Annual Joint Bleeding Rate Research Articles

The Efficacy of Recombinant FVIII Low-Dose Prophylaxis in Chinese Pediatric Patients With Severe Hemophilia A: A Retrospective Analysis From the ReCARE Study

This study explores the efficacy of recombinant factor VIII (rFVIII) low-dose prophylaxis in Chinese pediatric patients with severe hemophilia A from the Retrospective Study in Chinese Pediatric Hemophilia A Patients With rFVIII Contained Regular Prophylaxis (ReCARE) population. This is additional analysis of the multicenter, retrospective ReCARE study, in which the annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and safety of >12-week, low dose (10-30 IU/kg/wk) rFVIII prophylaxis divided into primary, secondary, and tertiary groups based on the joint status and joint bleeding history were analyzed. A total of 57 patients (median age: 8.2 [0.4-17.3] years) from the ReCARE study receiving primary (n = 3), secondary (n = 21), and tertiary (n = 33) prophylaxes were included. Low-dose prophylaxis had significant bleeding reduction in all 3 groups compared to the baseline ( S = 408.5, P < .001), with median ABR rates of -4.0 (-8.0 to -3.1), -4.0 (-24.0 to 8.0), and -13.9 (-110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively, with a significant difference between the secondary and tertiary groups ( P = .008). Median AJBR reduction rates were -2.3 (-6.3 to 8.4) and -14.9 (-61.5 to 19.1) in the secondary and tertiary groups, respectively. But there was no significant difference in AJBRs between the secondary and tertiary groups ( P = .061), which was related to damaged joint status. Hence, longer prophylaxis was associated with better prevention of joint bleeding ( P = .024). Despite significant ABR/AJBR reduction in all 3 groups, the efficacy of the primary prophylaxis was better than the secondary and tertiary prophylaxes.

Defining Haemostatic Safety Zones for the Practice of Sport in Patients with Severe Haemophilia By Thromboelastography

Introduction: Sport may comprise variable physical activity associated bleeding risk(BRisk) in haemophilia. We aimed to determine value of global thromboelastography (TEG) profile for tailoring prophylaxis in patients younger than 18 years old (YO) with severe haemophilia A (SHA) subjected to activities with different BRisk.Methods: Patients with SHA, younger than 18 YO and on prophylaxis at least 12 months before inclusion were invited to participate. Patients signed informed consent before inclusion. Samples before prophylactic dosing were collected. Factor VIII (FVIII) and kaolin-activated TEG profile were determined. Physical activity (PhA) and annual joint bleeding rate (AJBR) were recorded retrospectively. BRisk was categorized following the US-National Haemophilia Foundation guidelines (1= safe; 1.5= safe-moderate risk; 2= moderate risk; 2.5= moderate-dangerous risk; 3= dangerous risk of bleeding).Results: 26 patients, median age (min-max) 10.3 (6.8-14.3) YO were included. Sixty one percent of patients had BRisk= 1.0; 7.7% had BRisk= 2.0 and 2.5; 23,1% had BRisk= 3. In the last 12 months, haemarthrosis were presented in 33% of patients with BRisk=3.0 and 13% in those with BRisk= 1.0. Interesting, patients with BRisk= 2.0 or 2.5 did not present any joint bleeding in the previous year. Median levels of FVIII was 0.5 (0.0-1.9) IU/dl. There were no differences on trough FVIII levels between patients with or without joint bleeds (FVIII= 0.3 [0.0-1.9] and 1.1[0.2-4.4] IU/dl respectively, p=0.515) in the year before. There was no correlation between FVIII trough plasma levels and the AJBR (p=0.416). TEG trough profiles were similar in patients with and without haemarthrosis. However, patients with AJBR=0 presented a clear correlation between trough TEG parameters and BRisk (BRisk vs. k: r=-0,439; p= 0.047 and BRisk vs. alpha angle: r= 0.478; p= 0.025) so that, the higher the exercise-associated BRisk the higher procoagulant state needed to keep a joint-bleeding-free state. This correlation was not found for FVIII.Conclusions: Kaolin-activated TEG assay may help to define safety zones to minimize bleedings in response to PhA in patients < 18 YO with SHA and may guide prophylaxis tailoring depending on BRisk of PhA. DisclosuresNo relevant conflicts of interest to declare.

