scholarly journals Administration of Dexamethasone during Initial Exposure to Factor VIII Prevents the Development of Anti-Factor VIII Antibodies and Increases the Proportion of Thymic but Not Splenic Regulatory T Cells in the Exon 16 Knockout C57Bl6 Hemophilia Α Mouse Model

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 237-237 ◽  
Author(s):  
Maria T. Georgescu ◽  
Paul C. Moorehead ◽  
Kate Sponagle ◽  
Birgit M. Reipert ◽  
Christine Hough ◽  
...  
Keyword(s):  
Immune Response ◽  
Mouse Model ◽  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Initial Exposure ◽  
Inhibitor Development ◽  
Cd8 Cells ◽  
High Propensity

Abstract Background: The most severe complication of hemophilia A (HA) treatment is the development of inhibitory antibodies (inhibitors) to factor VIII (FVIII). The presence of immunological ‘danger signals’ during initial exposure to FVIII may increase the risk of developing inhibitors. Promoting an anti-inflammatory environment during initial exposure to FVIII may therefore prevent inhibitor development in HA patients. Glucocorticoids are used clinically for their immunosuppressive and anti-inflammatory properties. There has also been evidence to suggest that these agents have the ability to induce regulatory T cells (Tregs): a CD4+CD25+FoxP3+T cell subset involved in the maintenance of tolerance to self-antigens. Previous work in our laboratory showed that administration of the glucocorticoid dexamethasone (Dex) during initial FVIII exposure renders tolerance to FVIII in exon 17 knockout (E17KO) HLADRB1*1501 C57Bl6/S129 HA mice. When treated with recombinant human FVIII (rhFVIII) this model has an anti-FVIII antibody incidence of 30%. In contrast, the E16KO C57Bl6 HA mouse model has 100% antibody incidence when treated with rhFVIII. Using this second model provides a method for validating our treatment protocol in an animal model with no inherent tolerance to FVIII and facilitates future mechanistic studies due to its homogeneous genetic background. Aims: To assess the ability of Dex administration during initial FVIII exposure to reduce the FVIII immune response in a HA mouse model with high propensity for inhibitor development, and enumerate lymphocyte subsets in the spleen and thymus to examine possible mechanisms of this treatment. Methods: E16KO C57Bl6 HA mice received Dex (75 μg, intraperitoneally) and rhFVIII (6 IU, intravenously) (rhFVIII+Dex Group) or rhFVIII alone (rhFVIII Group) for five consecutive days. Five weeks later, blood was collected via cardiac puncture. Plasma anti-FVIII antibody titres and FVIII inhibitory activity were determined using an anti-FVIII immunoglobulin G (IgG) ELISA and Bethesda assay respectively. Statistical comparisons were calculated using the Fisher’s exact and Mann-Whitney U tests. To elucidate early effects of the treatment, E16KO C57Bl6 mice received rhFVIII, Dex, rhFVIII+Dex, or HBSS for five consecutive days. Three days later the spleen and thymus were harvested. The percentages of splenic B cells (CD19+) and Tregs (CD4+CD25+FoxP3+) as well as thymic Tregs (CD4+CD8-CD25+FoxP3+) were quantified by flow cytometry. Statistical comparisons were calculated using a 2-tailed Student’s t-test. Results: Five weeks after treatment, 77% of mice in the rhFVIII+Dex Group vs 100% of mice in the rhFVIII Group developed detectable anti-FVIII IgG (p=0.0485). Furthermore, mice in the rhFVIII+Dex Group had overall lower anti-FVIII IgG titres (p=0.0063) and lower inhibitory activity (p=0.0783) than mice in the rhFVIII Group. Examination of the spleen three days after Dex treatment showed a decrease in the percentage of CD19+ cells in comparison to HBSS (41% vs 54%, p=0.0152). The same effect was observed with Dex+rhFVIII in comparison to rhFVIII (48% vs 54%, p=0.0489) or HBSS (48% vs 54%, p=0.0212). No significant changes were detected in the percentage of CD4+CD25+FoxP3+splenocytes across treatment groups. In the thymus, Dex caused a decrease in the percentage of CD4+CD8+ cells (42% vs 76%, p=0.0184) and an increase in the percentage of CD4-CD8+ cells (24% vs 7%, p=0.0107) in comparison to HBSS. The same effects were observed with Dex+rhFVIII in comparison to rhFVIII (40% vs 72%, p=0.0204; 20% vs 8%, p=0.0368) or HBSS (40% vs 76%, p=0.0137; 20% vs 7%, p=0.0266). The percentage of CD4+CD8- cells remained unchanged across treatment conditions. Dex caused an increase in the percentage of thymic CD4+CD8-CD25+FoxP3+ cells when compared to HBSS (11% vs 4%, p=0.0188). The same effect was observed with Dex+rhFVIII in comparison to rhFVIII (12% vs 5%, p=0.0006) or HBSS (12% vs 4%, p=0.0001). Conclusions: Administration of Dex during initial FVIII exposure reduces the anti-FVIII immune response in a HA mouse model with high propensity for inhibitor development. The effect is accompanied by a decrease in the percentage of splenic B cells and thymic CD4+CD8+ cells, and an increase in the percentage of thymic CD4-CD8+ cells and Tregs. These findings suggest potential mechanisms whereby glucocorticoid administration results in tolerance to FVIII in HA mice. Disclosures Moorehead: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Reipert:Baxter Innovation GmbH: Employment. Hough:Bayer: Research Funding. Lillicrap:Bayer: Research Funding; Baxter: Research Funding; Biogen-Idec.: Research Funding; CSL-Behring: Research Funding.

