Superfactor Va, an Engineered Factor V Molecule, Effectively Reduces Bleeding and Acute Coagulopathy in Mouse Models of Trauma and Shock

Traumatic bleeding is a leading cause of death and disability, without targeted interventions available outside blood component resuscitation and tranexamic acid. Acute traumatic coagulopathy (ATC) in association with bleeding occurs in ~30-50% of patients and carries a high mortality risk. Recent evidence suggests a role of activated protein C (APC) in the development of ATC, whereby excessive generation of APC leads to rapid depletion of Factor(F) V, FVIII and hyperfibrinolysis causing depletion of fibrinogen. Here, we investigated to what extent targeted intervention with an engineered activated FV variant (superFVa), resistant to inactivation by APC, can reduce traumatic bleeding and prevent or normalize hemostasis parameters indicative of ATC, a process thought to be different from disseminated intravascular coagulation (DIC). SuperFVa was engineered to withstand cleavage by APC through mutations of 3 APC cleavage sites (Arg506/306/679Gln), with additional stability provided by introduction of a disulfide bond (Cys609-Cys1691) between the A2 and A3 domains. Materials and Methods First, an established trauma/shock model for ATC (Chesebro et al. 2009) was used. Here, trauma is induced by laparotomy and shock is induced by blood withdrawal (~500ul) to reduce and maintain the mean arterial pressure [MAP] from 75±5 to 35±5 mmHg for 1 hour. SuperFVa (0.4-0.8 mg/kg) was administered by continuous infusion 30 minutes after trauma/shock induction. Second, a liver laceration model was used where ATC develops as the consequence of severe bleeding. SuperFVa was administered either as bolus (0.4-0.8mg/kg) before injury or as continuous infusion (0.8mg/kg) started 30 minutes after injury. Bleeding, APTT clotting times, clotting factor activity levels (FII, FV, FVIII, FX, fibrinogen) and Thrombin-Antithrombin (TAT) complexes were assessed to determine the extent of ATC at various time points. Results In the trauma/shock model, only mice subjected to both trauma and shock developed ATC, evident from a significant APTT prolongation (25.4±0.2 to 36.1±0.2 seconds), associated with a severe reduction of FV (14%) and FVIII( 6%), a partial reduction of fibrinogen (44%), and no effect on FX (89%) and FII (89%). Administration of superFVa normalized the APTT (27.1±0.2 seconds) despite the persistence of shock, returned FV and FVIII levels to their normal range, but had no effect on fibrinogen. TAT levels increased significantly upon trauma/shock (1522 ±125 ng/mL) and were reduced by superFVa administration (511±125 ng/mL), suggesting improved hemostasis. After liver laceration severe bleeding occurred within 60 minutes, causing shock (MAP decreased to 35±5), selective reductions of FV, FVIII, and fibrinogen levels, and prolongation of the APTT clotting time, indicating the development of ATC. SuperFVa prophylaxis prior to liver laceration reduced blood loss significantly (non-treated mice 0.54±0.01 vs. pre-treated mice 0.34±0.01 mL, p<0.0001), prevented APTT prolongation and depletion of FV and FVIII. Thus, prophylactic administration of superFVa prevented the development of ATC. Most bleeding after liver laceration occurred in the first 15-30 minutes (0.44±0.01mL at 30 minutes) and ATC became evident at 30 min (APTT prolongation to 32.63±0.2 seconds; partial depletion (~50%) of FV and FVIII). To determine effects of superFVa on the reversal of ongoing ATC, superFVa intervention was started therefore at the 30-minute time point. superFVa blunted additional blood loss after 30 minutes, normalized prolonged APTT clotting times and reversed FV and FVIII levels to their normal range. Reversal of ATC by superFVa was associated with a reduction of TAT levels (646.5±125 ng/mL) that were increased by ATC (1577.0 ±125 ng/mL). Conclusion SuperFVa restored hemostasis in two mouse models of ATC where coagulopathy was induced by either trauma/shock or by severe bleeding. Improved hemostasis in ATC by superFVa was achieved by correction of APTT clotting times and normalization of depleted FV and FVIII levels and was associated with a reduction of elevated TAT levels. Because superFVa rescued traumatic bleeding to prevent the development of ATC and was also efficacious for the reversal of ongoing ATC, targeted interception of ATC by superFVa therefore may be an attractive strategy to reduce complications associated with ATC. Disclosures Mosnier: The Scripps Research Institute: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. von Drygalski:University of California San Diego: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Founder.

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An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

Blood Advances ◽

10.1182/bloodadvances.2021005257 ◽

2021 ◽

Author(s):

Bilgimol Chumappumkal Joseph ◽

Byron Y Miyazawa ◽

Charles Esmon ◽

Mitchell J Cohen ◽

Annette von Drygalski ◽

...