Improved Clinical Outcomes and Replacement FVIII Consumption in Patients with Hemophilia a after Prophylaxis Adjustment Using a FVIII Pharmacokinetics Estimation Based on Bayesian Models

INTRODUCTIONCurrent guidelines recommend that subjects with severe hemophilia A (HA) receive prophylaxis in order to prevent severe bleeding and recurrent hemarthrosis that lead to the development of arthropathy, an extremely painful and disabling condition. Success of this approach greatly depends on treatment individualization, and the pharmacokinetics (PK) of factor VIII (FVIII) replacement therapy in a given patient is a crucial consideration.Standard PK studies require extraction of 6 to 10 samples, a procedure that takes several hours and causes adult patients and the parents of pediatric patients to miss work and children to miss school. This represents a significant barrier for routine performance of PK tests, and more rapid methods are needed in order to universalize PK-based adjustment in clinical practice.Björkman et al. developed a method to estimate PK parameters of factor FVIII using Bayesian models (Haemophilia 2010, 16(4):597-605). This approach requires only 2-3 blood extractions between 4 and 48 h after infusion, and may help introduce PK-based tailoring in hemophilia clinics. Based on this methodology, an online tool was developed to perform PK estimates in patients using the FVIII product Advate® (myPKFiT®, www.mypkfit.com; Baxter Healthcare Corporation; Haemophilia 2014, 20 (Suppl.2):15).This report describes the impact of using this tool to adjust prophylaxis regimens in clinical practice, in terms of clinical bleeding and joint bleeding rates and FVIII consumption, in subjects with HA receiving prophylaxis.METHODSThis is an observational case series of 3 Spanish centers. Thirty-four patients were evaluated (30 severe and 4 moderate HA) aged 7-52 years (median 22 years). All were receiving prophylaxis, and all received Advate® as replacement factor.myPKFiT® was used for estimations in 2014-2015. FVIII trough levels were adjusted between 1% and 2%. We evaluated the annual bleeding rate (ABR), the annual joint bleeding rate (AJBR) and annual FVIII use before and after PK adjustment of prophylaxis using the study tool.RESULTSOf the 34 patients,16 had not previously undergone a PK study (NPAP group), while 18 had already had their therapy previously adjusted by trough FVIII levels determination (PAP group). Most patients (n = 23) were following an M/W/F infusion schedule before myPKFiT® study. Median weight was 60 kg (interquartile range [IQR] = 32-78). Two samples were used for determinations in 27 patients, 3 in 5, and 4 in 2. Median FVIII half-life calculated with the study tool was 11.95 h (IQR = 10.13-14.33); median clearance was 0.035 dl/h/kg (IQR = 0.027-0.042), and median time until FVIII level 1% was 59.5 (IQR = 50.8-72.0).FVIII use, ABR and ABJR before and after adjustment with the parameters provided by myPKFiT® are summarized in Table 1. Adjustment had an impact in the individual factor consumption of most patients: in 14 cases, the annual amount was reduced (mean −34824 ± 49925 IU/year), and in 16 it was increased (mean +60605 ± 43517 IU/year). However, this did not have a significant impact in the mean amount used in the whole series compared to that used the year prior to myPKFiT-adjusted prophylaxis (p = 0.196). Regarding clinical outcome, ABR and AJBR were both significantly reduced in the NPAP group, where 68.7% and 62.5% of patients reduced their ABR (p = 0.008) and AJBR (p = 0.008), respectively, after adjustment. These rates were generally maintained after myPKFiT-based personalization in the PAP group.CONCLUSIONSClinical experience in this series suggests that PK-adjusted prophylaxis by means of a tool such as myPKFiT® may have a favorable impact on the prophylaxis regimens of HA patients. Clinical benefit can be achieved in patients whose therapy has not previously been adjusted using PK-based methods, and this personalized approach can reduce bleeding rates without significantly increasing the overall cost of FVIII therapy. Furthermore, the maintenance of bleeding rates in patients with prophylaxis previously adjusted by determination of trough levels suggests that outcomes with this method might be comparable. DisclosuresMingot-Castellano:Amgen: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy; Bayer: Consultancy, Research Funding. Parra:Baxalta: Consultancy.