scholarly journals Lack of Inhibitor Development in the American Thrombosis and Hemostasis Network (ATHN)-2 Factor Switching Study: Preliminary Report of Primary Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1114-1114
Author(s):  
Robert F. Sidonio ◽  
Dunlei Cheng ◽  
Christine Guelcher ◽  
Janna M. Journeycake ◽  
Susan U Lattimore ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Primary Outcome ◽  
Hemophilia A ◽  
Advisory Board ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development

Introduction: With many standard half-life (SHL) and extended half-life (EHL) recombinant factor VIII and factor IX products licensed in the US over the last 6 years, it is likely that previously treated patients (PTPs) will consider switching to a new EHL FVIII or FIX product. Although past product switching surveillance suggests no increased inhibitor development risk, there is the need for a real-world data on the incidence of inhibitor development following switching from SHL to EHL rFVIII or rFIX in PTPs with hemophilia A and B. Methods: A longitudinal, observational study of participants with Hemophilia A or B who switched to a rFVIII or rFIX concentrate licensed after Jan 1, 2013. The study included retrospective (switched within 50 exposure days (EDs) and prospective arms. Participants were recruited from ATHN-affiliated Hemophilia Treatment Centers (HTCs). The primary outcome measure was the development of a new inhibitor (i.e. neutralizing antibodies to factor VIII or IX) a 1 year or during the 50 EDs following the product switch. Plasma samples were collected at baseline, 10 EDs and 50 EDs. Inclusion criteria include moderate or severe hemophilia A/B currently on a plasma-derived or recombinant FVIII or FIX concentrate with planned or recent switch to an EHL FVIII or FIX concentrate approved after Jan 1, 2013. Participants with an active inhibitor at time of enrollment or undergoing ITI or switched to a non-factor product were excluded. Results: 303 hemophilia participants from 27 treatment centers were enrolled from 2015 to June 2019. The median age at enrollment was 17 years (IQR 10-32 years). 300 of 303 participants were male, Caucasian (72.6%) and had private insurance (44.9%). 74.3% were FVIII deficient and 25.7% were FIX deficient. Most had severe hemophilia A or B, 82.3% (n=237) and 12.8% (n=37) had a prior history of inhibitor but were negative at the time of enrollment. Prior to the switching, 92.1% (n=197) and 7.9% (n=17) of hemophilia A participants took standard rFVIII or pdFVIII respectively, while 87.8% (n=65) and 12.2% (n=9) of hemophilia B participants took standard rFIX or pdFIX, respectively. The three most frequent switching reasons were extended half-life consideration (n=192; 66.7%), a desire for a longer acting version (n=55; 19.1%) and less than expected clinical response to the current product (n=15; 5.2%). Among 214 participants with hemophilia A, 182 (85.0%) switched to FVIII EHL products while 23 (10.7%) switched to new SHL FVIII. For nine patients (4.2%) switching product information was not available. 72 out of 74 (97.3%) participants with hemophilia B that switched products, switched to an EHL rFIX. Eleven hemophilia participants (six A and five B) entered a second cycle of switching after the completion of the first switching cycle. Following that, four switched to FVIII EHL products, two to new SHL rFVIII and five to rFIX EHL products. A total of 193 (63.7%; 148 FVIII, 45 FIX) participants completed the clinical trial while 36 (11.9%; 26 FVIII, 10 FIX) did not complete the trial and 74 (24.4%) are ongoing in the trial. None of 303 (0%) enrolled participants developed an inhibitor, the primary outcome for this study, through data updated 6/2019. Variability was noted in per-site enrollment. The median enrollment per Hemophilia Treatment Center (HTC) was 10, the IQR was 7-16 with a range of 1-31. The types of factors associated with patients switches are summarized in the figure. Conclusion: No new inhibitors were noted among 303 moderate/severe hemophilia A/B PTPs without active inhibitors at entry, who switched factor VIII or IX products over 50 exposure days or 12 months. This result provides real-world evidence of the rarity of inhibitor development after a product switch in PTPs. The study also achieved a key logistical objective: to demonstrate feasibility of a prospective observational study across ATHN sites. Figure Legend: Factor types to which ATHN-2 patients switched during the study. Disclosures Sidonio: Grifols: 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; Kedrion: 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; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guelcher:Takeda: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board. Takemoto:genentech: Membership on an entity's Board of Directors or advisory committees; novartis: Other: DSMB membership. Tarantino:Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI, Speakers Bureau; Roche: Consultancy; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Grant Reviewer , Research Funding; Octapharma: Consultancy, Speakers Bureau. Neufeld:Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

