scholarly journals An Individualized Approach to Treating Pups with Severe Hemophilia a: Which Factors Correlate with the Low Rate of Inhibitor Development?

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2106-2106
Author(s):  
Susan Halimeh ◽  
Hannelore Rott ◽  
Günther Kappert ◽  
Manuela Siebert ◽  
Dirk Reinhardt
Keyword(s):  
Hemophilia A ◽  
Treatment Approach ◽  
Human Cell Line ◽  
Management Approach ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
On Demand ◽  
Individualized Approach ◽  
Individualized Management ◽  
Low Rate

Abstract Introduction:Development of inhibitors to replacement factor VIII (FVIII) remains a significant challenge to the management of previously untreated patients (PUPs) with severe hemophilia A. Although several determinants have been associated with the risk of inhibitor development, the impact of treatment approach remains controversial. Here we report our experience with an individualized approach to managing PUPs at a single hemophilia treatment center (HTC) in Germany. Methods:PUPs with severe hemophilia A (FVIII:C <1%) treated at the Gerinnungszentrum Rhein-Ruhr (GZRR), Germany, between January 2013 and June 2021 were followed prospectively. Our treatment approach includes early prophylactic physiotherapy, pdFVIIIconcentrate for at least the first 50 exposure days (EDs), tailored prophylaxis with individualized dose escalation according to bleeding tendency, and avoidance of prolonged on-demand treatment by avoiding treatment of minor bleeds or hematomas. Potential bleeds were examined by a hemophilia specialist and a decision made as whether to treat with pdFVIII based on the bleed location and severity. Ultrasound was performed every 3-6 months to check for joint bleeds. Where on-demand treatment was necessary, we used a high initial dose of 60-80 IU/kg with the aim of reducing the need for subsequent doses. Non-urgent surgical procedures were postponed and venous access system implants were avoided within the first 100 EDs. Inhibitor levels were measured using the modified Bethesda assay every 3-4 EDs until ED 100, and every 3 months thereafter for 2 years. Results:Data from 28 consecutive caucasian PUPs were collected. Fourteen (50%) patients had a F8 gene mutation associated with a high risk for inhibitor development. At the time of data cut-off 23 patients had received over 50 EDs of FVIII treatment, with 21 patients having over 100 EDs; the remaining patients had up to 45 EDs.Of the 28 patients, 27 started prophylaxis within the first 10 EDs. The initial prophylaxis schedule was tailored to each patient and ranged from 21 IU/kg every 10 days up to 40 IU/kg twice per week. One patient was treated on-demand for an intracranial bleed from ED 1-100. Only 3 spontaneous bleeds in 3 patients were treated; 25 patients (89%) remained free of spontaneous bleeds during prophylaxis. All three spontaneous bleeds were treated successfully with FVIII ± tranexamic acid. None of the 28 patients developed inhibitors. Discussion:Our approach to managing PUPs includes treatment with pdFVIII for at least the first 50 EDs, during which we treat bleeds only where necessary and use high doses to minimize further infusions. We had no cases of inhibitor development in our prospective cohort of 28 patients. In contrast, between 2003 and 2012, four of nine (44%) PUPs treated at our center developed inhibitors during the first 20 EDs, with two patients developing low-titer and two high-titer inhibitors. At that time we used recombinant FVIII (rFVIII) for prophylaxis in most patients and were less selective about which bleeds to treat with FVIII. Our individualized management approach, choice of pdFVIII and restricted use of FVIII for on-demand treatment therefore appear to correlate with a reduction in inhibitor incidence at our center. We usually switch patients from pdFVIII to rFVIII after at least 50 EDs due to the lower administration volume. Given the low rate of inhibitor development reported for PUPs treated with human cell line-derived rFVIII, there is a rationale to consider starting PUPs on human cell line-derived rFVIII. Conclusion:Our data support the position, that the use of an individualized management approach minimizes the risk of inhibitor development and raise important questions about how different aspects of treatment approach could impact outcomes in PUPs with severe hemophilia A. Disclosures No relevant conflicts of interest to declare.