Individualized Prophylactic Treatment with Recombinant Factor VIII in Severe or Moderate Haemophilia a Patients. Association Between Pharmacokinetic Parameters and Clinical Variables

Background:Prophylaxis with recombinant factor VIII (rFVIII) is considered the optimal treatment for severe or moderate haemophilia A (HA). Bleeding into joints determines a proportional chronic joint damage to its frequency and severity. Knowledge of the individual's pharmacokinetics (PK) using Bayesian analysis helps to individualize prophylaxis therapy with recombinant factor VIII (rFVIII) in severe or moderate haemophilia A (HA) and minimize the risk of bleeding, extracting only 2-3 samples.MethodsRetrospective study in HA patients with rFVIII (Advate®) prophylaxis from January 2014 to May of 2016. Bayesian model (myPKFit®) was employed to perform an individual PK profile using the retrospective data of rFVIII levels. PK parameters analyzed were: clearance (Cl); steady state volume (Vss); plasma half-life (t1/2); and time to reach rFVIII levels <1% (T1%). Intraindividual and interindividual coefficients of variation (CV) of the t1/2 were calculated. Besides, Kruskal-Wallis test (R® version 3.1.2) was employed in comparisons between t1/2 and clinical variables: annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), Gilbert score (GS), Pettersson scale (PS) & lower extremity affected joints detected by NMR.ResultsNineteen patients were analyzed, with a mean age of 32 years (SD: 11.3; range 11-46) and 86 PK monitoring (4.5 per patient). Two patients with <15 years were excluded because t1/2 was lower than adult patients. The mean PK values in adult patients were: Cl 2.9 (0.40) mL/h/kg; Vss 50.0 (<0.001) ml/kg; t1/2 14.1 (2.1) h; and T1% 74.4 (14.4) h. The mean intraindividual CV in t1/2 was 3.6% (SD 0.02; range 0.3-6.6), whereas interindividual CV was 14.8%. We categorized t1/2 in short (<p25: 12.3 h), normal (p25-p75) and long (>p75 14.4 h), with average age of 19.5; 39.4 & 35.8 years, respectively.We detected significant differences between t1/2 and median values of joint state, but not in ABR and AJBR. The mean values of joint scores were: PS (5.5, 22.1; 17; p=0.028), GS (1, 25.9, 17.6; p= 0,008) and NMR (1.2, 2.6, 2.0; p=0.042) for short, normal and long t1/2, respectively.The limited number of patients only allows observe significant differences in patients with short t1/2, patients that also have significantly lower age (p=0.007). The younger age of these patients also justifies the lower joint damage observed. After excluding two patients <15 years significant differences in the scores of the joint state disappeared, showing that age could be a confounding variable.ConclusionPK monitoring showed a low intraindividual variability in t1/2, but significant interindividual CV. Age could modify PK parameters, so it should be assessed in an integrated manner with other clinical variables. Bayesian estimate with MyPKFit® allows know the PK profile of each patient and could be a useful tool to individualize prophylaxis adjusting by the physical activity and the bleeding pattern. We are performing a personalized one-year program to identify and treat the specific causes of poor bleeding control in prophylaxis therapy, and these are our preliminary results.Acknowledgments: This study will be supported by Baxalta grant "H15-29403". DisclosuresCid:Baxalta Innovations GmbH, now part of Shire: Other: Investigator Clinical Studies.

Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A

Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FⅧ preparation using dosage 16.7 (8.0-23.5) U/(kg·time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children.