scholarly journals Immunization Against Influenza but Not MMR Modulates the Anti-Factor VIII Immune Response in Hemophilia Α Mice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1501-1501
Author(s):  
Jesse Lai ◽  
Paul C. Moorehead ◽  
Kate Sponagle ◽  
Katharina Nora Steinitz ◽  
Birgit M Reipert ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Vaccine ◽  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Danger Signal ◽  
Mmr Vaccine ◽  
Advisory Committees ◽  
Danger Signals ◽  
Specific Igg

Abstract Introduction: The etiology of inhibitory factor VIII (FVIII) antibodies in 25-30% of hemophilia A (HA) patients remains poorly understood. It is possible that concurrent exposure to inflammatory stimuli, or ‘danger signals’, with FVIII increases the risk of inhibitor formation. HA patients generally begin FVIII replacement therapy around 12 months of age, and the median age of inhibitors onset is between 15-21 months. During this time frame, patients may be exposed to vaccines, such as the mumps-measles-rubella (MMR) and seasonal influenza vaccines. Our investigation is the first to address the concern that these vaccines may serve as danger signals that augment FVIII immunogenicity. Methods: Our studies used 8-12 week-old FVIII E17KO C57Bl6/S129 HA mice, which carry a complete knockout of all murine MHC class II molecules, and instead express a chimeric human-mouse HLA-DRB1*1501 allele associated with increased inhibitor risk. Our preliminary studies show that 40-80% of these animals develop FVIII inhibitors following treatment. HA mice were immunized with 10x the standard human dose of live-attenuated MMR vaccine (Priorix) subcutaneously or intravenously 24 hrs prior to 4 weekly intravenous infusions of 2 IU recombinant human FVIII (rhFVIII, Advate). Mice were subsequently re-challenged with MMR 24 hrs prior to 4 biweekly infusions of 6 IU rhFVIII. Blood samples were collected retro-orbitally or via cardiac puncture. Plasma from weeks 5 and 9 was assessed for anti-FVIII IgG by ELISA; inhibitor concentrations were assessed by a Bethesda assay on week 9. The inactivated influenza vaccine (Agriflu) was administered at standard human doses either intramuscularly or intravenously 24 hrs before, after, or concurrently with the first of 7 biweekly infusions of 6 IU rhFVIII. Week 5 plasma samples were subjected to anti-FVIII and anti-influenza IgG ELISA and Bethesda assays. Statistical comparisons were made using the Fisher’s exact Mann-Whitney U tests, as appropriate. Results: Subcutaneous MMR vaccination exhibited no significant differences in the incidence or titres of anti-FVIII IgG compared to HBSS-injected controls at weeks 5 and 9 (n=13). Similarly, no differences in the incidence or concentration of inhibitors were detected at week 9. We next evaluated the effects of intravenous MMR immunization on FVIII immunogenicity. Surprisingly, we again observed no differences in the incidence or magnitude of the anti-FVIII immune response at weeks 5 and 9 (n=28-30). Importantly, we found a significant decrease in the incidence of FVIII-specific IgG in mice that were immunized intramuscularly with the influenza vaccine 24 hrs after and at the same time as the first infusion of rhFVIII (t=-24 hrs: 30%, t=0 hrs: 20%, t=+24 hrs: 26% vs control: 67%; p=0.11, 0.06, 0.04; n=10-15). Similarly, there was a significant decrease in the incidence of inhibitors at all immunization time points (t=-24 hrs: 30%, t=0 hrs: 43%, t=+24 hrs: 11% vs control: 80%; p=0.03, 0.02, 0.0022). No differences in IgG titres or inhibitor concentrations were detected. When immunized intravenously with the influenza vaccine, we observed an increase in the presence of FVIII-specific IgG, but no differences in titres. However, these differences were not statistically significant and need confirmation (t=-24 hrs: 80%, t=0 hrs: 90%, t=+24 hrs 40% vs control: 50%; p=0.58, 0.14, 1.00; n=5-10). Conclusion: These are the first experimental studies to address vaccination as a potential danger signal in the development of an anti-FVIII immune response. Our results suggest that both subcutaneous and intravenous immunization of HA mice with the MMR vaccine do not influence the incidence or magnitude of the anti-FVIII immune response. In contrast, our data suggest that intramuscular immunization with the inactivated influenza vaccine modulates the anti-FVIII immune response and may enhance tolerance induction to FVIII, possibly through antigen competition. However, this proposal awaits further confirmation. Finally, a trend in increased antibody and inhibitor incidence in intravenously immunized mice suggests that the influenza vaccine can serve as a danger signal, but is dependent on the route of administration. Our findings contradict current vaccination concerns in the treatment of young HA patients, and instead suggest an inhibitor-protective effect from influenza immunization. Disclosures Moorehead: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Steinitz:Baxter: Employment. Reipert:Baxter: Employment. Hough:Bayer: Research Funding. Lillicrap:Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding.