Keyword(s):

Driving Forces ◽

Severe Bleeding ◽

Trauma Patients ◽

Factor V ◽

Activity Levels ◽

Normal Range ◽

Acute Traumatic Coagulopathy ◽

Liver Laceration ◽

Traumatic Bleeding ◽

Traumatic Coagulopathy

Acute traumatic coagulopathy (ATC) occurs in ≈30% of trauma patients and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond, is able to reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by APTT prolongation and reductions of FV, FVIII, and fibrinogen, but not FII and FX. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as the consequence of severe bleeding. SuperFVa prophylaxis prior to liver laceration reduced bleeding, prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. SuperFVa intervention started after the development of ATC stabilized bleeding, reversed the prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding.

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The Effects of Tranexamic Acid on Bleed Control, Coagulopathy and Survival with Trauma in Anemic Mice

Blood ◽

10.1182/blood-2021-148060 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3174-3174

Author(s):

Bilgimol Chumappumkal Joseph ◽

Richard FW Barnes ◽

Annette von Drygalski

Keyword(s):

Iron Deficiency ◽

Blood Loss ◽

Tranexamic Acid ◽

Board Of Directors ◽

Iron Content ◽

Research Funding ◽

Activity Levels ◽

Advisory Committees ◽

Liver Laceration ◽

Fviii Activity

Abstract Clinical evidence suggests that anemia increases surgical bleeding and is associated with poor outcomes. Globally, ~ 50% of anemia is attributed to iron deficiency as the most common nutritional disorder. To study the effects of iron deficiency anemia (IDA) on traumatic bleeding we developed a mouse model of IDA and traumatic injury, and tested the effects of prophylactic tranexamic acid (TXA), on blood loss, coagulopathy and survival. Materials and Methods C57BL/6J mice, both male and female, were fed with usual laboratory ("control mice") or iron deficient (4ppm iron) chow ("IDA mice") starting at 3 weeks of age. After 6 weeks, IDA was documented by blood count, red cell indices and liver iron content. Mice then were subjected to an established liver laceration model causing severe bleeding. Blood loss (weighing blood-soaked sponges in the abdominal cavity), seven-day survival and coagulation parameters (APTT, activity levels of Factor (F) V, FVIII, Fibrinogen) were determined at 15 and 60 minutes after liver laceration for "IDA" and "control mice", treated or not treated five minutes prior to injury with TXA (10mg/kg). All data were expressed as median and were compared using Mann-Whitney test. Results Compared to "control" mice, "IDA mice" developed hypochromic and microcytic anemia with a significantly lower mean hematocrit (32±1.7% vs 49±1.2%, p≤0.0001) and hepatic iron content (75.9±19.8µg/g vs 22.4±9.4 µg/g, p≤0.0001). "IDA mice" demonstrated significantly more bleeding after liver laceration compared to "control mice." Most of the bleeding had occurred at 15 minutes after injury with little incremental bleeding at 60 minutes. The blood loss in "IDA mice" was greater at both time points compared to "control mice" (15 minutes: 21.5±2.3µl/g vs 15.9±2.6µl/g, p≤0.0001; 60 minutes: 24.5±1.6µl/g vs 20.7±1.9µl/g, p≤0.0001). TXA reduced bleeding significantly in "IDA mice" at 15 and 60 min to ~15µl/g. In "control mice", bleed improvement was only present at 60 min (also reduced to ~15µl/g), without improvement below the ~15µl/g baseline threshold at 15 min. Coagulopathy developed in both groups over 60 min, with similar prolongation of the APTT from baseline (23.9±1.5s to 36.0±4.9s in "IDA mice"; 22.8±1.3s 35.0±3.8s in "control mice"), substantial depletion of FV and FVIII activity levels and partial reduction of fibrinogen. TXA administration normalized the APTT only in "control mice" at 60 minutes, but not in "IDA mice", although TXA reconstituted FV and fibrinogen to ~100% activity, with FVIII activity of ~50% in both groups. Survival of "IDA mice" was lower compared to "control mice" (50% vs 75%), but increased significantly with TXA (80%, p=0.04). Conclusion Enhanced bleeding and poorer survival was observed in "IDA mice" compared to "control mice" after liver laceration at similar degrees of coagulopathy. Prophylactic TXA corrected bleeding and reduced mortality in "IDA mice" to values similar to those observed for "control mice" despite incomplete correction of the coagulopathy in "IDA mice". This suggests that TXA may be of particular importance in the face of anemia, by mechanisms that may go beyond hemostasis correction alone, warranting further investigation. Disclosures von Drygalski: CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Assessing the Safety of Various VWF Regimens in Patients with Clinically Severe VWD: A Natural History Study

Blood ◽

10.1182/blood-2019-128318 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1132-1132

Author(s):

