thrombocytopenia in patients with cITP, with most patients demonstrating substantial platelet increases. In particular, treatment of cITP with AVA was not associated with an increase in gastric biomarkers including gastrin, gastrin-17 or pepsinogen and, therefore, no signal of gastric toxicity was identified with chronic AVA dosing of up to 26 weeks. Disclosures Bussel: Prophylix: Consultancy, Research Funding; Protalex: Consultancy; Amgen Inc.: Consultancy, Research Funding; Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Momenta: Consultancy; Novartis: Consultancy, Research Funding. Allen:Dova Pharmaceuticals: Employment, Equity Ownership. Tian:Dova Pharmaceuticals: Employment, Equity Ownership. Kuter:Pfizer: Consultancy; ONO: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Syntimmune: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; Argenx: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Research Funding; BMS: Research Funding; Principia: Research Funding.

Background: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and often serious disease characterized by antibody-mediated destruction of red blood cells (RBCs). Activation of Fc receptors on macrophages in turn activates spleen tyrosine kinase (SYK), which triggers a signaling cascade leading to phagocytosis of the antibody-bearing cells. Fostamatinib, a SYK inhibitor, markedly improved Hgb levels in 9 of 17 (53%) patients with wAIHA during a phase 2, open-label, multicenter study. This abstract reports the results of ongoing fostamatinib treatment as of 2 July 2018 in patients who completed the 24-week treatment period and rolled over into the extension period of the study. Methods: Eligible adult patients had primary or secondary wAIHA and had failed more than one prior treatment for wAIHA. Patients had to have hemoglobin (Hgb) ULN. In order to enter the extension period of the study, patients had to have [1] met the primary efficacy endpoint (Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion) OR have shown a beneficial trend during the 24-week treatment period and [2] tolerated study drug. Fostamatinib 150mg BID (or the dose taken at the end of the 24-week treatment period, if a dose reduction had occurred) was taken orally with no food restriction, and patients were seen every 6 weeks during the extension period. Results: Six patients have entered the extension period including 5 who had met the primary efficacy endpoint and 1 who showed a beneficial trend at Week 24 (and had a response at Week 30). One patient had lymphoproliferative disease. Prior AIHA treatment included splenectomy (1), steroids (6), and rituximab (2). The median duration of disease was 1.9 years (range 0.4-15.7). The mean age was 58.7 years (range 30-86), 5 were female, all were white, and 4 were Hispanic or Latino. At baseline the median Hgb was 9.1 g/dL (range: 8.6-9.5); the median lactate dehydrogenase was 273 U/L (range 233-781); the median reticulocyte count was 252.2 x109/L (range 7.8-350.0); and the median haptoglobin was 7.0 mg/dL (range 7.0-9.0). The direct antiglobulin test was positive for IgG in 5 patients at screening. Median Hgb levels increased over the course of the study. See figure. Four of 6 patients had an ongoing response as of the data cutoff date, and none has had rescue therapy or an RBC transfusion. All 6 patients had ≥1 adverse event (AE) during the study, including noninfectious diarrhea in 1 (treatment-related), hepatic disorders in 3 (treatment-related in 2; treatment interrupted in 1), and hypertension in 1 (not related). One patient had a serious AE (inappropriate antidiuretic hormone secretion), which was not related to fostamatinib. To date, no new safety signals have been detected. Summary/Conclusion: Patients with wAIHA continued to display markedly improved Hgb levels during the extension period of the study. Side effects were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure. Figure. Disclosures Kuter: ONO: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen Inc.: Consultancy; Principia: Research Funding; Bioverativ: Consultancy, Research Funding; Argenx: Consultancy; Syntimmune: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arnold:Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Boxer:Incyte: Speakers Bureau; Rigel: Speakers Bureau; AbbVie: Speakers Bureau. Broome:Bioverativ: Honoraria; Alexion: Honoraria. Field:Prolong: Research Funding; Ironwood: Consultancy, Research Funding; Incyte: Research Funding. Lowe:Rigel: Consultancy. Tong:Rigel: Employment, Equity Ownership. Zayed:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership.