scholarly journals Regulatory T Cell Response to Factor VIII in Mothers of Children with Hemophilia Inhibitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3512-3512
Author(s):  
Margaret V. Ragni ◽  
Lynn M. Malec ◽  
Craig D. Seaman ◽  
Lisa Butterfield
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
T Helper Cell ◽  
T Helper ◽  
Advisory Committees ◽  
Healthy Donors

Abstract Background: Inhibitor formation is among the most serious complications of hemophilia A. These alloantibodies are directed against foreign infused factor VIII (FVIII) and occur in up to 25-30% of children with severe hemophilia A, after the first 9-10 exposures to FVIII. The inhibitor neutralizes infused FVIII, requiring alternative "bypass" therapy to treat bleeds, e.g. factor VIIa or FEIBA, to "bypass" the missing factor, and immune tolerance to suppress the inhibitor. Despite these approaches, bleeding is poorly controlled, resulting in 2-fold as many hospitalizations, 10-fold the cost, and 1.7-fold higher mortality. As the burden of disease is high, efforts have been directed at preventing inhibitors. There is increasing evidence that a specialized subset of T cells known as T-regs or CD4+/CD25+/FoxP3+ regulatory T cells, may play a role in mediating immune response to FVIII. Differentiation and function of T-regs are controlled by the X-chromosome-encoded transcription factor, FoxP3, and are generated centrally in the thymus and peripherally in extrathymic tissues. In the inhibitor-prone hemophilia A mouse (FVIII exon 16 knockout) T-regs reduce or prevent immune response to factor VIII: this is presumed to occur through T-reg-mediated hyporesponsiveness of T helper cells to factor VIII. T-regs also mediate maternal tolerance to the fetus in normal pregnancy. In early pregnancy there is an increase in immunosuppressive T-regs, peaking during the second trimester, and declining postpartum. T-regs are hypothesized to modify maternal immune response to the fetal "allograft" to promote tolerance to foreign paternal-derived antigens in the developing fetus. We hypothesized that defects in maternal T regulatory response to factor VIII might be associated with lack of normal FVIII tolerance in their offspring, leading to an alloantibody response, i.e. inhibitor formation. We therefore sought to quantitate and functionally characterize T-regs in mothers of children with congenital hemophilia A with inhibitors, in order to determine if maternal lack of tolerance to FVIII is associated with inhibitor formation in their affected sons. Methods: Following informed consent, heparinized tubes were drawn from four mothers of hemophilic children, two with and two without inhibitors, cared for at the Hemophilia Center of Western PA (HCWP). T-reg responses to factor VIII were quantitated by flow cytometry, and phenotyping was performed by staining with anti-CD4/Foxp3/CD3/CD25/CD39 monoclonal antibody markers. Functional characteristics of the T-regs were determined in a T-reg proliferation assay using autologous antigen presenting cells (DCs) in the presence or absence of FVIII. Results: CD4+ T cell proliferative responses to factor VIII (FVIII) were decreased in all four mothers (Figure 1). Mothers of hemophilic sons with inhibitors demonstrated a 1.36-fold decrease (Pt 001) and a 1.1-fold decrease (Pt 002), as compared with mothers of hemophilic sons without inhibitors, who demonstrated a 1.47-fold decrease (Pt 003) and a 1.45-fold decrease (Pt 005) in CD4+ proliferative responses, unlike the two healthy donors who showed minimal (or no) factor VIII response. Patients showed slightly less proliferation with Factor VIII vs. no antigen; healthy donors showed minimal (or no) Factor VIII response (Figure 1). Discussion: These preliminary results demonstrate lower T cell proliferative responses to FVIII in mothers of children with inhibitor patients than in mother of children without inhibitors. This suggests there is lack of tolerance to FVIII in mothers of children with hemophilia, with or without inhibitors. These responses would also imply these mothers have no tolerance to paternal FVIII, but further studies will be needed to confirm these findings and to characterize maternal T regulatory response to factor VIII, and, in particular, paternal FVIII. Figure 1. Percent CD4+ T Helper Cell Proliferation +/- Factor VIII (FVIII) Figure 1. Percent CD4+ T Helper Cell Proliferation +/- Factor VIII (FVIII) Disclosures Ragni: Alnylam: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Biogen: Research Funding; SPARK: Research Funding; Pfizer: Research Funding; Ferring Pharmceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Medscape, Web MD: Honoraria; Genentech Roche: Research Funding; Vascular Medicine Institute: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; CSL Behring: Research Funding; Dimension Therapeutics: Research Funding; Biomarin: Research Funding. Malec:Biogen: Research Funding; Baxalta: Research Funding. Seaman:Vascular Medicine Institute: Research Funding.