Intermediate-Dose Tertiary Prophylaxis Show a Better Joint Protection in Adults with Severe Hemophilia Than Low-Dose Patterns

Background and Introduction:Prophylaxis treatment is considered optimal care for patients with severe hemophilia during childhood to prevent bleeding and reduce the incidence of joint disability. However, tertiary prophylaxis may also benefit Adults with Severe Hemophilia, but the optimal dose tailoring of FVIII is still unknown. We initiated a study to compare the low-dose and intermediate-dose regimen for tertiary prophylaxis in adults with severe hemophilia A.Methods:Patients with severe hemophilia A (F VIII < 1%) born between January, 1978, and January, 1988, who were treated at the hemophilia treatment centre at Nanfang hospital and treatment data available were eligible for enrollment in the study. The main exclusion criteria were a history of FVIII inhibitor (titer ≥ 0.6BU [Bethesda unit]), detectable FVIII inhibitors at screening (titer ≥ 0.4 BU), chronic liver disease, immunodficiency, another hemostatic defect and the need for major surgery. A total of 40 adults with severe hemophilia were enrolled, including 25 patients with low-dose prophylaxis (5-10 IU/kg twice a week) and 15 patients with intermediate-dose prophylaxis ( FVIII 15-20 IU/kg twice a week). Breakthrough acute bleedings were treated according to the regular practice and guidelines.Results:The study was conducted over a 2-year period (January 2014 to December 2015).Compared to low-dose prophylaxis group, Intermediate-dose tertiary prophylaxis group reduced the annual number of total and joint bleeds (median 13 vs 5.5 and median 10 vs 4; P= 0.001, respectively), and annual target joint bleeding rate were also significantly lower (median 8 vs. 3.5, P =0.002). The breakthrough bleeding events were largely lower in intermediate-dose group than in low-dose group (P=0.03). After prophylaxis, the FISH score in Intermediate-dose group increased from median 21 (range 15-28) to median 24 (range 17-28) (P=0.02) and in low-dose group from median 22 (range 14-28) to median 24 (range 14-28) (P=0.02) respectively. The improvement of FISH score were different between two groups (P=0.04). Meanwhile, The Health-related Qualityof life (HRQoL) in patients with severe hemophilia were measured by the SF-36. The SF-36 score showed better results in terms of overall perceived health status between patients with Intermediate-dose and with low-dose prophylaxis (P < 0.01).Conclusion:Compared to low-dose prophylaxis, Intermediate-dose tertiary prophylaxis may show a better joint protection in Adults with Severe Hemophilia, for Intermediate-dose regimen not only means less joint bleeding, but also helps joint function restore and Quality of life improvement. Our study established that Intermediate-dose tertiary prophylaxis may be a better choice for adults in a number of hemophilia treatment centers in China. DisclosuresNo relevant conflicts of interest to declare.

Prospective evaluation of treatment regimens, efficacy and safety of a recombinant factor VIII concentrate in haemophilia A: the German EffeKt study.

Collecting clinical data under routine conditions remains important to monitor continuously efficacy and tolerability of an established product. This prospective observational study aimed at evaluating efficacy and tolerability of full-length sucrose-formulated recombinant FVIII (rFVIII-FS; KOGENATE(®) Bayer/KOGENATE(®) FS) in routine use and analysing concomitant diseases and medication. Haemophilia A patients treated with rFVIII-FS were followed up for 24 or 36 months. Efficacy, tolerability, concomitant medication and diseases were assessed at yearly intervals. Two hundred and twenty-one documented patients were mainly pretreated, predominantly with prophylaxis (74%). On study, 54 (31%) patients in the efficacy set (n = 174) documented regular prophylaxis, 91 patients (52.3%) failed to document their prescribed prophylactic infusions, 25 (14.4%) received on-demand treatment and four patients (2%) inhibitor adapted therapy. Patients on regular prophylaxis reported 8.4% of infusions for bleeding treatment and on-demand patients reported 55.3%. Young patients experienced mainly trauma-related bleedings and older patients reported spontaneous bleedings. Joint status was good overall. Median annual spontaneous joint bleeding rate in all groups was zero. A total of 79.0% of all bleedings were successfully treated with one or two infusions. Degenerative arthropathy and arterial hypertension were the most prominent concomitant diseases. Eighty-seven patients (40.5%) took at least one concomitant drug on study, mostly drugs for pain treatment related to haemophilic arthropathy. Two patients presented with positive inhibitor titres on study, one of them was a previously untreated patient and the other had a positive inhibitor history. This study corroborates the tolerability and efficacy profile of rFVIII-FS.