Robert F. Sidonio ◽

Angela C. Weyand ◽

Dunlei Cheng ◽

Crystal Watson

Keyword(s):

Board Of Directors ◽

Study Design ◽

Real World ◽

Research Funding ◽

Laboratory Data ◽

Severe Bleeding ◽

Advisory Committees ◽

On Demand ◽

Type 3 ◽

Von Willebrand

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans affecting up to 1% of the population, while symptomatic prevalence is likely closer to 0.1%. A deficiency of von Willebrand factor (VWF) can be quantitative (type 1 or type 3) or qualitative (type 2) and lead to a bleeding diathesis of variable intensity roughly correlating with functional activity. Diagnosis can be challenging due to variable penetrance and large influence of multiple pre-analytic variables and a wide testing coefficient of variation. Treatment for VWD is focused on replacement of defective or deficient VWF with a plasma-derived or recombinant VWF-containing product, release and elevation of endogenous stores of VWF with Desmopressin (DDAVP), or prevention of premature fibrinolysis with an antifibrinolytic, such as aminocaproic acid. Although there is relative consensus on the management of mild VWD, there is scarce literature about the optimal treatment of patients with severe disease, especially in regard to factor replacement. Real World evidence for the use of primary (prior to significant bleeding) or secondary (following development of significant bleeding) prophylaxis is lacking with the majority of studies relying heavily on retrospective data. Additionally, ongoing VWD prophylaxis studies typically only allow participants to enroll if they previously have not been on prophylaxis, limiting our ability to learn about this growing population of patients. Study Design and Methods: Approximately 1,900 VWD patients were identified in the ATHNdataset with a VWF:Ag or VWF:RCo of ≤ 30%, with ~170 of these on prophylaxis. This group, in addition to those VWD patients with clinically significant bleeding and ≤ 40% of normal VWF:Ag or VWF:RCo, provide a potential unmet opportunity to examine prophylaxis and treatment patterns. Furthermore, a standardized laboratory assessment (including a standardized diagnostic battery, genetic evaluation of VWF gene, and inhibitor testing) will provide significant enrichment of the ATHNdataset by fully characterizing patients that are highly likely to utilize factor concentrates. Inclusion criteria are patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GP1bM or VWF:Ag≤ 30%, patients with clinically severe VWD as defined by VWF:Rco, VWF:GP1bM or VWF:Ag ≤ 40% with severe bleeding phenotype requiring recurrent use of factor concentrates, and co-enrollment in the ATHNdataset. Patients with platelet-type or acquired VWD are excluded. The primary objective is to assess the safety of various VWF regimens for different indications (on-demand, surgery, and prophylaxis) in adult and pediatric patients with clinically severe VWD. Safety is measured by the number of reported events as defined by the European Haemophilia Safety Surveillance (EUHASS) program. Secondary objectives are to enrich and analyze data from clinically severe congenital VWD patients by collecting laboratory data; to establish sub-studies for patients who are treated with VWF products on demand or who have started on or switched to a particular VWF containing product; to evaluate the use of factor replacement as prophylaxis in a cohort of severe VWD participants over 6 month time periods; to describe bleeding events, changes in overall bleeding, and annualized bleed rate as measured by the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) and if applicable the Pictorial Bleed Assessment Chart (PBAC); and to describe real-world effectiveness of VWD treatment as measured by health care utilization and quality of life measures (PROMIS® and V-WIQ questionnaires). Descriptive statistics will be calculated to analyze the primary and secondary outcomes. For each categorical variable, its frequency and percentage will be reported. In terms of a continuous measurement, its mean, median, standard deviation, interquartile range, minimum, and maximum values will be disclosed. The study will attempt to enroll a target number of at least 50 participants who are receiving VONVENDI but will not mandate the use of VONVENDI. More study design details are outlined in Table 1. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: 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; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2019-126659 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1126-1126

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Paulette Bryant ◽

Jenny McDaniel ◽

Kelly Tickle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Acute Bleeding ◽

Fviii Activity ◽

Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: 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; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Spontaneous Bleeding and Poor Bleeding Response with Extended Half-Life Factor IX Products: A Survey of Select US and Canadian Hemophilia Treatment Centers

Blood ◽

10.1182/blood-2019-126196 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2407-2407 ◽

Cited By ~ 2

Author(s):

Lynn M Malec ◽

Stacy E. Croteau ◽

Michael Callaghan ◽

Davide Matino ◽

Kenneth Dale Friedman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Bleeding Events ◽

Advisory Committees ◽

Spontaneous Bleeding ◽

Recombinant Factor Ix ◽

Traumatic Bleeding ◽

Hemophilia Treatment Centers

Background: Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels >10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (>10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: 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; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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C3 Inhibition with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Paddock and Palomino Trials

Blood ◽

10.1182/blood-2020-134436 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Raymond S Wong ◽

Kalina Ignatova ◽

Humphrey Pullon ◽

Jameela Sathar ◽

Pimjai Niparuck ◽

...