scholarly journals Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2409-2409
Author(s):  
Tiffany Lin Lucas ◽  
Shveta Gupta ◽  
Joanna A. Davis ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Haemophilia A ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Octapharma: Membership on an entity's Board of Directors or advisory committees.

Iron Overload Diminishes the Effectiveness of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4071-4071
Author(s):  
Patrick B Walter ◽  
Paul R Harmatz ◽  
Annie Higa ◽  
David Killilea ◽  
Nancy Sweeters ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Iron Overload ◽  
Board Of Directors ◽  
Innate Immune Response ◽  
Research Funding ◽  
Innate Immune ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Fluorescent Intensity

Abstract Abstract 4071 Poster Board III-1006 Introduction Infection is the second most common cause of death in thalassemia. The innate immune system provides a first line of defense against infection and specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) are important for transducing the signal for bacterial Lipopolysaccharide (LPS), resulting not only in cytokine production, but also in the control of extracellular iron levels through production of neutrophil gelatinase associated Lipocalin (NGAL). However, the exact role that NGAL plays and the expression level of PRRs are unknown in thalassemia. Thus, the goal in these studies is to investigate the relationship of iron overload to the innate immune cell expression of PRRs and NGAL in thalassemia. Patients and Methods Fifteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox (an oral iron chelator) and deferoxamine were enrolled (Novartis sponsored CICL670AUS24T). Fasting blood samples were obtained i) at baseline after a 72 hr washout of chelator, and ii) at 6 and 12 months on study. Five healthy controls (13 - 18 yrs old) were also enrolled. Fresh monocytes were isolated using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes were verified by flow cytometry. The expression of TLR4, also examined by flow cytometry is reported as the mean fluorescent intensity (MFI). In patients with thalassemia, liver iron concentration (LIC) was analyzed by biomagnetic susceptibility (“SQUID”, Ferritometer®). The plasma levels of NGAL were analyzed by ELISA. Results At baseline the expression of monocyte TLR4 (mean 18.8 ± 3.5 MFI) was reduced 30% compared to the healthy controls (mean 26.9 ± 7.6 MFI, p<0.05). The expression of TLR4 over the follow-up period of 52 weeks in patients receiving intensive combination chelator therapy significantly increased 27% / year (7 MFI / year, p=0.005). Interestingly the expression of monocyte TLR4 was negatively correlated with LIC (r=-0.6, p=0.04). Finally, thalassemia patients at baseline have significantly higher levels of NGAL (80 ± 20 ng/ml) compared to controls (42 ± 15 ng/ml, p=0.01). Conclusions These preliminary studies support the hypothesis that iron burden has a negative impact on the innate immune response in thalassemia as demonstrated by the decreased expression of TLR4. After intensive chelation, the levels of TLR4 increased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. Finally, the iron transport protein NGAL is significantly elevated in thalassemia possibly acting to prevent essential iron uptake by pathogenic bacteria. Disclosures: Harmatz: Novartis: Research Funding; Apotex : Membership on an entity's Board of Directors or advisory committees; Ferrokin: Membership on an entity's Board of Directors or advisory committees. Vichinsky:Novartis: Consultancy, Research Funding.