Introduction: Despite therapeutic advances and the increasing number of available regimens, multiple myeloma (MM) remains largely incurable, with a decreased durability of response with successive therapies (Majithia et al, Leukemia 2016). The monoclonal antibodies (mAbs) daratumumab (dara) and elotuzumab (elo), targeting CD38 and SLAMF7, respectively, have demonstrated significant efficacy in relapsed/refractory (RR) MM and may lead to a paradigm change in the treatment of RRMM. In the USA, dara is indicated for the treatment of RRMM when given in combination with dexamethasone (dex) plus either lenalidomide (len; Ld) or bortezomib for patients (pts) with ≥1 prior line of therapy (LoT). Dara in combination with pomalidomide/dex (pom; Pd) was also recently approved for pts with RRMM after ≥2 prior LoTs, including len and a proteasome inhibitor (PI), on the basis of data from a single-arm trial that demonstrated a median progression-free survival of 9.9 mo (Facon et al, Blood 2017), and as a monotherapy in pts with ≥3 prior LoTs. Elo, combined with Ld, is approved for treatment of RRMM after 1-3 LoTs. In ELOQUENT-3 (NCT02654132), an ongoing phase 2 randomized study in pts with RRMM after failure of len and a PI, elo plus Pd was associated with a 46% reduction in risk of progression or death vs Pd alone (Dimopoulos et al. EHA 2018 [LB2606]). There is a lack of current data on the array of treatments received by pts with RRMM after failing mAb therapy. This study evaluated treatment sequences among pts with RRMM after failure of dara-based therapy. Methods: Pts from the USA aged ≥18 y with RRMM, who received dara in their second to sixth LoT from November 2015 onward, were identified from PREAMBLE (NCT01838512), an ongoing, prospective, observational study, and the McKesson electronic medical record (EMR) database. Pts who had received a prior mAb were excluded. Pts were followed until database lock (PREAMBLE, April 2018; McKesson EMR, May 2018). Baseline demographics and clinical characteristics were assessed using descriptive analysis, and statistical comparisons were made using t or Mann-Whitney U tests (continuous variables) and chi-square tests (categorical variables). Kaplan-Meier analyses were used to estimate duration of therapy (DoT). Results: In total, 1016 pts received dara as their first mAb in their second to sixth LoT. Baseline characteristics are shown in Table 1A. The most common dara-based regimen was dara plus an immunomodulatory drug (IMiD; 37% of pts, of whom 50% received dara plus pom), followed by dara plus dex and/or chemotherapy (32%), dara plus a PI (27%), dara plus a PI and an IMiD (4%), and dara plus panobinostat ( Conclusions: In this analysis, pts with RRMM after failure of dara switched to a variety of regimens. The majority received regimens containing IMiDs and PIs despite having been exposed to those agents in the past. Elo-based regimens were received by 21% of pts with RRMM after failure of dara, with most pts receiving elo in combination with len, and were associated with a higher DoT (151 d) after dara than other regimens in this analysis. Elo plus Pd may therefore be an option after dara, as pom is used less frequently in earlier LoTs. Study support: Bristol-Myers Squibb (BMS). Medical writing: K Tran, Caudex, funded by BMS. Disclosures Vij: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chen:Bristol-Myers Squibb: Employment. Yasenchak:Seattle Genetics: Consultancy; Bristol-Myers Squibb: Consultancy. Davis:Bristol-Myers Squibb: Employment.