Keyword(s):

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Normal Range ◽

Open Label ◽

Private Company ◽

Advisory Committees ◽

Regional Office ◽

Lower Limit Of Normal

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by chronic complement-mediated intravascular and extravascular hemolysis (IVH and EVH), and thrombosis. C5 inhibitors reduce IVH by inhibiting membrane attack complex formation and are the current standard of treatment for PNH. EVH persists in the presence of C5 inhibition. Pegcetacoplan is a C3 inhibitor targeted to control both IVH and EVH. The PADDOCK and PALOMINO studies assessed the safety and preliminary efficacy of pegcetacoplan in complement inhibitor-naïve patients. METHODS PADDOCK was a phase 1b, open-label, pilot study (NCT02588833) with 2 cohorts. Subjects in cohort 1 received pegcetacoplan at a suboptimal dose of 180 mg/day for 28 days; subjects in cohort 2 received pegcetacoplan 270 mg/day for up to 1 year. Subjects could participate in both cohorts. PALOMINO was a phase 2a, open-label, single-cohort study (NCT03593200) in which subjects received pegcetacoplan 270 mg/day for up to 1 year. Both studies enrolled subjects ≥18 years old diagnosed with PNH and no prior treatment with eculizumab. Primary efficacy endpoints in both studies were change from baseline in lactate dehydrogenase (LDH), haptoglobin, and hemoglobin. Secondary efficacy endpoints included change from baseline in reticulocyte count, total bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The number of packed red blood cell transfusions was also recorded. Primary safety endpoints were the incidence and severity of treatment emergent adverse events (TEAEs). RESULTS Three subjects were enrolled in PADDOCK cohort 1 and 20 in cohort 2; 1 subject was enrolled in both cohorts. PALOMINO enrolled 4 subjects. PADDOCK cohort 2 and PALOMINO efficacy data are shown in the Table. At baseline, mean LDH levels were >8× upper limit of normal in both studies. At day 365, mean LDH had decreased to <2× upper limit of normal in PADDOCK and was within the normal range in PALOMINO. At baseline, mean hemoglobin levels were below the lower limit of normal in both studies. At day 365, mean hemoglobin levels had increased to within the normal range in both studies. In PALOMINO, 3 subjects achieved hemoglobin levels above the lower limit of normal at day 365, and 1 subject had a hemoglobin level of 10.14 g/dL. An increase from baseline in mean FACIT-Fatigue scores of 7.1 and 6.5 at day 365 was observed in PADDOCK and PALOMINO, respectively. In PADDOCK and PALOMINO, mean reticulocyte count decreased from 194.9 × 109 cells/L and 238.3 × 109 cells/L at baseline, respectively, to 96.4 × 109 cells/L and 94.0 × 109 cells/L at day 365. Total bilirubin levels also decreased from 42.6 µmol/L and 30.85 µmol/L at baseline to 13.9 µmol/L and 9.33 µmol/L at day 365 in PADDOCK and PALOMINO, respectively. In PADDOCK cohort 2, 18/20 subjects received ≥1 transfusion in the 12 months prior to screening, and 13/20 subjects did not require a transfusion during the study. In PALOMINO, all subjects received ≥1 transfusion in the 12 months prior to screening, and none required a transfusion during the study. Overall, 143 TEAEs were reported in 19/22 subjects (86.4%) in PADDOCK cohorts 1 and 2, of which 35 were either possibly or probably related to pegcetacoplan. Thirteen serious adverse events (SAEs) were reported in PADDOCK. Three SAEs (aplastic anemia, abdominal neoplasm, and hypersensitivity) led to pegcetacoplan discontinuation in 3 subjects. Two of these SAEs (aplastic anemia and abdominal neoplasm) resulted in study discontinuation. The aplastic anemia SAE was fatal and considered not related to pegcetacoplan. In PALOMINO, 60 TEAEs were reported in 3 (75.0%) subjects, of which 52 were possibly treatment-related. One SAE (rib fracture) was reported and was considered not related to pegcetacoplan. In PALOMINO, no TEAEs led to death, pegcetacoplan discontinuation, or study discontinuation. CONCLUSIONS In PADDOCK and PALOMINO, pegcetacoplan improved hematological parameters by controlling both IVH and EVH in patients with PNH. Improvements in clinical parameters were also observed. Pegcetacoplan was shown to have an acceptable safety profile and was generally well tolerated in both studies. PADDOCK and PALOMINO demonstrate the therapeutic potential of pegcetacoplan in the treatment of PNH and support further evaluation in the ongoing phase 3 PRINCE trial (NCT04085601) in complement inhibitor-naïve patients. Disclosures Wong: Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sathar:Novo Nordisk: Honoraria; Bayer: Honoraria; Roche: Honoraria. Tse:MSD: Research Funding; Janssen: Research Funding. Roman:Alexion: Speakers Bureau; Novartis: Speakers Bureau. Amine:Acibadem City Clinic Tokuda Hospital: Current Employment. Tan:Apellis: Consultancy, Patents & Royalties. Di Casoli:Apellis: Current Employment, Current equity holder in private company. Deschatelets:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Francois:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Grossi:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Bogdanovic:Takeda (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Investigator fee in clinical trial; Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