Treatment Of Serious Bleeds With a B-Domain Deleted Recombinant Porcine Sequence Factor VIII (OBI-1) In Patients With Acquired Hemophilia A: A Prospective Clinical Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 206-206 ◽  
Author(s):  
Rebecca Kruse-Jarres ◽  
Jean St. Louis ◽  
Anne Greist ◽  
Amy D. Shapiro ◽  
Hedy Smith ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Positive Response ◽  
Acquired Hemophilia A ◽  
Advisory Committees ◽  
Baxter Healthcare ◽  
Bayer Healthcare ◽  
Travel Grant

Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder, resulting from auto-antibodies to human factor VIII (hFVIII). The challenges created by the management of AHA and the co-morbidities present in this typically elderly population, can be managed by a recombinant, highly pure, B-domain deleted, porcine sequence FVIII (OBI-1) that is not generally susceptible to the inhibitory activity of anti-human FVIII antibodies. Treatment with OBI-1 allows for monitoring of FVIII levels which provides a reproducible and objective surrogate predictor of hemostasis. Eradication of hFVIII inhibitors with immunosuppressive therapy is critical for disease management. During immunosuppression, the patient transitions from a bleeding state at initial presentation to a relative hypercoagulable state which can be an issue in patients who are susceptible to thromboembolic events due to their comorbidities. This transition period is of most concern especially when using traditionally utilized bypassing agents that cannot be monitored. OBI-1 enables measurement of FVIII levels, guiding dosing and enhancing treatment safety during this critical period. Methods This global, prospective, multi-center phase 2/3 open label clinical trial investigates the efficacy and safety of OBI-1 in the treatment of serious bleeds in adults with AHA conducted under ICH guidelines and local IRB/Ethics Committee oversight. Primary efficacy endpoint was assessed at 24 hours (eg. effective, partially effective). All subjects (N= 18) presented with a serious bleed and were treated with an initial dose of OBI-1 (200 U/kg), followed by additional doses based on the subject's target factor VIII levels, anti-OBI-1 titer, and clinical factors. Results In all 18 subjects, a positive response (14 effective/4 partially effective) to treatment was observed at 24 hours. This positive response to OBI-1 treatment was seen by 8 hours in 14/18 of the subjects and at 16 hours in 16/18 of the subjects. Median total exposure to OBI-1 per subject was 1782.5 U/kg. The median total first dose was 14,000 U. For subjects who received additional doses of OBI-1, the median dose was reduced from the initial dose, but did not differ considerably over subsequent doses (9180 to 13561 U; median 11000 U). The majority of subjects (17/18) received concomitant immunosuppressive therapies. No related serious adverse reactions occurred. Non-serious adverse events related to treatment were noted in 5/18 (27.8%) subjects. One subject had mild tachycardia, hypotension and constipation. One subject had 2 instances of mild PICC line occlusion. One subject had a mild hypofibrogenemia. All of these adverse effects completely resolved. Three subjects developed anti-porcine inhibitors after infusion of study drug (range 8-108 BU) and two were discontinued from treatment. Anti-porcine inhibitors were detected prior to infusion in 6/18 patients (range 0.8-29 BU). All of these subjects had a favorable clinical response at 24 hours post-OB-1 infusions. Conclusions Data from this prospective study demonstrate OBI-1 as a safe and effective treatment of bleeding episodes in patients with AHA, with the added advantage over other bypass therapies of allowing FVIII monitoring throughout treatment and healing phase. Disclosures: Kruse-Jarres: Baxter Healthcare: Consultancy; Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy. St. Louis:CSL Behring: Research Funding; Octapharma: Consultancy, Research Funding; Baxter: Consultancy; Novo Nordisk: Honoraria. Shapiro:Kedrion Biopharma: Consultancy; Chugai Pharma USA: Consultancy; Biogen IDEC: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Baxter Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Chowdary:Baxter Healthcare: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel grant Other; Novo Nordisk: Honoraria, Research Funding, Travel grant, Travel grant Other; Bayer HealthCare: Honoraria, Travel grant, Travel grant Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant Other; Biogen IDEC: Honoraria, Travel, Travel Other. Drebes:Octapharma: Travel grant Other; CSL Behring: Travel grant, Travel grant Other; Leo-pharma: Travel grant, Travel grant Other; Bayer Healthcare: Consultancy, Honoraria. Gomperts:Baxter Healthcare: Consultancy; Asklepios Biopharmaceutoicals Inc: Consultancy; Cangene Inc: Consultancy. Chapman:Baxter Healthcare: Employment. Mo:Baxter Healthcare: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3778-3778
Author(s):  
Amy L. Dunn ◽  
Alexis A. Thompson ◽  
Werner Engl ◽  
Marlies Sharkhawy ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Point Estimate ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

scholarly journals Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 891-891
Author(s):  
Annamaria Gulla ◽  
Eugenio Morelli ◽  
Mehmet K. Samur ◽  
Cirino Botta ◽  
Megan Johnstone ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Clinical Outcome ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Escape ◽  
Publicly Traded ◽  
Advisory Committees