Discontinuing early prophylaxis in severe haemophilia leads to deterioration of joint status despite low bleeding rates.

Prophylaxis is the recommended treatment for children with severe haemophilia A, but whether prophylaxis should be continued in adulthood is still under debate. Previous studies with limited follow-up have suggested that some patients may be able to stop prophylaxis in adulthood, while maintaining good joint health. This single-centre observational cohort study examined patients with severe haemophilia A born 1970-1988 without inhibitor development, and assessed the long-term consequences of discontinuing prophylaxis. Patient-initiated changes in prophylaxis, including all switches to on-demand treatment lasting a minimum of two consecutive weeks, were recorded from the time self-infusion began until the last evaluation. Sixty-six patients were evaluated at a median age of 32.4 years: 26 % of patients had stopped prophylaxis for a median of 10 years, 15 % had interrupted prophylaxis and 59 % had continued prophylaxis. Annual joint bleeding rate (AJBR), Haemophilia Joint Health Score (HJHS-2.1; 0-124 points), radiological Pettersson score (0-78 points) and Haemophilia Activities List score (HAL; 100-0 points) were compared between patients who stopped and patients who continued prophylaxis. Although self-reported bleeding rates and functional limitations were similar in both groups (AJBR: 1.5 vs 1.2 and HAL: 84 vs 84 for those who stopped and continued prophylaxis, respectively), objective assessment of joint status showed increased arthropathy after 10 years of on-demand treatment in patients who stopped prophylaxis compared with those who continued (HJHS: 23 vs. 14 and Pettersson: 16 vs 5, respectively; P< 0.01). These results support continuation of long-term prophylaxis in adults and demonstrate the need for objective monitoring of joint status.

Comparison of Short-Term Tertiary Prophylaxis at Low-Dose and Intermediate-Dose for Adults with Severe Hemophilia a in China

▪Background: Some studies had indicated that the joint damage progression could not be prevented by low-dose prophylaxis regimen though it had been practiced and achieved good outcomes as well as largely reduced bleedings. we initiated a retrospective study to compare the different outcomes between low-dose and intermediate-dose regimen of tertiary prophylaxis for adults with severe hemophilia A.Methods: Data collected from the hemophilia treatment centre at Nanfang hospital from July 2010 to February 2015 ( median 2 years of follow-up), a total of 40 adult patients with severe hemophilia A (FVIII < 1%) who are receiving prophylaxis treatment≥1 year and treatment data available were eligible for enrollment in the study, including 25 patients in low-dose regimen(F‡[8-15 IU/kg 1-2times weekly or weekly<30 IU/kg), and 15 patients in intermediate-dose regimen( F‡[ 15-20 IU/kg 2-3 times weekly or weekly≥40IU/kg and <75 IU/kg). Collect the data with patients' characteristics, previous condition and treatment, treatment efficacy indexFannual bleeding rate(ABR), annual joint bleeding rate(AJBR), number of target joint, annual target joint bleeding rate, annual severe bleeding event, etc.), FVIII consumption. Use FISH scoring system to evaluate patients' joint status, use the difference between the beginning of this study and one year ago of FISH score to represent the improvement of joint function. To analyze the joint function in various subgroups(joint bleeding rate ≤5 times or >5 times) under prophylaxis treatment. Screening out patients whose dosage and frequency adherence both >75% in two groups, including 15 patients in low-dose regimen and 14 patients in intermediate-dose regimen, observed the situation that breakthrough bleeding events occurred in different time period after clotting factors' injection and calculate the proportion.Results: 1. There were no statistical differences between two groups in age, weight, age at first bleeding, age at first treatment, family history of hemophilia and history of hepatitis. (the range of p-value was 0.221-1.000). 2. Intermediate-dose prophylaxis regimen reduced ABR than the low-dose regimen (median 13 vs. 5.5, P=0.000), as well as AJBR (median 10 vs. 4, p=0.001) and the annual target joint bleeding rate (median 8 vs. 3.5, p=0.002) .Reduced median annual absent days was found in intermediate-dose regimen group (median 7.5 vs. 0, p=0.005). In terms of total annual usages of FVIII, the intermediate-dose regimen group increased 35% than low-dose regimen group(2630 IU/kg/year vs.1950 IU/kg/year,P=0.000), but decreased 63% ABR, 60% AJBR and 56% annual target joint bleeding than low-dose regimen group. There was no statistical differences between low-dose and intermediate-dose groups in terms of target joint numbers (median 1 vs.1,P=0.579) and annual severe bleeding events(median 0 vs.0, P=0.911). 3. There was statistical differences between two groups on the improvement of FISH(P=0.008). The proportion that patients' annual joint bleeding rate ≤5 in low dose and intermediate-dose group were 12% and 73.3%. When AJBR ≤5, the mean improvement of Fish score of low-dose and intermediate-dose group was 0.33 and 1.18, When AJBR>5, the mean score was -0.09 and 1.00 respectively, while the joint function still improved in intermediate-dose group.3. The low-dose group had higher proportion of breakthrough bleeding in 24-48h after FVIII injection (median 45.5% vs.27.95%, P=0.000), while intermediate-dose group got higher proportion in more than 48h after FVIII injection (median 60% vs.43.75%,P=0.001).Conclusion: 1. Compared to low-dose prophylaxis regimen, the ABR, AJBR, annual target joint bleeding rate, annual absent days and joint functionwere significantly decreased in patients treated with intermediate-dose regimen.2. It is indicated the intermediate-dose prophylaxis treatment would be better in long-term effect than low-dose regimenin improving joint function. 3. The low-dose group had higher proportion of breakthrough bleeding in 24-48h after FVIII injection, while intermediate-dose group got higher proportion in more than 48h after FVIII injection. Once every other day regimen is beneficial to further reduce bleedings in intermediate-dose prophylaxis treatment. DisclosuresNo relevant conflicts of interest to declare.

