Risk Of Inhibitor Development Research Articles

Predicting inhibitor development using a random peptide phage-display library approach in the SIPPET cohort

AbstractInhibitor development is the most severe complication of hemophilia A (HA) care and is associated with increased morbidity and mortality. This study aimed to use a novel immunoglobulin G epitope mapping method to explore the factor VIII (FVIII)–specific epitope profile in the SIPPET cohort population and to develop an epitope mapping–based inhibitor prediction model. The population consisted of 122 previously untreated patients with severe HA who were followed up for 50 days of exposure to FVIII or 3 years, whichever occurred first. Sampling was performed before FVIII treatment and at the end of the follow-up. The outcome was inhibitor development. The FVIII epitope repertoire was assessed by means of a novel random peptide phage-display assay. A least absolute shrinkage and selection operator (LASSO) regression model and a random forest model were fitted on posttreatment sample data and validated in pretreatment sample data. The predictive performance of these models was assessed by the C-statistic and a calibration plot. We identified 27 775 peptides putatively directed against FVIII, which were used as input for the statistical models. The C-statistic of the LASSO and random forest models were good at 0.78 (95% confidence interval [CI], 0.69-0.86) and 0.80 (95% CI, 0.72-0.89). Model calibration of both models was moderately good. Two statistical models, developed on data from a novel random peptide phage display assay, were used to predict inhibitor development before exposure to exogenous FVIII. These models can be used to set up diagnostic tests that predict the risk of inhibitor development before starting treatment with FVIII.

Race and ethnicity and the success of immune tolerance induction among people with severe haemophilia A in the United States.

Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe haemophilia A with inhibitors. Since the risk of inhibitor development is greater among Black and Hispanic persons, it has been hypothesized that race and ethnicity may influence ITI success. Limited studies have evaluated this hypothesis. To examine the success of ITI according to race and ethnicity. Participants who entered the Community Counts (CC) Registry between 2013 and 2017, were aged ≥3 years at study entry, and received ITI were included (n=559). The proportion of participants with successful ITI was examined with adjusted prevalence ratios (aPRs) and corresponding 95% confidence intervals (95% CIs). Among 559 participants, 56.9%, 19.1%, 18.1% and 4.3% were Non-Hispanic (NH) White, NH Black, Hispanic and Asian, respectively, and 1.7% were coded as other or missing.Approximately 80% of Hispanic, NH Black and NH White participants had good/very good prognosis, defined as having a pre-ITI peak inhibitor of<200 Bethesda Units per millilitre. Nearly 60% of participants (59.7%) achieved successful ITI, 20.7% and 19.5% experienced partially successful or failed ITI, respectively. Successful ITI was non-significantly lower in NH Black (54.2%; aPR=0.95, 95% CI 0.62-1.44) and Hispanic (55.4%; aPR=0.89, 95% CI 0.71-1.13) relative to NH White participants (62.6%). In this study, 60% of participants in the CC Registry had successful ITI, consistent with previous studies. The proportion with successful ITI was generally comparable across racial and ethnic groups with similar prognosis. These findings do not support the hypothesis that ITI response varies according to race or ethnicity.

Genetic variant detection in a South African haemophilia B population.

Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Patient and caregiver preferences for haemophilia treatments: A discrete-choice experiment.

An evolving haemophilia treatment landscape provides new possibilities for previously unattainable lifestyles. We sought to understand how people with haemophilia (PwH) and their caregivers value the potential benefits of novel prophylactic treatments. We conducted a discrete-choice experiment (DCE) to quantify preferences for features of haemophilia treatments among adults and caregivers of children with haemophilia. A best-worst scaling (BWS) exercise measured the perceived burden of treatment administration features. A cross-sectional, web-based survey was administered to male adults (≥18years) and caregivers of male children (≤17years) living with haemophilia in the United States. Respondents evaluated eight pairs of hypothetical haemophilia treatment profiles defined by six attributes in the DCE and 15 features in the BWS. In the DCE, both adults with haemophilia (n=151) and caregivers (n=151) prioritised avoiding the risk of developing inhibitor/ anti-drug antibodies and treatments that allowed for a more active life. They placed a lower priority on reducing the number of spontaneous bleeding episodes, route and frequency of administration, and avoiding the risk of hospitalisation due to adverse events. The BWS documented the burdensomeness of IV infusions and medications that require mixing and refrigeration. PwH and caregivers prefer treatments that enable a more active lifestyle with a lower risk of inhibitor development. Both groups valued the ability to lead an active life over reducing spontaneous bleeding, with caregivers placing the most weight on this attribute. As new treatments expand possibilities, healthcare professionals and PwH should continue to share decision-making, incorporating clinical judgment and individual preferences.