Abstract Immune therapies including CAR T cells and bispecific T cell engagers are demonstrating remarkable efficacy in relapsed refractory myeloma (MM). In this context, we have recently shown that proteasome inhibitor bortezomib (BTZ) results in immunogenic cell death (ICD) and in a viral mimicry state in MM cells, allowing for immune recognition of tumor cells. Induction of a robust anti-MM immune response after BTZ was confirmed both in vitro and in vivo: treatment of 5TGM1 MM cells with BTZ induced tumor regression associated with memory immune response, confirmed by ELISPOT of mouse splenocytes. We have confirmed the obligate role of calreticulin (CALR) exposure in phagocytosis and the ICD process, since BTZ-induced ICD is impaired in CALR KO MM cells both in vitro and in vivo. We further showed that the therapeutic efficacy of BTZ in patients was correlated with ICD induction: BTZ-induced ICD signature was positively correlated with OS (p=0.01) in patients enrolled in the IFM/DFCI 2009 study. Together, these studies indicate that ICD is associated with long-term response after BTZ treatment. In this work, we reasoned that genomic or transcriptomic alterations associated with shorter survival of MM patients after BTZ treatment may impair activation of the ICD pathway. To this aim, we performed a transcriptomic analysis of purified CD138+ cells from 360 newly diagnosed, clinically-annotated MM patients enrolled in the IFM/DFCI 2009 study. By focusing on genes involved in the ICD process, we found that low levels of GABA Type A Receptor-Associated Protein (GABARAP) were associated with inferior clinical outcome (EFS, p=0.0055). GABARAP gene locus is located on chr17p13.1, a region deleted in high risk (HR) MM with unfavorable prognosis. Remarkably, we found that correlation of low GABARAP levels with shorter EFS was significant (p=0.018) even after excluding MM patients with del17p; and GABARAP is therefore an independent predictor of clinical outcome. GABARAP is a regulator of autophagy and vesicular trafficking, and a putative CALR binding partner. Interestingly, among a panel of MM cell lines (n=6), BTZ treatment failed to induce exposure of CALR and MM cell phagocytosis by DCs in KMS11 cells, which carry a monoallelic deletion of GABARAP. This effect was rescued by stable overexpression of GABARAP. Moreover, CRISPR/Cas9-mediated KO of GABARAP in 3 ICD-sensitive cell lines (AMO1, H929, 5TGM1) abrogated CALR exposure and ICD induction by BTZ. GABARAP add-back by stable overexpression in KO clones restored both CALR exposure and induction of ICD, confirming GABARAP on-target activity. Similarly, pre-treatment of GABARAP KO cells with recombinant CALR restored MM phagocytosis, further confirming that GABARAP impairs ICD via inhibition of CALR exposure. Based on these findings, we hypothesized that GABARAP loss may alter the ICD pathway via CALR trapping, resulting in the ICD resistant phenotype observed in GABARAP null and del17p cells. To this end, we explored the impact of GABARAP KO on the CALR protein interactome, in the presence or absence of BTZ. Importantly, GABARAP KO produced a significant increase of CALR binding to stanniocalcin 1 (STC1), a phagocytosis checkpoint that mediates the mitochondrial trapping of CALR, thereby minimizing its exposure upon ICD. Consistently, GABARAP KO also affected CALR interactome in BTZ-treated cells, which was significantly enriched in mitochondrial proteins. Importantly, co-IP experiments confirmed GABARAP interaction with STC1. These data indicate a molecular scenario whereby GABARAP interacts with STC1 to avoid STC1-mediated trapping of CALR, allowing for the induction of ICD after treatment with ICD inducers; on the other hand, this mechanism is compromised in GABARAP null or del17p cells, and the STC1-CALR complex remains trapped in the mitochondria, resulting in ICD resistance. To functionally validate our findings in the context of the immune microenvironment, we performed mass Cytometry after T cell co-culture with DCs primed by both WT and GABARAP KO AMO1 clones. And we confirmed that treatment of GABARAP KO clones with BTZ failed to activate an efficient T cell response. In conclusion, our work identifies a unique mechanism of immune escape which may contribute to the poor clinical outcome observed in del17p HR MM patients. It further suggests that novel therapies to restore GABARAP may allow for the induction of ICD and improved patient outcome in MM. Disclosures Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Chauhan: C4 Therapeutics: Current equity holder in publicly-traded company; Stemline Therapeutics, Inc: Consultancy. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 382-382 ◽  
Author(s):  
Beth Boulden Warren ◽  
Dianne Thornhill ◽  
Jill Stein ◽  
Michael Fadell ◽  
Sharon Funk ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Joint Damage ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Episodic Treatment ◽  
Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