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Impact of Etiological Cytogenetic Abnormalities on Immunoparesis and Progression-Free and Overall Survival in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2020-133516 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-6

Author(s):

Jessica Caro ◽

David Cairns ◽

Tom Menzies ◽

Charlotte Pawlyn ◽

Eileen M Boyle ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Normal Range ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Trial Entry ◽

Polyclonal Igg ◽

Immunoglobulin Levels

Introduction: Immunoparesis, or suppression of polyclonal immunoglobulins, is a common issue in multiple myeloma (MM). Prior studies have shown that the degree of IgM immunoparesis is prognostic for survival, as patients with the most severe IgM immunoparesis at diagnosis have the poorest survival outcomes. Little is known regarding the cause of this immunoparesis, with many assuming it is due to tumor bulk alone. More recent data has suggested that MM can be divided into subgroups with distinct biologies and outcomes based on etiological cytogenetic abnormalities. These include hyperdiploidy and translocation t(11;14), t(4;14), t(14;16), or t(14;20), with the latter three groups being associated with high-risk disease. We hypothesized that the different etiological cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis and subgroup-dependent effects on clinical outcomes. Methods: We performed a retrospective review of newly diagnosed MM patients enrolled in the MRC Myeloma IX and Cancer Research UK Myeloma XI trials. Patients with hyperdiploidy, t(11;14), t(4;14), t(14;16), or t(14;20) were included in the analysis. Polyclonal IgG, IgA, and IgM levels were measured at diagnosis, and the normal range was established by the 5th - 95th percentiles of adults over age 45 years in the UK: IgG 6 - 16 g/L, IgA 0.8 - 4 g/L, and IgM 0.5 - 2 g/L. Cytogenetic abnormalities were determined by FISH, multiplex ligation-dependent probe amplification (MLPA), or next generation sequencing (NGS). Overall survival (OS) was defined as time from date of trial entry to date of death, or censored at date last known to be alive. Progression-free survival (PFS) was defined as time from date of trial entry to progression or death, or censored at date last known to be alive and progression-free. Results: The study included 985 patients, of whom 47% were at least age 65 years and 61.1% were male. The most common MM subtype was IgG (63.4%), followed by IgA (24.5%), light chain only (8.4%), IgD (1.9%), oligosecretory (1.0%), IgM (0.5%), and non-secretory (0.3%). Hyperdiploidy represented 58.9% of cases, with t(11;14) seen in 18.2%, and t(4;14), t(14;16), or t(14;20) seen in 22.9%. The MM subtype was not distributed evenly amongst the different etiological cytogenetic abnormalities with IgG overrepresented in the hyperdiploid subgroup (69.4%), compared to 11% in t(11;14) and 19.5% in high-risk cases. IgA was overrepresented in high-risk cases (45.2%), compared to 41.1% in hyperdiploidy and 13.7% in t(11;14). The high-risk subgroup had more immunoparesis compared to the hyperdiploid and t(11;14) subgroups (median polyclonal IgG 3.0 vs. 3.8 vs. 3.9 g/L, IgA 0.2 vs. 0.4 vs. 0.2 g/L, IgM 0.1 vs. 0.2 vs. 0.2 g/L, respectively). There were also significantly more patients in the high-risk subgroup with polyclonal immunoglobulin levels below the normal range compared to the hyperdiploid and t(11;14) subgroups (IgG 96.9% vs. 86.0% vs. 88.2%, p = 0.0045; IgA 89.9% vs. 77.1% vs. 92.4%, p < 0.0001; IgM 94.0% vs. 88.9% vs. 92.7%, p < 0.0001). With median follow up of 77 months, the overall median PFS and OS were 19 months and 53 months, respectively. As expected, patients in the high-risk subgroup had significantly lower PFS and OS (14 and 35 months, respectively, p < 0.001), compared to the hyperdiploid (21 and 60 months) and t(11;14) subgroups (22 and 53 months). The effect of the degree of immunoparesis on PFS depended on the cytogenetic subgroup. Using polyclonal IgM as a continuous variable, Cox regression analysis demonstrated a significant effect on PFS in patients with hyperdiploidy (HR 0.482, 95% CI 0.325 - 0.717, p = 0.0003). No difference was seen in the t(11;14) (HR 0.610, 95% CI 0.262 - 1.418, p = 0.2507) or high-risk subgroups (HR 1.087, 95% CI 0.505 - 2.341, p = 0.8304). Conclusions: Our study demonstrates that the etiological cytogenetic subgroup influences the degree and clinical impact of immunoparesis in newly diagnosed MM patients. A significant proportion of patients with t(4;14), t(14;16), or t(14;20) have IgG, IgA, and IgM levels below the normal range compared to patients with hyperdiploidy and t(11;14). This suggests that the underlying genetic abnormality (i.e., NSD2, C-MAF, and MAF-B, respectively) drives changes in the bone marrow microenvironment remodeling the plasma cell niche, resulting in suppression of normal plasma cell function and immunoglobulin levels. Disclosures Cairns: Celgene: Other: Travel Support; Celgene, Amgen, Merck: Research Funding. Menzies:Celgene, Amgen, Merck: Research Funding. Pawlyn:Takeda: Consultancy, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses. Morgan:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Cook:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy. Kaiser:Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses. Jackson:Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Gsk: Honoraria, Speakers Bureau. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Bleeding Manifestations and Management of Children with Persistent and Chronic Immune Thrombocytopenia (ITP): Data From the Intercontinental Cooperative ITP Study Group.