Joint Bleeding Patterns in Patients Treated Prophylactically with an Extended Half-Life, Pegylated, Full-Length Recombinant Factor VIII (BAX 855)

BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In a pivotal trial, 101 previously treated patients (PTPs) received BAX 855 for prophylaxis twice weekly (in the per protocol analysis set). At screening, 67/101 (66.3%) of patients had arthropathy (reported in medical history or history of joint surgery) and 69/101 (68.3%) had at least 1 target joint. A target joint was defined as a single joint (ankle, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period.Overall, among these 101 PTPs, the mean (standard deviation) annualized joint bleeding rate (AJBR) was 1.8 (3.0) and 57.4% of patients had zero joint bleeding episodes. There were 32, 40, and 29 subjects with 0, 1-2, and ≥3 target joints, respectively, at screening. Patients with more target joints at screening experienced higher AJBRs: with mean AJBRs of 1.15, 1.84, and 2.58 for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Of the individual joints, ankle and knee joints had highest AJBRs.BAX 855 demonstrated efficacy in the treatment of joint bleeding, with the majority of joint bleeding episodes, irrespective of target joint status, treated with 1-2 infusions: 92.8%, 91.9% and 94.4% for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Hemostatic efficacy of BAX 855 at 24 hours was rated as excellent or good in >90% of patients, regardless of target joint status at screening.Patients with 0 target joints at screening had 57.1% of joint bleeding episodes considered mild in severity, while patients with 1-2 or ≥3 target joints had 59.5% and 66.7% of joint bleeding episodes, respectively, rated moderate in severity. There were few joint bleeding episodes considered severe.Similar doses per infusion of BAX 855 were used to treat joint bleeding episodes: the mean dose per BAX 855 infusion was 35, 33.8, and 36.2 IU/kg for patients with 0, 1-2, and ≥3 target joints, respectively.In conclusion, BAX 855 demonstrated a favorable efficacy profile in the treatment of breakthrough joint bleeding episodes, and twice-weekly use was efficacious in prevention of bleeding, with the lowest overall AJBRs achieved in patients in the trial without target joints. DisclosuresManco-Johnson:Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Ma:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Klamroth:Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau. Engl:Baxalta: Employment, Equity Ownership. Griparic:Baxalta: Employment. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors

Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible.Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy.Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week)Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2).Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. [Display omitted] [Display omitted] DisclosuresOzelo:Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.