Simoctocog alfa (Nuwiq®) in children: early steps in life's journey for people with severe hemophilia A.

People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq®) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.

Transcriptomic Profiling to Understand Inhibitor Development in Previously Untreated Patients with Severe Hemophilia a

Background: When starting treatment with factor VIII (FVIII) concentrate in individuals with severe hemophilia A, minimizing the risk of FVIII inhibitor development is an important concern for clinicians, patients and their families. Despite increased understanding of some of the genetic and environmental risk factors for inhibitor formation from epidemiological studies, identification of previously untreated patients (PUPs) at risk of developing inhibitors remains a challenge. Prediction of inhibitor development may help optimize care in PUPs with hemophilia A. RNA sequencing (RNA-Seq) with next-generation sequencing (NGS) could be used to investigate the underlying mechanisms of inhibitor development. Aims: Toevaluate peripheral blood transcriptomic profiles prior to and during early FVIII treatment in severe hemophilia A patients who did or did not develop inhibitors to simoctocog alfain the prospective NuProtect study. Methods: The NuProtect study (NCT01712438; EudraCT 2012-002554-23) was a multicenter, multinational, open-label, non-controlled, phase III study that enrolled male PUPs with severe hemophilia A (FVIII:C &amp;lt;1%) of any age and ethnicity. Patients received simoctocog alfa for prophylaxis or on-demand treatment, as well as for surgical prophylaxis. RNA-Seq was performed on blood samples collected from baseline and every 3-4 exposure days (ED) up to 20 EDs or until inhibitor development to assess messenger RNA (mRNA) expression profiles. Bioinformatics analyses were performed for the following timepoints: baseline, early treatment and a later timepoint on treatment. Principal component analysis (PCA) was performed to identify differences in global mRNA expression profiles between inhibitor and non-inhibitor patients. Gene ontology (GO) analyses were performed to detect differences in GO clusters between inhibitor and non-inhibitor patients. Results: Within this first analysis of the full dataset, transcriptomic profiles from 78 of 108 severe hemophilia A PUPs were analyzed (inhibitors n=22, non-inhibitors n=56). Median (range) age at ED1 was 13 (0.5-146) months; 44.9% of patients had the intron 22 inversion F8 gene mutation. Although the PCA indicated no strong global signal for differential expression profiles between non-inhibitor and inhibitor patients, GO analyses demonstrated differences between these patient groups. Inhibitor patients demonstrated increased gene expression of metabolic processes (GO:0008152) and cellular processes (GO:0009987) at baseline. Upregulation of immune system processes (GO:0002376) was seen in inhibitor patients at the early timepoint compared with non-inhibitor patients. Expression of ribosomal proteins, including RPL17 and RPS8 were significantly upregulated at baseline in inhibitor patients (p&amp;lt;0.05). Inhibitor patients further demonstrated upregulation of proteins involved in adaptive immune responses: IGHV1-69-2 at all timepoints (p&amp;lt;0.01) and IGHV2-70D at baseline and the early timepoint (p&amp;lt;0.01) compared with non-inhibitor patients. Upregulation of the B-cell related factors DPP4 at baseline and the early timepoint (p&amp;lt;0.05) and CD20 at the late timepoint (p&amp;lt;0.05) was observed in inhibitor patients compared with non-inhibitor patients. Conclusion: Differential transcriptomic profiles were seen in severe hemophilia A patients who developed inhibitors compared with those who do not, even before commencing FVIII treatment. Inhibitor patients demonstrated alterations in ribosomal protein expression that could disrupt protein synthesis efficiency, protein folding and quality control processes, and trigger cellular stress responses. Inhibitor patients also showed an upregulation of B-cell mediated factors involved in adaptive immune mechanisms. Additional analyses are ongoing to evaluate dynamic changes in gene expression during commencement of FVIII replacement to further identify patients at risk of inhibitor development.

