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

Peri-Procedural Management and Outcomes of Patients with Hemophilia on Emicizumab Prophylaxis

Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor X and is administered via subcutaneous injection. It provides protection against bleeding in patients with hemophilia A (HA) with and without inhibitors of all ages. Since licensure, the use of emicizumab has increased across hemophilia treatment centers (HTCs). Management of patients on this drug who require procedures has not been well established. The objective of this study was to report peri-procedural hemostasis management as well as bleeding and thrombotic outcomes in a heterogenous group of patients with HA on emicizumab requiring interventional procedures. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019 that underwent a surgical, dental or interventional procedure prior to July 15, 2019. Data extraction included: demographics, diagnosis, inhibitor, emicizumab dosing data, surgery type, factor used during surgery, and bleeding or thrombotic complications during or after surgery. Results There were a total of 19 procedures in 19 subjects during the study period. 18 were male and all had severe HA. Age at initiation of emicizumab in this cohort ranged from 5 weeks to 27 years; median 5.7 (IQR) yrs. There were 6 patients with an active inhibitor at the time of emicizumab initiation. All patients received emicizumab 3.0 mg/kg weekly x 4 loading doses, followed by either weekly (8), every other week (10), or monthly (1) dosing. There were 18 minor procedures during the study period (14 port removals and one of each of the following: PE tube removal, laparoscopic inguinal hernia repair, arthroscopy, and dental extraction) and one major procedure (intracranial ventricular shunt revision )(Table 1). Of the 14 port removals, 5 patients (1 with inhibitor) did not receive pre-procedure factor replacement; the other 7 received rVIIa or factor VIII pre-procedure and 2 of these patients received a subsequent dose as part of their plan. Three of the 14 patients that underwent port removal (one with inhibitor) were noted to have swelling and hematoma at the surgical site 1-2 days post-op and received 1-2 doses of subsequent factor to treat these bleeding events; only one of these patients did not receive pre-procedure factor. The patient who underwent major surgery received multiple doses of FVIII (to keep FVIII levels >50% x 1 week) and did not have bleeding complications. There were no thrombotic complications. Conclusions In general, the 19 patients with HA who required procedures while on emicizumab did well. Port removal was the most common procedure, which was not surprising given the transition from intravenous to subcutaneous prophylaxis. There was variation in practice, particularly in regard to the need for clotting factor prior to port removal. Most patients did well with 0-1 treatments prior to minor procedures, and no additional replacement. Although 3 of the 14 patients required 1-2 unplanned infusions of clotting factor post port removal, there was no clear relationship between pre-procedure factor replacement and post-procedure port hematoma. This observational study provides useful information for providers who manage patients with HA on emicizumab, although larger studies are clearly needed to help determine best practice. Disclosures Guelcher: Takeda: Other: Advisory Board; Octapharma: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board. Butler:Hema-Biologics: Consultancy; pfizer: Other: Advisory board; genetech: Other: Advisory board. Guerrera:Bioverativ: Consultancy; Novo Nordisk: Consultancy; Pfizer: Other: Advisory Board; Bayer: Other: Advisory Board; Shire: Other: Advisory Board; Kendrion: Other: Advisory Board; Genetech: Other: Advisory Board. Raffini:Roche: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board.

AGING WITH HEMOPHILIA: THE CHALLENGE OF APPROPRIATE DRUG PRESCRIPTION

In high-income countries persons with severe hemophilia (PWH) A and B are aging, like their age-matched peers without hemophilia from the general population. Aging is associated not only with the comorbidities stemming from their inherited bleeding disorder (arthropathy, chronic viral infections such as hepatitis and AIDS) but also with the multiple chronic ailments associated with aging (cancer, cardiovascular disease, COPD). Multimorbidity is inevitably associated with polypharmacy, i.e., the chronic daily intake of at least five drugs, and with the related risk of severe adverse events associated with the use of inappropriate drugs and drug-drug interactions. Information on the pattern of drug prescription and usage by PWH is relatively scanty, but on the whole, the available data indicate that the rate of polypharmacy, as well as the risk of drug-drug interaction, is relatively low in PWH and better than that in their age peers without hemophilia followed by general practitioners. It is believed that this advantage results from the collaborative coordination on drug prescribing exerted, through their integration with practitioners and organ specialists, by specialized hemophilia treatment centers in the frame of comprehensive care programs. However, the available cross-sectional data were mainly obtained in relatively young PWH, so that there is a need to obtain more accurate data from the ongoing prospective studies that are being carried out in more and more progressively aging PWH. Keywords: Hemophilia; Aging; Comorbidity; Drugs Interaction.