Introduction: Although proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and PI+IMiD combinations have become the standard of care in multiple myeloma (MM), they are not considered curative. Most patients (pts) eventually relapse or become refractory to treatment, and outcomes are poor after treatment failure. A median overall survival (OS) of 13 mo was reported in pts with relapsed/refractory MM (RRMM) who were double-refractory to a PI and IMiD and received ≥3 prior therapies (Kumar et al, Leukemia 2017). Recently developed therapies with novel mechanisms of action (MoAs), including the monoclonal antibodies (mAbs) elotuzumab and daratumumab, are associated with prolonged progression-free survival (PFS) in clinical trials of RRMM (Dimopoulos et al, Cancer in press; NEJM 2016). However, there is little up-to-date information on real-world survival outcomes. Herein we report survival patterns across key milestone timepoints in pts with RRMM in a real-world clinical setting. Methods: PREAMBLE (NCT01838512) is an ongoing international, prospective, observational cohort study. Adults with RRMM who were not participating in a clinical trial at the time of enrollment, had ≥1 prior therapy and documented disease progression, and began treatment with a PI, IMiD, PI+IMiD combination, or newer agent (those with newer MoAs, such as mAbs, histone deacetylase inhibitors, and novel combinations) ≤90 d before to 30 d after informed consent, were included and followed for up to 3 years. During the observational period, data were collected at each healthcare visit, and vital status was assessed every 6 mo throughout the follow-up period. Clinical efficacy and patient characteristic data were collected by healthcare providers using electronic case report forms. Descriptive statistics were used to describe pt characteristics and Kaplan-Meier plots were generated for time-to-event data. Multivariate Cox regression, with stepwise variable selection to select independent variables, was used to assess the association between baseline characteristics and PFS or OS. Results: At database lock (Nov 30, 2017), 1159 pts with RRMM were enrolled from the USA (31%) and Europe (67%), and included in this analysis. After a median (IQR) follow-up of 12.4 (6.3-24.9) mo, 39% of pts were still on study and 34% had died; most deaths (67%) were due to MM progression. At enrollment, median (range) age was 69 (34-92) y; 77% of pts had relapsed disease and 21% refractory disease. Among pts with a medical history, the most common comorbidities were vascular disorders (49%), metabolism and nutrition disorders (34%), and musculoskeletal/connective tissue disorders (29%). Pts received a median of 2 prior therapies before enrollment, with 50% having received an IMiD, 61% a PI, 21% a PI+IMiD, and 2% a newer agent. At enrollment, 45% of pts were receiving an IMiD, 41% a PI, 10% a PI+IMiD, and 4% a newer agent. Since enrollment, a total of 58% of pts received an IMiD, 49% a PI, 16% a PI+IMiD, and 10% a newer agent (including regimen received at enrollment). Median (95% CI) PFS was 11.4 (10.5-12.2) mo and OS was 33.7 (28.5-37.5) mo. Survival rates at milestone timepoints are shown in Table 1. Among pts who died due to MM progression (n=266), MM-related mortality was 56% at 12 mo, 85% at 24 mo, and 97% at 36 mo. In multivariate analysis, risk of disease progression/death was lower in pts with relapsed vs refractory disease at baseline (hazard ratio [HR] 0.82; 95% CI 0.68-0.99; p=0.0425) and higher in pts who had received 2-3 (HR 1.37; 95% CI 1.15-1.64; p=0.0004) or ≥4 (HR 1.54; 95% CI 1.22-1.95; p=0.0003) vs 1 prior therapy. Multivariate analysis for OS identified younger age, female sex, non-white race, relapsed disease, early-stage disease, fewer prior therapies, and the absence of baseline cardiac or gastrointestinal disorders as independent predictors of longer OS (Table 2). Conclusions: Real-world data suggest that over the last decade, survival has improved for pts with RRMM; however, OS remained low (48%) after 3 years in this analysis and most deaths were attributed to MM. Baseline comorbidities may also increase the risk of death and should be carefully considered when selecting treatments. Newer treatment options are still needed to further extend survival in pts with RRMM. Study support: Bristol-Myers Squibb (BMS). Writing support: Janice Zhou, Caudex, funded by BMS. Disclosures Cook: Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria. Cella:Novartis: Consultancy, Research Funding; Janssen Global services: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Chen:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment. Durie:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Goldschmidt:Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Moreau:Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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. Vij:Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: 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, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Management goals and normalization concept for type 1 Gaucher disease : Results from a survey of expert physicians