Characteristics Associated with the Success of Immune Tolerance Induction Among People with Severe Hemophilia a in the United States

Introduction: Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe hemophilia A with inhibitors (PwSHAi). An earlier study reported lower receipt of ITI treatment in non-Hispanic (NH) Black and Hispanic compared to NH White PwSHAi (Kempton CL, 2022). Since risk of inhibitor development is greater among Black and Hispanic persons with hemophilia, it has been hypothesized that race and ethnicity may impact the success of ITI. Limited studies have evaluated this hypothesis. This study examined the success of ITI by race and ethnicity among PwSHAi in the Community Counts (CC) Registry between 2013-2017 in the United States (US). Methods: This cross-sectional study used data from the CC Registry, which is a collaboration of the American Thrombosis &amp; Hemostasis Network (ATHN), Centers for Disease Control and Prevention (CDC), and the Hemophilia Center Network (HTCN) using ATHN Study Manager. The CC Registry collects data from people who received care from &amp;gt;135 US hemophilia treatment centers (HTCs). PwSHAi who entered the CC Registry between 2013-2017 and received ITI were selected (n=679); those who were &amp;lt;3 years old at Registry enrollment (n=41) and had history of an inhibitor for &amp;lt;3 years (n=79) were excluded, resulting in 559 people were available for the analyses. Data from 2013-2017 were chosen to represent the pre-emicizumab era where ITI was the standard of care without debate. The 3-year age and inhibitor history cut-point was chosen to ensure ample time for PwSHAi to receive and respond to ITI. The primary outcome was ITI response defined as 1) successful (PwSHAi receiving FVIII replacement therapy at standard doses); 2) partially successful (receiving FVIII replacement therapy at increased dosing); and 3) failed (receiving bypassing agents). Primary independent variables included race/ethnicity, likelihood of ITI success defined with pre-ITI peak inhibitor values alone, grouped as very good [&amp;lt;25 Bethesda Units (BU)], good (25-199 BU), poor (200-999 BU), and very poor (≥1000 BU) prognosis, based on the Future of Immunotolerance Treatment (FIT) group's recent management algorithm (Carcao, 2019). Unadjusted (PR) and adjusted prevalence ratios (aPR) and corresponding 95% confidence intervals (CI) were computed with logistic models with predicted marginals. Results: Among 559 PwSHAi included, 318 (56.9%) were NH White, 107 (19.1%) were NH Black, 101 (18.1%) were Hispanic, 24 (4.3%) were Asian, and 9 (1.7%) were coded as other or missing (Table 1). The median age at Registry enrollment and inhibitor detection was 16 years and 2 years, respectively. Approximately 64% of NH Black, Hispanic, and NH White PwSHAi had either good or very good prognosis, though less than half (41.7%) of Asian PwSHAi had very good or good prognosis. While 59.7% of PwSHAi achieved successful ITI, 20.7% and 19.5% only achieved partially successful or experienced failed ITI, respectively (Table 1). Success of ITI linearly increased according to prognostic group where 21.7%, 36.3%, 55.6% and 69.6% of those with very poor, poor, good, and very good prognosis achieved successful ITI, respectively (χ 2 p-value&amp;lt;.001, Cochran-Armitage Trend p-value&amp;lt;.001). The proportion with successful ITI was non-significantly lower in NH Black (54.2%; PR=0.87,95%CI 0.71,1.05), Hispanic (55.4%; PR=0.89,95%CI 0.73,1.08), and Asian (58.3%; PR=0.93, 95%CI 0.66,1.32) PwSHAi relative to NH White (62.6%) PwSHAi in both crude and adjusted analyses (Table 2). In analyses restricted to those PwSHAi with very good or good prognosis, successful ITI prevalence was nearly identical in NH Black (63.8%) and NH White (64.9%). ITI success was similar across age at inhibitor detection, registry enrollment, health insurance and HTC size (Table 2). Conclusion: Using US CC Registry data, approximately 60% of PwSHAi treated with ITI had a successful response, a proportion similar to previous studies. The proportion of PwSHAi who had successful ITI linearly improved with predicted prognosis, defined by the peak inhibitor titer alone. In our study, prognosis category was generally similar in Hispanic, NH White, and NH Black PwSHAi and the proportion with successful ITI did not vary significantly according to race/ethnicity. These findings do not support the hypothesis that ITI response varies according to race/ethnicity, and it suggests that the benefits of ITI are similar across race and ethnicity.

Development Of Inhibitors In Hemophilia A Patients Receiving Different Treatment Options