Consumption Of FVIII Concentrate During On-Demand and Prophylactic Treatment With Human-cl rhFVIII In Prospective Clinical Studies In Adult Patients With Severe Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3595-3595 ◽  
Author(s):  
Andreas Tiede ◽  
Sigurd Knaub ◽  
Johannes Oldenburg ◽  
Johann Bichler
Keyword(s):  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Fold Increase ◽  
Human Cell Line ◽  
Adult Patients ◽  
Study Entry ◽  
Severe Hemophilia ◽  
Ample Evidence ◽  
Bleeding Rate ◽  
On Demand

Abstract Background There is ample evidence to support prophylactic treatment with factor VIII (FVIII) in children with severe hemophilia A (HA). Adults with severe HA are often treated on-demand and the potential benefit of regular prophylaxis is linked to a higher consumption of FVIII concentrates. During the clinical development of Human-cl rhFVIII, the first recombinant FVIII concentrate from a human cell line, its efficacy and safety was evaluated in previously treated adult patients (PTPs) during on-demand treatment only (GENA-01) and prophylaxis (GENA-08). Aims To compare post-hoc the annualized bleeding rate (ABR) and the consumption of FVIII concentrate in patients treated exclusively on-demand with those treated prophylactically. Methods Both prospective multi-centre studies were approved by the Ethics Committees of each participating institution and informed consent was obtained from the patient prior to any trial activity. In GENA-01, patients were to be treated on-demand for ≥6 months and ≥50 exposure days with protocol recommended doses ranging from 20 to 60 IU/kg, depending on the severity of the bleed. In GENA-08, patients were to be treated prophylactically with Human-cl rhFVIII every other day with 30-40 IU/kg for ≥6 months. Human-cl rhFVIII was also to be used in case of breakthrough bleeds. Results 22 PTPs with severe HA were enrolled in GENA-01, and 32 in GENA-08. The study populations were reasonably well comparable to each other (GENA-01 vs. GENA-08, mean±SD), regarding age (39.6±14.1 vs. 37.3±13.6 years), body mass index (23.9±4.8 vs. 25.8±4.9 kg/m2), hemophilia joint health score (38.4±30.3 vs. 34.6±32.2), race (>80% White in both studies) and historical bleeding sites. In GENA-08, the majority of patients (65.6%) had been treated prophylactically prior to study entry. Their historical mean±SD ABR was 6.6 ±11.3 (median: 2.0, range: 0-48.7) and their mean prophylactic dose/month was 293 IU/kg. The other 11 patients who had been treated on-demand had a mean±SD ABR of 47.4±34.6 (median: 36.5, range: 12.2-121.7). In GENA-01, all but 2 patients were treated on-demand prior to study entry. The historical mean±SD ABR of all GENA-01 patients was 49.5±35.9 (median: 44.6, range: 2.0-158.7). The ABR and FVIII consumption during the studies are shown in Table 1. Conclusion The data suggest that regular prophylactic treatment with Human-cl rhFVIII in adult PTPs with severe HA resulted in an approximately 25-fold reduction of bleeding rate, and a 3-fold increase of FVIII concentrate consumption. Disclosures: Tiede: Octapharma AG: Consultancy, Investigator Other. Knaub:Octapharma AG: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Bichler:Octapharma AG: Employment.

scholarly journals Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 162-162
Author(s):  
Elena Santagostino ◽  
Kathelijn Fischer ◽  
Christoph Koenigs ◽  
Claudia Djambas Khayat ◽  
Samantha Lucas ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Safety And Efficacy ◽  
Inhibitor Development ◽  
On Demand ◽  
Peak Titer