Early prophylaxis in children with severe haemophilia A: clinical and ultrasound imaging outcomes.

This observational study was undertaken with the aim to describe the characteristics and evaluate the outcomes of prophylactic treatment in children with severe haemophilia A (HA) treated at our centre. Twenty-five patients aged 4-19years with severe HA, no history of inhibitors and treated with at least two infusions of factor VIII (FVIII) per week were studied. Prophylactic doses and annual joint bleeding rate (AJBR) were retrospectively evaluated over the last 5years. Current joint status was assessed using the Haemophilia Joint Health Score (HJHS) (136 joints of 23 patients) and the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) procedure (124 joints of 21 patients). Median AJBR was 0.2 and median prophylaxis dose 65.4IU-1 kg-1 week-1 . Median total HJHS was 0 (range 0-13) and total HEAD-US 1 (0-8). At the joint level, 85.3% of joints were normal on HJHS and 79.0% on US. The ankle was the joint most commonly affected, considering bleeding and ultrasound results. Correlation was found between HEAD-US scores and bleeding scores but not between HEAD-US and HJHS scores. HJHS and HEAD-US scores were concordant in 91/124 (73.4%) joints (86 joints normal and five abnormal). Ultrasound detected minimal changes in 19.6% of joints with normal physical function, whereas 12.2% of joints considered normal on ultrasound showed changes at HJHS. A well-preserved joint status was found in our cohort. High-resolution US detected a higher percentage of abnormalities than the physical evaluation, but the clinical implications of these findings still need to be ascertained.

Bleeding Phenotype with Various Bay 94-9027 Dosing Regimens: Subanalyses from the Protect VIII Study