Introduction: Hemophilia A is the most common inherited bleeding disorder in Pakistan. Apart from frequent bleeds and joint deformities, the formation of inhibitors is the major complication of hemophilia. Inhibitors are antibodies formed against the coagulation factor. The purpose of this study is to determine the incidence of inhibitor development in hemophilia A patient receiving different treatment modalities namely fresh frozen plasma (FFP)/cryoprecipitate, plasma derived FVIII concentrates and long-acting recombinant FVIII concentrates. Aims &amp; Objectives: To assess the development of inhibitors in hemophilia A patients receiving treatment modalities. Place and Duration of Study: The study was conducted at Chughtai Institute of Pathology from November 2021 to November 2023. Material &amp;Methods: A total of 75 registered patients of the Hemophilia Patient Welfare Society, Lahore and Sundas Foundation were initially screened for FVIII inhibitors. Those who were found negative for these inhibitors were included in the study and then divided into three equal groups of 25 patients each. One group received only FFP/cryoprecipitate for treatment, the other group received plasma derived FVIII concentrates and the last group received recombinant factor VIII concentrates. These patients were observed for two years i.e after 15-20 exposures and following this period their inhibitors screening was done again to establish the effect of different treatment modalities on inhibitor development. The data collected was entered and analyzed by SPSS-21, a p-value of ?0.05 was considered significant. Results: Our study showed that only 3 patients out of 25, receiving FFP as treatment modality developed inhibitors. Whereas, none of the patients receiving plasma derived FVIII concentrates and recombinant factor VIII concentrates developed inhibitors. The P value calculated is 0.044 which is significant. Conclusion: Plasma derived FVIII concentrates and recombinant FVIII concentrates are safer as compared to FFP/Cryoprecipitate and have lesser risk for inhibitor development.

Characterization of an Anti-Factor VIII Inhibitor Related To P.Arg2178Cys Mutation in A Patient with Mild Haemophilia A

In patients with inherited mild haemophilia treated with clotting factor concentrates, the risk of inhibitor development is lower than in severe haemophilia. We report the observation of a 38-year-old man, with mild haemophilia A, previously treated for mucosal bleeding, who presented no major immunization risk factors except an exon 23 missense mutation p.Arg2178Cys in the F8 gene in the C1 domain. He developed an inhibitor against Octocog alfa. The implication of the mutation in this particular immunization process is well known. Characterization of this inhibitor has been extended as a type I inhibitor with classical epitope mapping and solely directed against exogenous factor VIII. Due to the occurrence of an anamnestic response associated with a high titre inhibitor, we had recourse to Eptacog alfa during a critical bleeding situation.

Large Intron Inversions in Romanian Patients with Hemophilia A-First Report.

Background and Objectives: Despite the vast heterogeneity in the genetic defects causing hemophilia A (HA), large intron inversions represent a major cause of disease, accounting for almost half of the cases of severe HA worldwide. We investigated the intron 22 and intron 1 inversion status in a cohort of Romanian unrelated patients with severe HA. Moreover, we evaluated the role of these inversions as relative risk factors in inhibitor occurrence. Materials and Methods: Inverse shifting-a polymerase chain reaction method was used to detect the presence of intron 22 and intron 1 inversions in 156 Romanian patients with HA. Results: Intron inversion 22 was found in 41.7% of the patients, while intron 1 inversion was detected in 3.2% of the patients. Overall, large intron inversions represented the molecular defect in 44.9% of the studied patients. Our findings are in accord with previously published reports from Eastern Europe countries and with other international studies. The risk of inhibitor development was higher in patients with inversion 1 compared to the patients with HA without any inversion detected. Conclusions: The current study demonstrates the major causative role of large intron inversions in severe HA in Romanian patients. Moreover, our study confirms the contribution of intron 1 inversion in inhibitor development.

Impact of ABO blood group antigens on residual factor VIII levels and risk of inhibitor development in hemophilia A

The clinical phenotype of hemophilia A (HA) does not always correlate with severity. Similarly, the presence of inhibitors does not necessarily increase the risk of bleeding. This paradox between clinical and laboratory findings may be partially attributed to non-modifiable factors, such as blood group, which is known to influence FVIII levels in healthy individuals. Our aim was to assess the effect of ABO blood group antigens on FVIII levels across the severity spectrum of HA and risk of inhibitor development. Data of consecutive patients with HA who visited the coagulation unit of a northern Indian tertiary care hospital between 2010‒2021 were reviewed. Patients with missing blood group data, transfusion histories, or baseline FVIII levels were excluded. Mild, moderate, and severe HA was present in 41 (6.9%), 72 (12.2%), and 479 (80.9%) patients, respectively. There were no differences in the FVIII levels among the various blood groups across the HA severity spectrum. Inhibitors were administered to 35 patients (5.9%). In the multivariate analysis, blood group A was an independent risk factor for the development of inhibitors (adjusted odds ratio 2.70, P=0.04) after adjusting for age at onset of bleeding, FVIII transfusion, age at first FVIII transfusion, and severity of HA. Unlike what is observed in healthy individuals, blood group did not influence residual FVIII levels across the severity spectrum of HA. Patients in group A had a higher risk of developing inhibitors.

Real pandemic world results of pharmacokinetic-tailored personalized prophylaxis of bleeds in Polish children and adolescents with severe hemophilia A.