Blood ◽

10.1182/blood.v114.22.1315.1315 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1315-1315 ◽

Cited By ~ 2

Author(s):

Cindy Neunert ◽

George R. Buchanan ◽

Paul A. Imbach ◽

Paula HB Bolton-Maggs ◽

Carolyn M. Bennett ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Threshold Value ◽

Acute Onset ◽

Additional Patient ◽

Severe Bleeding ◽

Study Group ◽

Advisory Committees ◽

Fatal Hemorrhage

Abstract Abstract 1315 Poster Board I-339 ITP during childhood is generally characterized by acute onset of thrombocytopenia and bleeding in an otherwise well child. While the platelet count has traditionally been viewed as a marker of disease severity, additional patient characteristics such as bleeding severity have not been well defined. The Intercontinental Cooperative ITP Study Group (ICIS) Registry II was designed to characterize the location, frequency, timing, and severity of bleeding in children with ITP (Blood, 2008;112: 4003-8). We report here data from Registry II with a focus on bleeding symptoms reported at 6 and 12 months. Patients enrolled on Registry II had research visits at diagnosis, and 28 days, 6 months, 12 months, and 24 months following diagnosis. Bleeding manifestations were retrospectively recorded at 6 and 12 months capturing all sites of bleeding (e.g skin, epistaxis, and gastrointestinal) since the last research visit. Of the 1318 children enrolled at diagnosis, 891 were evaluated at 6 months and 718 at 12 months. Mean platelet counts were 198 × 109/l (s.d. 130) and 195 × 109/l (s.d.122) at 6 and 12 months respectively. At 6 months 29% (261/891) of patients still had a platelet count <100 × 109/l; of these 45% (118/261) were <30 × 109/l. At 12 months these values were 28% (203/718) and 40% (82/203) respectively. Number of bleeding sites reported since the last research visit at 6 months and 12 months are outlined in Table 1. There were no reports of intracranial hemorrhage (ICH) or fatal hemorrhage. The most common bleeding site reported at both 6 and 12 months was skin, followed by epistaxis. 4 children with a platelet count <30 × 109/l at both 6 and 12 months were reported as having undergone splenectomy. Red cell transfusions were infrequent (3 reported) and administered only in children with bleeding from ≥ 3 sites. The percentage of patients with a platelet count <30 × 109/l who received platelet count enhancing therapy (including platelet transfusions) is outlined in Table 2. Table 1 Number of bleeding sites reported since last research visit at 6 and 12 months 6 month visit 12 month visit Number of sites Platelet count <100 × 109/l (n= 261) Platelet count <30 × 109/l (n= 118) Platelet count <100 × 109/l (n= 203) Platelet count <30 × 109/l (n= 82) None 60 (23%) 10 (9%) 74 (36%) 16 (19%) 1 110 (42%) 44 (37%) 82 (40%) 33 (40%) 2 61 (23%) 39 (33%) 32 (16%) 21 (26%) 33 30 (12%) 25 (21%) 15 (7%) 12 (15%) Table 2 Patients with platelet count <30 × 109/l reported as having received platelet count enhancing therapy Number of bleeding sites reported between research visits Treatment reported between 28 days and 6 months (n = 118) Treatment reported between 6 and 12 months (n = 82) None 1/10 (10%) 4/16 (8%) 1 29/44 (66%) 19/33 (58%) 32 58/64 (91%) 26/33 (78%) In summary, approximately 30% of children with ITP enrolled on ICIS Registry II remain thrombocytopenic 6 and 12 months later, many still having a platelet count <30 × 109/l, a threshold value sometimes used to determine drug treatment and enrollment in prospective intervention studies. This cut-off may be appropriate since bleeding was more common when the platelet count was <30 × 109/l. However, even below this threshold life-threatening hemorrhage was uncommon, few patients required packed red blood cell transfusions, and approximately half the patients reported no more than one site of bleeding. Treatment was infrequently used in patients in this group if they had no bleeding, and platelet enhancing therapy was often employed if more bleeding sites were involved. These data suggest a trend towards reserving treatment for patients with more severe bleeding manifestations rather than because of a specific platelet count. Disclosures Buchanan: AMG 531: Research Funding. Bolton-Maggs:Baxter: Travel support to meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; United Kingdom Immune Thrombocytopenic Pupura Support Association: Research Funding; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blanchette:AMG 531: Membership on an entity's Board of Directors or advisory committees. Kuehne:F. Hoffman-La Roche Ltd: Research Funding; Amgen: Research Funding.