scholarly journals Surveillance of Hemophilia in Indiana: A Preliminary Report

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3516-3516
Author(s):  
Amanda Okolo ◽  
John M Soucie ◽  
Scott D. Grosse ◽  
Chris Roberson ◽  
Isaac Janson ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Claims Data ◽  
Factor Ix ◽  
Clotting Factor ◽  
Advisory Committees ◽  
Mortality And Morbidity ◽  
Factor Ix Deficiency

Abstract Background and objectives: Hemophilia is a rare heritable bleeding disorder resulting from missing or deficient levels of factor VIII or factor IX. Hemophilia related complications result in high utilization of health care resources and include severe, debilitating chronic joint disease. In 1998, Soucie et al. published the results of a six-year surveillance study investigating the incidence and prevalence of hemophilia in six U.S. states. The study also described the relationship between mortality and morbidity and each patient's primary source of hematologic care (i.e. whether each patient had visited a federally designated hemophilia treatment center (HTC)). The Indiana Hemophilia Surveillance Project (IHSP) aims to identify all persons with hemophilia who resided in Indiana in 2011-2013, to calculate the prevalence and incidence of hemophilia in Indiana, and to determine the percentage of patients cared for at a federally recognized HTC. The IHSP further aims to compare morbidity and mortality data to the results of the Soucie et al. study. Methods: A hemophilia case in this study is defined as a male with physician-diagnosed hemophilia A or B and a measured baseline factor VIII or IX activity level less than 50%. A retrospective review of medical charts and other records was conducted to identify hemophilia cases during the surveillance years from 2011-2013. Case finding methods involved obtaining medical information from a variety of medical care resources including: HTCs in Indiana and surrounding states, hospitals, vital records, Indiana's birth defects registry, hospital and administrative claims data from the Regenstrief Institute, Medicaid claims data, clinical laboratories, specialty pharmacies, hematology/oncology clinics, and primary care physicians. Demographic and clinical data were collected on all identified cases. Data collected included: demographic information, clinical characteristics, joint health assessments, insurance status, clotting factor product utilization and cost, source of hemophilia care, hospitalizations and emergency room visits, and mortality information. Associations between clinical characteristics were assessed for statistical significance using chi-square and fisher's exact tests. Incidence was calculated by using the number of births from prevalent cases during the three surveillance years as the numerator and the number of live male births in Indiana for each year as the denominator. Results: 704 hemophilia cases were identified in Indiana in 2011-2013. Of those cases, 456 (64.8%) had factor VIII deficiency and 248 (35.2%) had factor IX deficiency. The median age of the population was 25 years. 453 cases (64.3%) were adult patients and 251 cases (35.7%) were pediatric patients under 18 years. Among those with known severity levels (n=685), 233 (33.1%) were severe, 185 (26.3%) were moderate, and 267 (37.9%) were mild. Overall, 81.7% of the hemophilia patients identified visited an HTC at least once during the three year study period, which was the minimum requirement for being considered a patient of an HTC. Age-adjusted prevalence was 21.8 cases per 100,000 males; 14.3 per 100,000 for factor VIII and 7.5 per 100,000 for factor IX. Mean incidence of hemophilia over the three year study period was 1:4059 live male births in Indiana. 24 cases (3.4%) died within the study period; 4.2% of the deaths occurred in HIV positive patients. Of those with a known cost of clotting factor (n=184), the average and median cost of factor over the three year period was $375,532 and $71,525 respectively. Conclusions: There was a significantly higher percentage of patients seen at an HTC (81.7%) as compared to the results of the Soucie et al. study (67%; p =<0.001). Indiana has a 62% higher prevalence and 24% higher incidence of hemophilia than in the Soucie et al. study. A high frequency of factor IX deficiency associated with a founder mutation in the Amish community contributes to the higher incidence of factor IX deficiency in Indiana, with a 64% higher percentage of factor IX deficiency among hemophilia cases. The higher prevalence likely reflects improved survival and increased utilization of HTCs in the past two decades. This report is the first follow-up study of the original Soucie et al. report using the same systematic approach. Further analysis on mortality and morbidity complications in this population will be completed and reported in future reports. Disclosures Shapiro: Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Bio Products Laboratory: Consultancy; Prometic Life Sciences: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; BioMarin: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; OPKO: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Octapharma: Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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