In 2020, the new nationwide protocol of prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). The study aimed to: (1) assess the safety of switching from pdFVIII to rFVIII, (2) assess the safety and efficacy of pharmacokinetically based (PK-based) personalized prophylaxis in severe hemophilia A. 151 children and adolescents receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of the optimal model of prophylaxis was performed in all patients. Two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed, with parents leaving the choice to their decision. Parents reported all episodes of bleeds. Screening for inhibitor was performed every 3 months. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks. 141/151 (93.4%) patients completed the study. 34 patients decided to continue standard prophylaxis with rFVIII (Group I), whereas 107 were switched to PK-based prophylaxis (Group II). The risk of inhibitor development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitor with its spontaneous elimination. The retrospective analysis of bleeds during the last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis had historically lower ABR and AJBR than those who started PK-based personalized prophylaxis. After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period. However, the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis. (1) Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, (2) PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA.

Assessing Sequence Similarity between FVIII-Derived B-Cell Epitopes and Pathogen-Derived B-Cell Epitopes and the Risk of Inhibitor Development in Patients with Severe Hemophilia a

Assessing Sequence Similarity between FVIII-Derived B-Cell Epitopes and Pathogen-Derived B-Cell Epitopes and the Risk of Inhibitor Development in Patients with Severe Hemophilia a

Real Pandemic World Results of Personalized Prophylaxis of Bleeds in Polish Children and Adolescents with Severe Hemophilia a

Introduction and aim of the study: In the autumn of 2020, the new nationwide protocol of bleeding prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). It created the opportunity to perform the study aiming to: 1. assess the safety of switching from pdFVIII to rFVIII 2. assess the safety and efficacy of pharmacokinetically-based (PK-based) personalized prophylaxis in children and adolescents with severe hemophilia A. Patients and methods: A total of one hundred fifty-one patients (median age 166 [93-209] months) receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of optimal (dosing and timing) model of prophylaxis was performed in all patients. All pros and cons of two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed with parents/guardians and/or patients leaving the choice to their decision. Episodes of bleeds in two study groups were reported by parents/guardians using e-diaries and verified by local hemophilia treaters. Screening for inhibitor (INH) development was performed every three months and in every case of clinical suspicion. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks with respect to models of prophylaxis and a type of FVIII used. Rates of bleedings were compared using the Student's t-test. Results: Due to COVID-19 pandemic-related problems, 141/151 (93.4%) patients completed the study. Thirty-four patients decided to continue standard prophylaxis with rFVIII (Group I), whereas one hundred seven were switched to PK-based prophylaxis (Group II). The risk of INH development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitors (0.8 BU/ml after 120 exposure days (EDs) and 1.8 BU/ml after 78 EDs, respectively) with no clinical manifestation and with spontaneous elimination of the inhibitor in both cases. The retrospective analysis of bleeds during last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis (Group I) had better ABR and AJBR than those who started PK-based personalized prophylaxis (Group II). After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period, however the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis (Group II). The prophylaxis results are presented in Figure 1. Conclusions: 1. Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, 2. PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA, especially in those in whom results of previous prophylaxis were unsatisfactory. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patients with Hemophilia and Their Caregivers Prefer Treatment Attributes That Enable a More Active Lifestyle with Lower Risk of Inhibitor Development