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Thromboembolic Events Observed in Eltrombopag Clinical Trials in Chronic Immune Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v114.22.2423.2423 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2423-2423 ◽

Cited By ~ 8

Author(s):

James B. Bussel ◽

Gregory Cheng ◽

Mansoor N. Saleh ◽

Sandra Vasey ◽

Manuel Aivado ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Thromboembolic Events ◽

Study Medication ◽

Normal Range ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 2423 Poster Board II-400 BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA), an oral, small molecule, thrombopoietin receptor agonist, was recently approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). Limited published data indicate that patients with chronic ITP experience thromboembolic events (TEEs) with a frequency of 3% to 6%. (Aledort, Am J Hematol, 2004; Bennett, Haematologica, 2008). OBJECTIVE: To evaluate the incidence of TEEs in patients with chronic ITP treated with eltrombopag and to determine if the occurrence of TEEs was associated with elevated platelet counts. METHODS: Data from 446 patients from 3 placebo-controlled eltrombopag studies (TRA100773A, TRA100773B, and RAISE) and 2 open-label studies (REPEAT and EXTEND) were analyzed. The frequency of TEEs or suspected TEEs before and after the first dose of study medication (placebo or eltrombopag) was examined across the program. Potential risk factors, including platelet counts proximal to the event, were evaluated in patients experiencing a TEE. RESULTS: Prior to the initiation of study medication (placebo or eltrombopag), 16/493 (3.2%) of the patients entering the program had a history of TEEs (one of these patients experienced 2 additional TEEs [TIA, MI] while on treatment with eltrombopag). Across the ITP clinical program, 17/446 patients treated with eltrombopag (3.8%) experienced 22 TEEs. No patient treated with placebo experienced a TEE. The patient-years (PYs) of exposure to study medication was approximately 14 times greater for patients treated with eltrombopag compared to placebo (eltrombopag 377 PYs; placebo 26 PYs). Most patients (13/17) experienced 1 TEE; 3 patients experienced 2, and 1 patient experienced 3 (2 TEEs were 6 months off-therapy). The most common TEEs were deep vein thrombosis (n=8) and pulmonary embolism (n=6). A total of 18/22 events were resolved or resolving at the time of this analysis; all patients experiencing a TEE had at least 1 risk factor for these events other than ITP (eg, use of IVIg [n=3], hospitalization with no prophylactic anticoagulation [n=4], oral corticosteroids [n=6]). The platelet counts proximal to the event ranged from 14,000/μL to 420,000/μL. The majority of patients had platelet counts below 150,000/μL (9; 53%) or between 150,000/μL and 400,000/μL (5; 29%); 2 had platelet counts above 400,000/μL and the platelet count in 1 was unknown. All 446 patients were categorized by the maximum platelet count achieved during treatment with eltrombopag (above normal [>400,000/μL], normal range [150–400,000/μL], below normal range [<150,000/μ]; Table 1). The majority of patients (14; 82%) experienced the TEEs at a platelet count lower than their maximum platelet count, while 3 patients (18%) experienced a TEE proximal to their maximum platelet count. CONCLUSION: TEEs occurred with eltrombopag. None occurred with placebo; however, the PYs of exposure was considerably less with placebo than with eltrombopag. The frequency of TEEs observed during eltrombopag treatment (3.8%) is similar to that reported in the literature and prior to enrollment in the eltrombopag program (3.2%). No discernible correlation has been observed between platelet count increases and TEEs, and these events do not appear to be associated with maximum platelet counts during treatment with eltrombopag. Disclosures: Bussel: Sysmex: Research Funding; Eisai, Inc: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Cheng:GlaxoSmithKline: Research Funding. Saleh:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Vasey:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

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Transcranial Doppler Screening in Children with Sickle Cell Anemia Is Feasible in Central India and Reveals High Risk of Stroke