Background: rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII comprised of covalently bonded FVIII heavy and light chains designed to have a high binding affinity to von Willebrand factor. Aims: This multicenter, open-label, phase III extension study investigates the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in 50 previously untreated patients (PUPs) for at least 50 Exposure Days (EDs). An ITI substudy was implemented to allow the use of rVIII-SingleChain to attempt inhibitor eradication for PUPs who develop an inhibitor to FVIII. Method: PUPs with severe hemophilia A (no prior exposure to any FVIII product, and endogenous Factor VIII <1%) were assigned by the investigator to a prophylaxis or on-demand treatment regimen. Inhibitors were assessed monthly. Patients diagnosed with an inhibitor to FVIII (two consecutive central laboratory [CL] results of ≥0.6 BU/mL) could be enrolled into the ITI substudy or remain in the main study. The ITI substudy regimens are: 50 IU/kg 3x/week (low), 100 IU/kg daily (medium), or 200 IU/kg daily (high). Inhibitor eradication was defined as two consecutive CL results of <0.6 BU/mL. One subject was withdrawn per protocol due to high titer inhibitor diagnosis prior to ITI substudy implementation. Results: As of March 28, 2019, 23 PUPs were treated with rVIII-SingleChain. Median age: 1 y (range 0-5). Mean (SD) time on study: 21.6 (12.6) months. Race distribution; Asian 2, Black 7, White 14. There have been 147 bleeding events treated with rVIII-SingleChain rated for hemostatic efficacy by the investigator. While patients were inhibitor negative, the overall treatment success (rating of excellent/good) was 93%, and the annualized spontaneous bleeding rate (AsBR) was 0.58. The adverse event profile was as expected, as the most frequently occurring adverse events were upper respiratory tract infections and inhibitors. Twelve subjects (52%) [95% CI 31%, 73%] were diagnosed with an inhibitor to FVIII; 6 (26%) high titer (peak titer ≥5 BU/mL), and 6 (26%) low titer (peak titer <5 BU/mL). Seven of 11 inhibitor negative subjects achieved >50 EDs, 1 achieved 47 EDs, and 3 achieved <20 EDs. The median ED for inhibitor development (initial result) was 10, range 4-23. All PUPs enrolled had ≥1 risk factor for inhibitor development (Table 1) including genetic mutation, age of first exposure, initial treatment reason and assigned regimen, as well as bleeding events and infections; inhibitor positive and negative subjects were comparable. Of the 12 inhibitor positive subjects, 11 continued treatment with rVIII-SingleChain, 7 were treated with approximately 50 IU/kg 3x/week (low dose ITI), 3 with an increased prophylaxis regimen, 1 with no change in regimen, and 0 with high or medium dose ITI regimen (Table 2). Eight of 11 (73%) inhibitor positive subjects (2 high titer, 6 low titer) achieved eradication; 5 low titer subjects were eradicated within 6 months. The clinically relevant inhibitor subjects (2 high titer, and 1 persistent low titer) achieved eradication in a median of 15.7 months, 2 using low dose ITI, and 1 using increased prophylaxis. Eradicated patients were negative for a median of 13.6 months, and no inhibitor relapse was observed. Three remaining inhibitor positive patients are early in their rVIII-SingleChain inhibitor treatment (2.1, 3.5, and 5.4 months). Detailed analysis of the antibody signature was performed, and revealed epitope isotypes and subclass distribution comparable to other FVIII molecules. Conclusion: Overall, rVIII-SingleChain demonstrates a positive benefit:risk profile for safety and efficacy in PUPs. The crude high titer inhibitor rate is 26% which is consistent with other rFVIII products, whereas the crude low titer inhibitor rate is currently 26% which is on the higher end in comparison to other rFVIII products. Immunological analyses suggest a low affinity antibody population in subjects with low titer inhibitors. The majority of subjects (73%) who continued treatment with rVIII-SingleChain achieved eradication on a low dose ITI or prophylaxis regimen of approximately 50 IU/kg 3x/week or less. Additional time on study for the currently enrolled subjects is required to determine the final inhibitor and eradication rates in PUPs treated with rVIII-SingleChain. Disclosures Santagostino: Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire / Takeda: Consultancy, Speakers Bureau. Koenigs:Roche: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Bayer Vital GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; Intersero: Research Funding; Grifols: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Djambas Khayat:Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Lucas:CSL Behring: Employment. Salazar:CSL Behring: Employment. Brainsky:CSL Behring: Employment. Chung:CSL Behring: Employment. Goldstein:CSL Behring: Employment. Mahlangu:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Unique: Research Funding; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3184-3184
Author(s):  
Robert F. Sidonio ◽  
Christine Knoll ◽  
Flora Peyvandi ◽  
Oleksandra Stasyshyn ◽  
Ali Bulent Antmen ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Publicly Traded ◽  
Open Label ◽  
Inhibitor Development ◽  
On Demand ◽  
Fviii Inhibitor ◽  
Hemostatic Efficacy ◽  
Recombinant Fviii