Background: The treatment landscape for hemophilia is evolving. Hence it is important to understand how people with hemophilia and their caregivers value attributes of existing and novel prophylactic treatments. A discrete-choice experiment (DCE) was used to quantify preferences for features of hemophilia treatments among adults and caregivers of children with hemophilia in the US. Methods: A cross-sectional, web-based DCE survey was administered to male adults (≥18 years) and caregivers of male children (≤17 years) living with hemophilia in the US. Respondents evaluated 8 pairs of hypothetical hemophilia treatment profiles defined by 6 attributes - number of annual spontaneous bleeding episodes, lifestyle benefits from improvement in function, route of administration, frequency of administration, risk of developing inhibitors or anti-drug antibodies, and risk of hospitalization due to adverse events (AEs). Attributes for the DCE were informed by a literature review and ranking exercise among adult patients, caregivers, physicians, and stakeholders. The DCE data were analyzed using a random parameters logit (RPL) model and used to calculate the maximum acceptable risk (MAR) of AEs respondents were willing to accept for specific improvements in other study attribute levels. MAR is calculated as the point where the disutility of an increase in risk balances the utility associated with an improvement in a treatment attribute. Results: The final sample included 151 adults (average age 40 years) and 151 caregivers (average age 38 years old, 92% female). For the adult sample, avoiding a 30% risk of developing inhibitors or anti-drug antibodies had the greatest relative importance, followed by improving the ability to live a more active life from limited to high, reducing the number of spontaneous bleeding episodes each year from 6 to 0, change in mode of administration from an intravenous (IV) with vial(s) and syringe to mix to a subcutaneous (Sub-Q) injection with pre-filled pen, reducing frequency of administration from once every 2-3 days to once a month, and avoiding a 5% risk of hospitalization due to AEs (Figure 1a). For caregivers, improving the ability to live a more active life from limited to high had the greatest relative importance, followed by avoiding a 30% risk of developing inhibitors or anti-drug antibodies, reducing the number of spontaneous bleeding episodes each year from 6 to 0 annual bleeds, avoiding a 5% risk of hospitalization due to AEs, reducing frequency of administration from once every 2-3 days to once a month, and a change in mode of administration from an IV with vial(s) and syringe to mix to a Sub-Q injection with vial(s) and syringe to mix (Figure 1b). In general, adults and caregivers preferred treatments that needed to be taken less frequently (e.g., once a month compared with every 2-3 days). Adults preferred a Sub-Q injection with a pre-filled pen compared with other routes of administration. Caregivers preferred Sub-Q options to an IV. Looking at the MAR results, caregivers were willing to accept higher risks of developing inhibitors or anti-drug antibodies than adults for improvements in other attributes. Caregivers were willing to accept a risk of developing inhibitors or anti-drug antibodies greater than 30% for an improvement in the ability to live a more active life from limited to high and 21% for a reduction in the number of spontaneous bleeding episodes each year from 6 to 0, compared to 26% and 17% for adults, respectively. Both groups were willing to accept similar levels of risk of hospitalization due to AEs for improvements in other attributes, accepting greater than 5% for improvements in the ability to live a more active life from limited to moderate or high and for a reduction in the number of spontaneous bleeding episodes each year from 6 to either 1 or 0 spontaneous bleeds. Conclusion: Patients and caregivers prefer treatments that enable more active lifestyle with lower risk of inhibitor development. Both groups valued the ability to lead an active life even over reducing spontaneous bleeding, with caregivers placing the most weight on this attribute suggesting that with the changing landscape in hemophilia treatments, patients and caregivers are willing to trade off benefits and risks of hemophilia treatments. These findings highlight the need for healthcare professionals and patients to share decision making based on clinical judgement and individual preferences. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

U.S. Cohort Study of Previously Untreated Patients with Congenital Hemophilia (ATHN 8: PUPs Study): Inhibitor Development and Treatment Characteristics

Background: Persons with hemophilia (PWH) are at risk of developing neutralizing inhibitors to factor product. While some risk factors for inhibitor development are known, mechanisms to delay or prevent this complication are less well understood. American Thrombosis and Hemostasis Network (ATHN) 8: U.S. Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia (NCT03818529) is a longitudinal cohort study of PUPs with moderate or severe hemophilia A (HA) or B (HB) born between 1/2010 and 12/2021 and enrolled from participating ATHN-affiliated hemophilia treatment centers (HTCs). Through this study we sought to understand variables that contribute to inhibitor development. Methods: At each HTC, data were entered for participants until 50 clotting factor exposure days (EDs), development of a confirmed neutralizing inhibitor, or study closure. The primary outcome was inhibitor development defined as a Bethesda Unit (BU) titer of >0.6 for HA or >0.3 for HB and a change in treatment. Secondary outcomes included diagnosis and treatment characteristics. Summary statistics were performed. For participants who met study endpoints at the time of enrollment, logistic regression analysis was utilized to evaluate birth cohort, race, hemophilia severity, genetic variant (for F8 gene only, classified as large structural changes >50 bp, other, and not sequenced), prophylaxis, and 5 or more consecutive EDs as risk factors for inhibitor development. Results: The study enrolled 234 eligible male participants including 135 who had met study endpoints at the time of enrollment; 94 with 50 EDs and 41 with inhibitor. A total of 128 (128/234 = 55%) were White, non-Hispanic. Of 114 HA participants who met a study endpoint prior to enrollment, 38 (38/114 = 33%) developed an inhibitor (3 moderate, 35 severe). The median EDs prior to inhibitor development was 14 (min 1, max 75). Of 21 HB participants who met a study endpoint prior to enrollment, 3 (3/21 = 14%) developed an inhibitor, all with severe disease. The median EDs to inhibitor development was 9 (min 8, max 10). Of the 234 eligible participants, 135 (135/234 = 58%) were on prophylactic treatment at any point. Of these, 33 (33/135 = 24%) received extended half-life (EHL) factor products (HA 20/114 = 17.5%; HB 13/21= 62%), while 14 (14/114 = 12%) with HA were receiving emicizumab. Over the course of the study, the rate of usage of emicizumab rose from 2% to 12% in participants with HA. Seventeen (17/39 = 44%) with HA were on prophylaxis at the time of inhibitor development, including 11 (11/39 = 28%) on standard half-life clotting factor, 1 (3%) on EHL clotting factor, and 0 on emicizumab. One participant with HB was on prophylaxis at the time of inhibitor development: none on standard half-life clotting factor, 1 (1/3 = 33%) on EHL clotting factor. Those who were on prophylaxis had decreased risk of confirmed inhibitor compared to those who were not (Odds ratio 0.24; 95% CI 0.09, 0.67). 89 participants with HA had F8 genetic testing completed, including 10 (11%) with large structural deletions. Large structural deletions were associated with higher inhibitor risk compared to other mutations in PUPs with HA at the time of inhibitor development (Odds Ratio = 5.32 vs. those with other mutations, 95% CI 1.27, 22.25). Race, ethnicity, birth cohort, and 5 or more consecutive EDs were not associated with inhibitor development. Conclusion: In ATHN 8, inhibitor rates for PUPs with HA were consistent with published data and within the typical ED range. Prophylaxis appears to decrease the risk of inhibitor development. As expected, inhibitor development was associated with large structural deletions compared to other variant types in HA. Inhibitor occurrence was not associated with other traditional risk factors. For HB, the inhibitor rate was higher than most previous reports, which may be due to the small number of participants. For PUPs with HA, emicizumab prophylaxis increased over the course of the study period. These results support the use of prophylaxis as a prevention strategy for inhibitor development. Longitudinal follow-up is needed to determine if new treatment products (EHL clotting factor and emicizumab) are associated with changes in inhibitor rates or age at inhibitor development. Although ATHN 8 was closed to enrollment, PUPs will continue to be enrolled and followed in ATHN Transcends (NCT04398628), a natural history study including PUPs with hemophilia.