Follow-up and Treatment Expectancy and Compliance of Y-Generation Hemophiliacs

Introduction: Generation is called for the human community, which is born in the same time frame, shaped by similar events, tendencies or developments. Y-generation; born between 1981-1999, 40% of our country's population, are the most active community of labor life. There are 4860 Hemophilia A and 878 Hemophilia B patients in our country and 45% of them are members of Y-generation. Compliance is the most important problem in the management of this congenital bleeding disorder. It is necessary to recognize, understand, communicate and cooperate with Y-generation PwHs. Materials and Methods: In our multicentre cohort study, between November 2016 and May 2017, 65 Y-generation PwHs and 56 caregivers (totally 121) were included and the focus groups were conducted with face to face interviews. Results: While the rate of regular prophylaxis remained at 46% in the answers given by the PwHs individuals, their caregivers reported it as 71% which is significantly different. Intravenous administration and other physical difficulties respectively were reported as major problems for not doing prophylaxis regularly by PwHs and their caregivers (60% and 25%). The other reported problems are supply of medication (15% and 18%), treatment periods and emotional support (17% and 9%). It has been identified that the items Y-generation PwHs and their caregivers most need are; medication and treatment support, emotional support, social inclusion, financial support, and specialized centers (HTC) that offer hemophilia management like hemophilia treatment centers, respectively. When the usage of social media was questioned, for PwHs and their caregivers, it was found that; Facebook was 85% - 55%, Instagram was 83% - 32% and Youtube was 74% - 21%. Discussion: Y-generation PwHs, do not show sufficient care to maintain the gold standard prophylaxis. To be successful, the treatment should be individualized, the life conditions and activities of the patient should be taken into account and the patient should be included in the decision making. Considering Y-generation PwHs and their caregivers priorly requests for support for accesing medication and treatment in our country.; it is important to underline that it should not be the only purpose in the management and adequate education is necessary for the comprehensive care. In this respect, it will enable a more active life and the time-spent outside the house, for social activities like sports and travelling will increase. In conclusion; It is important to understand, negotiate and cooperate with Y-generation PwHs in order to be successful in the management of the disease. In order to emphasize the contribution of prophylaxis on quality of life, the number of educational platforms (camps, meetings, etc.) where PwHs and their caregivers can reach the right information, should be increased and; primarly, multidisciplinary Hemophilia Treatment Centers should be established under the leadership of a hematologist. Disclosures No relevant conflicts of interest to declare.

Secondary prophylaxis with anti-inhibitor coagulant complex (AICC) : from anecdote to reality.

Background. Evidence of prophylaxis benefit in patients without inhibitors to reduce hemarthrosis and severe bleeding have not been demonstrate in patients with hemophilia A (HA) and inhibitors, however, we could assume the reduction in bleeding episodes. Several publications have shown good results of secondary prophylaxis with AICC agents to reduce safely the number of bleeding events. We report the results in hemophilia treatment centers of two cities in a developing country, with access difficulties related to the high cost of this therapy to the health system. Objective. To describe the frequency of hemarthrosis and other bleeding episodes in patients with HA and inhibitors under AICC (Feiba®) prophylaxis.

Alloantibodies in von Willebrand Disease

Abstractvon Willebrand disease (VWD), the most commonly known inherited bleeding disorder, is caused by a partial (type 1) or total (type 3) deficiency or dysfunction (type 2) of von Willebrand factor (VWF). Its management encompasses the prevention or treatment of bleeding by raising endogenous VWF levels using a synthetic agent, such as desmopressin, or providing exogenous VWF concentrates. The development of inhibitory alloantibodies against VWF is a rare but often severe complication encountered during the treatment of type 3 VWD, which is associated with a lack of hemostatic response to infused VWF concentrates and more rarely with allergic, even anaphylactic, reactions. This narrative review will focus on the characteristics of such alloantibodies and their management, which can be very challenging for physicians operating at hemophilia treatment centers.

New therapies for hemophilia

Individuals with severe hemophilia have benefitted from 5 decades of advances that have led to widespread availability of safe and efficacious factors VIII and IX, a multidisciplinary integrated care model through a network of specialized hemophilia treatment centers, and aggressive introduction of prophylactic replacement therapy to prevent bleeding and preserve joint health. Yet, there are remaining challenges and treatment gaps which have prevented complete abrogation of all joint bleeding, and progressive joint deterioration may continue in some affected individuals over the course of a lifetime. Some of these challenges can now be addressed with recombinant clotting factors with extended half-life that may improve adherence to prophylaxis regimens through more convenient infusion schedules, maintain higher plasma levels for longer when clinically necessary, and allow for better adaptation to individual phenotypic and pharmacokinetic variability. Real-world case studies will be presented that illustrate practical application of these newly approved therapies in clinical practice and the clinical trial data that have demonstrated the potential for improved clinical outcomes by implementing these strategies.