Abstract Background Management of severe hemophilia A includes on-demand treatment or prophylaxis with replacement factor VIII (FVIII) concentrate. FVIII inhibitors can develop following exposure to exogenous FVIII in approximately 30% of previously untreated patients (PUPs), typically in the first 50 exposure days (EDs), with serious complications. This is the first study evaluating the safety, immunogenicity, and hemostatic efficacy of rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA), an extended half-life (EHL) recombinant FVIII, in PUPs with severe hemophilia A. Methods This prospective, open-label, multi-center, phase 3 study (NCT02615691) was conducted in patients ˂6 years of age with severe hemophilia A (FVIII <1%). Patients were previously untreated, or had <3 EDs to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitory antibodies prior to screening (≥0.6 Bethesda units) were not eligible. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Prophylaxis was started before 3 years of age or after a maximum of 2 joint bleeds, whichever occurred first. The primary endpoint was the incidence of FVIII inhibitor development. Secondary endpoints included safety and efficacy (annualized bleeding rate [ABR] and hemostatic efficacy). This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing an inhibitor to FVIII or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. Demographic and baseline characteristics were summarized using continuous and categorical data. The incidence of FVIII inhibitor development was calculated using the Clopper Pearson exact 95% CI computed for the proportion of patients who developed FVIII inhibitors during the study. ABR was analyzed by point and interval estimates derived from a negative binomial model with treatment regimen as a covariate. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) was recorded for all patients receiving rurioctocog alfa pegol. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients (screen failures) did not meet the eligibility criteria and 4 discontinued prior to treatment. 54 patients received prophylaxis and 35 received on-demand treatment at any time during the study period. The mean (SD) patient age at baseline was 11.8 (8.2) months. The number of patients with 0 EDs prior to screening was 36 (61.0%), with 9 (15.3%) patients having 1 ED and 14 (23.7%) having 2 EDs. Overall, 32 patients had a family history of hemophilia A. A large deletion, intron 1 or intron 22 inversion, or substitution nonsense hemophilia gene mutation was present in 29 (49.2%) patients and 21 (35.6%) had either a small deletion, small duplication, or substitution missense gene mutation. Of the 52 patients who qualified for this interim analysis, 10 developed an inhibitory antibody to rurioctocog alfa pegol during the study; the incidence of inhibitor development was 0.192 (95% CI, 0.096-0.325) (10/52). Rurioctocog alfa pegol exposure data and ABRs for patients receiving prophylaxis or on-demand treatment are presented in Table 1. At bleed resolution, hemostatic efficacy was rated by patients as "excellent" for 88/269 bleeds (32.7%) and "good" for 73/269 bleeds (27.1%). Overall, 52 (88.1%) patients receiving rurioctocog alfa pegol experienced a total of 283 AEs, and 13 patients experienced 14 rurioctocog alfa pegol-related AEs (including 10 SAEs). SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate a relatively low inhibitor rate compared with other EHL recombinant FVIII products and a safety and efficacy profile consistent with that previously observed for rurioctocog alfa pegol in the treatment of bleeding episodes in patients with hemophilia A. Figure 1 Figure 1. Disclosures Sidonio: Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst: Consultancy. Peyvandi: Takeda: Honoraria; Spark: Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Bioverativ: Honoraria; Grifols: Honoraria. Stasyshyn: Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding; Shire: Consultancy; Grifols: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Antmen: Takeda: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy. Yeoh: Takeda: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Grifols: Honoraria. Maggiore: IQVIA: Current Employment. Engl: Baxalta Innovations GmbH, a Takeda company: Current Employment; Takeda: Current equity holder in publicly-traded company. Allen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Tangada: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc: Current Employment.

scholarly journals Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1123-1123
Author(s):  
Teresa Ceglie ◽  
Berardino Pollio ◽  
Irene Ricca ◽  
Maria Messina ◽  
Claudia Linari ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Null Mutation ◽  
Severe Hemophilia ◽  
Factor Level ◽  
On Demand ◽  
Active Life ◽  
Genetic Assessment

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

Investigating the influence of LCT rs3754689 polymorphism on inhibitor development in Iranian and Afghan patients with severe hemophilia A

2020 ◽  
Vol 31 (1) ◽  
pp. 11-15
Author(s):  
Sobhan Bahrami Zadegan ◽  
Sayed H. Mousavi ◽  
Narges Damavandi ◽  
Mohammad H. Samiee Aref ◽  
Sirous Zeinali
Keyword(s):  
Hemophilia A ◽  
Severe Hemophilia ◽  
Inhibitor Development

scholarly journals F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

Blood ◽  
2012 ◽  
Vol 119 (12) ◽  
pp. 2922-2934 ◽  
Author(s):  
Samantha C. Gouw ◽  
H. Marijke van den Berg ◽  
Johannes Oldenburg ◽  
Jan Astermark ◽  
Philip G. de Groot ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gene Mutation ◽  
Hemophilia A ◽  
High Titer ◽  
Meta Analysis ◽  
Gene Mutations ◽  
Secondary Outcome ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Inhibitor Development

Abstract This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

Blood Group O Protects against Inhibitor Development in Severe Hemophilia A Patients

2016 ◽  
Vol 43 (01) ◽  
pp. 069-074 ◽  
Author(s):  
Antonio Coppola ◽  
Carlo Mengoli ◽  
Gianna Rivolta ◽  
Federica Riccardi ◽  
Giovanni Minno ◽  
...  
Keyword(s):  
Blood Group ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Inhibitor Development