The Dilemma of the Perpetual Previously Untreated Patient with Hemophilia a

BACKGROUND: Inhibitor development is the most dreaded complication of contemporary hemophilia therapy affecting 30 to 40% of previously untreated patients with hemophilia A and typically occurring within 20 to 50 exposure days. The advent of emicizumab has broadened the therapeutic panorama for hemophilia A, especially for persons with inhibitors. However, could the exclusive use of emicizumab in previously untreated patients delay inhibitor development until the second decade of life because of infrequent exposures to rFVIII? Moreover, administration of high-dose, high-intensity rFVIII for breakthrough bleeding events, trauma, or during surgery may accentuate inhibitor development risk (Sharathkumar et al. JTH, 2003). METHOD: The literature was perused for articles addressing exclusive emicizumab use in previously untreated patients. Additionally, we sought out the advice of physicians on the relevance of exogenous FVIII in persons with hemophilia A and the clinical/psychosocial impact of delayed inhibitor development in previously untreated patients treated exclusively with emicizumab. With this information we propose a therapeutic algorithm for previously untreated patients (Figure 1). RESULTS: Previously untreated patients treated exclusively with emicizumab may generate enough thrombin to recapitulate a mild hemophilia A phenotype. Real-world data on bleeding patterns showed that 51% (36/70) and 61% (43/70) of prospectively followed patients treated with emicizumab experienced at least one episode of spontaneous or traumatic bleeding event, respectively (Levy-Mendelovich et al. J Clin Med 2021). Patel et al. (J Med Econ, 2019) estimate that inhibitor development may be delayed for approximately 14 years after emicizumab exposure. Mason and Young (Haemophilia 2021) describe 4 infant cases highlighting the treatment challenges confronting families and physicians- 3 chose emicizumab prophylaxis cognizant of the prolonged inhibitor risk and 1 chose rFVIII prophylaxis followed by emicizumab to reduce anxiety regarding inhibitor development. An advisory board comprising physician thought leaders in hemophilia was convened to address the relevance of rFVIII as the foundation of hemophilia A therapy. Figure 1 depicts an algorithm to illustrate 2 therapeutic pathways- 1 using a human cell line-derived FVIII product and the other using emicizumab- and the potential patient-related complications with each therapy. Physician feedback suggests that following the rFVIII pathway the time to inhibitor development is finite and afterward breakthrough bleeding episodes become the major therapeutic concern. Following the emicizumab pathway the time to inhibitor development and high-risk treatment periods (breakthrough bleeding episodes, trauma and surgery) with rFVIII will persist until adolescence. Families and physicians will need to constantly think about inhibitor development and plan for this complication. CONCLUSION: Our hypothesis that previously untreated patients exposed exclusively to emicizumab (or other non-factor therapies) may experience a protracted timeline to reach 50 exposure days, which may result in a "perpetual" previously untreated patient status. High-risk treatment periods will be inevitable. Factor and non-factor treatment strategies are available each with its respective set of trade-offs, and families and healthcare providers must consider downstream consequences when selecting one strategy over another. Long-term clinical scrutiny and further research are required to resolve issues arising from this new therapeutic paradigm. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