Blood ◽

10.1182/blood-2019-131416 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2279-2279

Author(s):

Dipty Jain ◽

Kavitha Ganesan ◽

Sati Sahota ◽

Deepika S. Darbari ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

High Risk ◽

Oxygen Saturation ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Central India ◽

Normal Range ◽

Advisory Committees ◽

Tribal Populations

Introduction: India has been identified as having the second largest number of births with sickle cell anemia (SCA) in the world after Africa, with estimated 44,400 new-borns affected per year. SCD was previously reported to have a milder course in children from India, with less severe disease among aboriginal tribal populations than in non-tribal populations. Recent reports indicate the occurrence of severe manifestations of SCD in both tribal and non-tribal populations in India. Stroke is one of the serious complications of SCD, but there are no data on transcranial Doppler (TCD) screening for evaluating children with SCD in India who may be at high risk for strokes. The objective of this study was to assess the feasibility of using TCD to measure time averaged maximum of the mean velocities (TAMMV) in the intracranial arteries in children attending a tertiary centre in central India. Methods: STUDY DESIGN: A cross sectional study was conducted in consecutively recruited stable children of either sex with homozygous SCA proven by electrophoresis and high performance liquid chromatography in the age group of 1-26 years. Patients who were febrile, acutely ill, hypoxic or asleep were not included in the study as these conditions can falsely elevate the intracranial blood flow velocities. Patients with hemoglobinopathies other than HbSS or S/b0 Thalassemia and those with a history of congenital neurological illness were excluded. DETERMINATION OF TCD VELOCITY: TCD was performed in a tertiary care center in Nagpur using either an imaging machine (Lasiq s8) in the department of radiology or a portable non-imaging TCD (Compumedics); for both a probe of frequency 2Mhz was used. Maximum values for TAMMV in the Middle (MCA) and Anterior (ACA) cerebral arteries were measured in all; for the non-imaging TCD values for posterior cerebral artery (PCA) and basilar artery were also obtained. The results of the first scan performed on these individuals were included in this study. Using values similar to the STOP trial, TAMMV of each of these vessels were categorized as follows: Normal <= 170cm/s; Conditional - between 170 and 199 cm/s; Abnormal >= 200 cm/s; Low <50 cm/s and unobtainable. MEASUREMENT OF HAEMATOLOGICAL VALUES: Laboratory parameters such as Hemoglobin, white blood cell count (WBC), Mean corpuscular volume (MCV) and hemoglobin F (HbF) levels of the patients in the study were also included if the parameters were available on the day of TCD or within 90 days of TCD study. MEASUREMENT OF HEIGHT, WEIGHT AND BMI: The height and weight of each of the patients on the day of TCD or within a period of 60 days from the TCD were measured and the body mass index (BMI) was calculated. Results One hundred and twenty children and youth aged 1-26 (median 7) years, 67 male (56%), were recruited. Of the 120 patients, 106 (88.5%) belonged to the Scheduled Caste category, 3 (2.5%) to the Scheduled Tribe category and 11 (9.1%) to the Other Classes category. Three (2.5%) had had a clinical stroke and 8 (7%) had had seizures, one of whom also had a stroke. Twenty-seven (23%) children had TAMMV outside the normal range. Five had abnormal TAMMV in the MCA (n=4) and/or ACA (n=1), 8 had conditional TAMMV in the MCA (n=7) and/or ACA (n=1) while 14 patients had low (n=12) or unobtainable (n=2) TAMMV in the MCA. One child with stroke had low TAMMV and one had conditional TAMMV while the third had normal TAMMV. Of the 7 with isolated seizures, one had low TAMMV and one had conditional TAMMV while the remaining 5 were normal. BMI was 8.6-25.3 (median 14.1), height/weight was 3.4-10.3 (median 6.5), hemoglobin was 43-134 (median 81) g/L, oxygen saturation 87-100 (median 99)%, HbF was 1.9-60 (median 21) g/dL, MCV was 59.1-96.7 (median 83.2) fl, WBC was 2.3-35.9 (median 10.1)*109. Those with TAMMV outside the normal range were not different from those with normal TAMMV in terms of age, BMI, Height/weight, or recent hemoglobin, oxygen saturation, HbF, MCV, or WBC. Discussion This study demonstrates the feasibility and importance of TCD screening in Indian SCD population. TAMMV on TCD was outside the normal range in nearly a quarter of children with SCD, as has been reported in studies in other populations. The findings of this study may not be representative of stroke risk in tribal populations since they were underrepresented in this study. These data provide the rationale for implementing systematic screening with TCD to reduce the risk of stroke in children affected by SCD in India. Disclosures Darbari: Novartis: Membership on an entity's Board of Directors or advisory committees; Hilton Publishing: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: one day advisory board meeting .

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