▪Introduction: Factor VIII (FVIII) products with a longer half-life may allow for longer intervals between treatments for patients with hemophilia A and may facilitate prophylaxis tailored to an individual’s bleeding phenotype. BAY 94-9027, a PEGylated FVIII product, demonstrated an extended half-life in a phase 1 trial and was well tolerated and efficacious in a phase 2/3 study with dosing intervals up to every 7 days. In this subanalysis of the phase 2/3 trial, bleeding frequency calculated based on the BAY 94-9027 prophylactic dosing regimen during the study was compared with reported bleeding frequency in the 12 months before enrollment. Also, on-study annualized bleeding rates (ABRs) for joint, spontaneous, and trauma bleeds are presented by treatment group.Methods: PROTECT VIII was a multinational, partially randomized, open-label, 36-week study in previously treated patients aged 12–65 years with severe hemophilia A and no history of FVIII inhibitors. Patients received BAY 94-9027 for 36 weeks either on demand or prophylactically. Patients were assigned to 1 of 3 prophylaxis dosing regimens based on the number of bleeds observed during a 10-week run-in period, during which all patients in the prophylaxis arm were treated with 25 IU/kg BAY 94-9027 2x/week. Patients with ≤1 breakthrough bleed during the 10-week period were randomized 1:1 to BAY 94-9027 45–60 IU/kg every 5 days or 60 IU/kg every 7 days. Patients with ≥2 breakthrough bleeds received 30–40 IU/kg BAY 94-9027 2x/week. ABR and annualized joint bleeding rate (AJBR) for the 12 months before the study (collected retrospectively at screening) were compared with values calculated in patients previously treated with prophylaxis who used BAY 94-9027 prophylaxis during the study (weeks 0–36 for the combined prophylaxis groups [including the 10-week period]; weeks 10–36 for the 3 assigned prophylaxis dosing regimens). ABRs for joint, spontaneous, and trauma bleeds during the study were analyzed for the on-demand and combined prophylaxis groups (weeks 0–36) and in relation to patients’ BAY 94-9027 dosing regimen (weeks 10–36).Results: The intent-to-treat population comprised132 patients (prophylaxis, n=112; on demand, n=20). In patients previously treated with prophylaxis, median ABR and AJBR during BAY 94-9027 prophylaxis (weeks 0–36) were lower than corresponding prestudy values; ABR and AJBR during weeks 10–36 for every-5-day, every-7-day, and 2x/week BAY 94-9027 dosing were also lower than or comparable to prestudy values (Table). Median ABRs for joint, spontaneous, and trauma bleeds were lower for the combined prophylaxis groups (weeks 0–36) compared with the on-demand group (combined prophylaxis groups: 1.5, 1.4, and 0.0, respectively; on-demand group: 16.3, 14.3, and 9.1). In the prophylaxis arms (weeks 10–36), median ABRs for joint, spontaneous, and trauma bleeds were 2.1, 0.0, and 0.0 for 2x/week dosing; 1.9, 0.0, and 0.0 for every-5-day dosing; and 1.9, 1.9, and 0.0 for every-7-day dosing.Abstract 1526. TableBleeding Frequency During BAY 94-9027 Prophylaxis vs Prestudy ValuesCombined Prophylaxis,2x/week, week 10–36Every 5 Days,Every 7 Days,week 0–36(n=87)*Required†(n=9)NotRandomized‡(n=6)week 10–36(n=34)week 10–36(n=37)ABR, medianPrestudy5125.532Study2.828.70.751.482.88P value0.00150.24450.07660.00390.4981AJBR, medianPrestudy293.522Study1.467.2401.401.39P value0.00450.34840.06730.01310.4111P values (paired Student’s t test) are nominal, as no multiplicity control was applied.*n=86 for AJBR.†Patients with ≥2 breakthrough bleeds in weeks 0–10.‡Patients with ≤1 bleeds in weeks 0–10 who were not randomized (randomized arms were filled).Conclusions: BAY 94-9027 prophylaxis resulted in lower ABRs and AJBRs during the 36-week study period compared with prestudy values in patients previously treated with prophylaxis. Subgroup analyses based on prophylactic dosing regimens (including dosing intervals of up to every 7 days) showed that patients who were randomized based on bleeding phenotype during the 10-week run-in period achieved bleeding control that was better than or comparable to their prestudy levels, highlighting the value of individualized phenotype-based dosing with BAY 94-9027. In addition, prophylaxis with BAY 94-9027 resulted in reduced joint, spontaneous, and trauma bleeds compared with on-demand treatment. DisclosuresBoggio:Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, and Pfizer: Consultancy. Hong:Bayer HealthCare: Employment. Wang:Bayer HealthCare Pharmaceuticals: Employment. Michaels:Bayer HealthCare Pharmaceuticals: Employment.

ADVATE prophylaxis: post hoc analysis of joint bleeding episodes

SummaryIntroductionThe ADVATE (rAHF‐PFM) Prophylaxis Study compared the efficacy of (i) standard factor (F) VIIII prophylaxis (SP) (20–40 IU kg−1 every other day) vs. pharmacokinetic‐tailored prophylaxis (PKP) (20–80 IU kg−1 every third day) and (ii) both prophylactic regimens with on‐demand therapy (OD) in 66 previously on‐demand‐treated patients (median age: 26 years; range: 7–59) with FVIII ≤2% and ≥8 joint haemorrhages in the year before enrolment.AimThe aim of this study was to evaluate joint bleeding episodes during the on‐demand and prophylactic study periods.MethodsA post hoc analysis of joint bleeding episodes in the per protocol analysis set (n = 53) was conducted.ResultsThe annualized joint bleeding rate (AJBR) was significantly lower for subjects treated with 12 months of SP (n = 30) or PKP (n = 23) as compared with 6 months of OD (n = 53): 55 {median AJBR 0.48 [interquartile range (IQR) 1.96]}, 72 [1.00 (4.07)] and 1164 [38.65 (24.81)] respectively (P &lt; 0.0001). Median AJBR was comparable during both prophylaxis arms (0.5 and 1.0 respectively). In contrast, median AJBR during on‐demand therapy was 38.7 (P &lt; 0.0001).ConclusionBoth SP and PKP significantly increased the median number of days between joint bleeding episodes compared with OD: 268.9, 182.9 and 7.4 respectively (P &lt; 0.0001). Study subjects experienced these joint‐protective benefits of prophylaxis regardless of the number of baseline target joints.