F9 mutations causing deletions beyond the serine protease domain confer higher risk for inhibitor development in hemophilia B

F9 mutations causing deletions beyond the serine protease domain confer higher risk for inhibitor development in hemophilia B

Correlation Analysis of FⅧGene Mutation and the Production of FⅧ Inhibitor with Severe Hemophilia A Patients in a Single Medical Center

To investigate the relationship between the type of FⅧgene mutation and the development of FⅧ inhibitors in patients with severe haemophilia A (HA). The medical records of 172 patients with severe hemophilia A from January 2009 to September 2020 were reviewed. The types of FⅧgene mutations and the production of factor Ⅷ inhibitors were collected and divided into high-risk mutation group ( intron 1 inversions, large deletions, nonsense mutations), low-risk mutation group (missense mutations, small deletions and insertions, splice site mutations) and intron 22 inversions group. The correlation of FⅧgenotype and the production of FⅧ inhibitors in patients with HA were analyzed. Among 172 patients with severe HA, 21 cases(12.21%) developed FⅧ inhibitors. The cumulative incidence of FⅧ inhibitor development was 32%(10/31) in high risk group (75% patients with large deletions, 43% patients with intron 1 inversions, 20% patients with nonsense mutations) and 5%(2/43) in low risk group(6% patients with missense mutations, 5% patients with small deletions or insertions and 0% patient with a splice site mutation) and 9%(9/98) in intron 22 inversions group. Compared with the risk of FⅧ inhibitor development in intron 22 inversions group, the risk of FⅧ inhibitor development in high risk group was higher (OR＝4.7, 95% CI： 1.7-13.0), the risk of FⅧ inhibitor development in low risk group was equal (OR＝0.5, 95% CI： 0.1-2.3). Compared with the risk of inhibitor development in low risk group, the risk of FⅧ inhibitor development in high risk group was higher (OR＝9.8, 95% CI： 2.0-48.7). Gene mutations of patients with severe HA in high-risk group which include intron 1 inversions, large deletions, nonsense mutations are a risk factor for FⅧ inhibitor production.

Low‐dose immune tolerance induction in children with severe hemophilia A with high‐titer inhibitors: Type of factor 8 mutation and outcomes

BackgroundNo studies evaluated the role of F8 mutations in outcomes for low‐dose immune tolerance induction (ITI) in people with severe hemophilia A (SHA) with high‐titer inhibitors. ObjectivesTo explore the association between F8 mutation types and low‐dose ITI outcomes in children with SHA with high‐titer inhibitors. MethodsChildren SHA with high‐titer inhibitors who received low‐dose ITI therapy at least for 1 year were included instudy. Based on the risk of inhibitor development, F8 mutations were classified into a high‐risk group and a non–high‐risk group. Rapid tolerance and the final ITI outcomes were assessed at the 12th and 24th month of treatment, respectively, and the predictor of outcomes was analyzed. ResultsOf 104 children included, 101 had F8 mutations identified. The children with non–high‐risk mutations presented a higher rate of rapid tolerance than those with high‐risk mutations (61.0% vs. 29.2%; p = 0.006). Among 72 children beyond 24 months of ITI, 55 children (76.4%) achieved success, 3 (4.2%) achieved partial success, and 14 (19.4%) failed. The children in the non–high‐risk group showed a higher success rate (86.8% vs. 43.8%; p = 0.001) and a shorter time to success (mean time, 9.3 months vs. 13.2 months; p = 0.04) compared to those in the high‐risk group. In multivariable logistic regression, F8 mutations were an independent predictor of ITI success (non–high‐risk group vs. high‐risk group, adjusted odds ratio [OR], 20.3; 95% confidence interval [CI], 3.5–117.8), as was the interval from inhibitor diagnosis to ITI start (adjusted OR, 0.95; 95% CI, 0.90–0.99). They remained the significant predictors when success time was taken into account in a Cox model. ConclusionsTypes of F8 mutation were a key predictor of outcomes for low‐dose ITI in children with SHA with high‐titer inhibitors. It can help to stratify the prognosis and guide clinical decisions.