Incidence and Outcome of Discontinuation of Prophylactic Treatment among Young Adults with Severe Hemophilia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3086-3086
Author(s):  
Karin van Dijk ◽  
Kathelijn Fischer ◽  
Johanna G. van der Bom ◽  
Elma Scheibel ◽  
Jørgen Ingerslev ◽  
...  
Keyword(s):  
Young Adults ◽  
Treatment Outcome ◽  
Chronic Disease ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Clinical Score ◽  
Annual Number ◽  
Severe Hemophilia ◽  
On Demand

Abstract Introduction Most of the current discussion about prophylaxis for severe hemophilia patients is on the dose and when to start. However, as hemophilia is a chronic disease, it is important to evaluate the duration of prophylaxis. The aim of this study was to study and compare adherence to prophylaxis and outcome of severe hemophilia patients. Methods All patients with severe hemophilia A and B (factor VIII/IX<0.01 IU/ml), born between 1970 and 1980 and treated in Copenhagen, Århus (Denmark) or the Van Creveldkliniek, Utrecht (The Netherlands) were studied. Data on treatment were collected from the patients’ files from 1972 until 2003. In addition, a questionnaire on adherence to prophylaxis was used. For assessment of outcome the clinical score according to Gilbert and the radiological Pettersson score were used. Patients were categorized according to adherence to prophylactic treatment: patients who never discontinued prophylaxis (never), patients who temporarily discontinued prophylaxis (temporarily) and patients had switched to on demand regimen (permanently). Results 83 patients were studied. Median follow up was 19 years (range 6–29). Median age at start of prophylaxis was 5.9 years (interquartile range (IQR) 4.0–8.7). 34% of patients stopped taking prophylaxis temporarily and 35% stopped taking prophylaxis permanently at a median age of 21.5 years (IQR 18.4–24.4). Follow up since the last stop was 3.6 years (IQR 1.4–7.9), the annual number of joint bleeds on on demand treatment was 3.0 (IQR 1.4–8.7). The median clinical score was 3.0 points (IQR 1.0–6.0) in patients who never or temporarily stopped and 4.0 (IQR 0.0–6.3) in patients who permanently stopped taking prophylaxis. Pettersson scores were available for the Dutch patients and the median Pettersson score was 13 points (IQR 5–23) for patients who never or temporarily stopped and 13 (IQR 1–24) for patients who stopped permanently. The proportion of patients who discontinued prophylaxis and outcome parameters were similar for the Dutch and Danish patients. Conclusion Two thirds of young adults with severe hemophilia on prophylaxis discontinue prophylaxis at least once. One third permanently stop taking prophylaxis, while maintaining a low joint bleed frequency. Four years after switching to on demand treatment, outcome in these patients is similar to outcome in patients who continue taking prophylaxis.

The Role of Age at First Exposure and Therapy Regimen on the Development of Neutralizing FVIII Antibodies in Hemophilia A.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3082-3082 ◽  
Author(s):  
Carmen Escuriola Ettingshausen ◽  
Alexandra Zyschka ◽  
Inmaculada Martinez Saguer ◽  
Christine Heller ◽  
Thomas Klingebiel ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Inhibitor Development ◽  
Therapy Regimen ◽  
On Demand ◽  
Intron 22 Inversion ◽  
Group 2 ◽  
A Prospective Study ◽  
The Impact ◽  
Group 1

Abstract In order to assess the impact of age at first exposure to F VIII and therapy regimen on neutralizing FVIII-antibodies in previously untreated patients (PUP) with hemophilia A a prospective study was performed. Over a 23-years study period a total of 74 severely affected hemophilia A -PUPs have been consecutively recruited, treated with F VIII and investigated for inhibitor development. The patients were divided into two groups according to their treatment regimen: Group 1 (n=23) started prophylaxis at the age of 1 year (before or immediately after the first relevant bleed). Group 2 (n=43) was treated on-demand or prophylaxis was started after more than 2 bleeds. The following parameters were equally distributed among both groups: caucasian ethnicity, intron-22-inversion, age at 1st ED >0.5 years. Out of 74 hemophilia A patients 23 developed inhibitors (31%). Inhibitor incidence was 0% (1 transient inhibitor out of 23 patients) in those patients who received early prophylaxis (group 1) and 42% (18/43 patients) in case of delayed prophylaxis or on-demand treatment (group 2) (p=0.002). No linear correlation was found between the age at first exposure and inhibitor formation. However, patients treated before the age of 0.5 years showed a significantly higher inhibitor incidence (62%) than those treated at an more advanced age. Our data confirm that very early age at first exposure is a risk factor for inhibitor development in severe hemophilia A patients. Early prophylaxis might be protective against inhibitor development. To confirm the data a larger patient cohort has to be investigated.

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